Molekulare Medizin: Grundlagen, Pathomechanismen, Krankheitsbilder

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Author: Matthias W. Hentze | Andreas E. Kulozik | C. R. Bartram | Christian Hagemeyer

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TPT f$6 0(16&+/,&+( i(120

[

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5’ Steuereinheit

5’

S

E

transkribierte Einheit

3’ Steuereinheit

P

E Exon1 mit 5’UTR

Intron

Exon

Intron

3’

Exon mit 3’UTR

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SR

T o2/(.8/$5( c1$720,( 45S rRNA Vorläufermolekül 5’

3’ 13000 Nukleotide RNA Reifung

18S rRNA

5,8S rRNA

28S rRNA

5S RNA

60S

ribosomale Proteine 40S

c%%P TPU

u&+(0$7,6&+(5 c%/$8) '(5 5tpcO 81' t,%2620(16<17+(6(P

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TPT f$6 0(16&+/,&+( i(120

SS

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ST

T o2/(.8/$5( c1$720,(

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Telomer p Arm Centromer q Arm Telomer

c%%P TPV

u&+(0$7,6&+( f$567(//81* (,1(6 e+52026206P

g,1( /,&+70,.526.23,6&+( w17(568&+81* 921 |(//(1 81' '(5(1 |(//.(51(1 />M7 ,1 '(1 0(,67(1 r+$6(1 '(6 |(//=<./86 185 :(1,*( t@&.6&+/@66( $8) ',( q5*$1,6$7,21 '(5 fpc ,0 |(//.(51 =8P k1 '(5 o(7$3+$6( 921 o(,26( 81' o,726( J6,(+( m$3P UPXK .21'(16,(57 ',( fpc '$*(*(1 =8 /,&+70,.526.23,6&+ '(71,(5%$5(1 u758.785(1N '(1 e+5202620(1P c86 ',(6(0 i581'( :(5'(1 /,&+70,.526.23,6&+( w17(568&+81*(1 =85 e+5202620(1=$+/ 81' O6758.785 925 $//(0 $1 o(7$3+$6(Or5>3$5$7(1 '85&+O *()@+57P e+5202620(1$1$/<6(1 :(5'(1 $1 .(51+$/7,*(1 81' 7(,/81*6)>+,*(1 |(//(1 '85&+*()@+57P f,( 6&+(0$7,6&+( f$567(//81* (,1(6 e+52026206 ,1 c%%,/'81* TPV ,'(17,7=,(57 6(,1( &+$5$.7(5,67,6&+(1 d(67$1'7(,/(\ ',( e+5202620(1(1'(1 Jv(/20(O 5(KN '$6 e(17520(5N '(1 0,7 3 J3(7,7N )5$1=?6,6&+K %(=(,&+1(7(1 .85=(1 c50 81' '(1 0,7 4 J1>&+67(5 d8&+67$%( ,0 c/3+$%(7K %(=(,&+1(7(1 /$1*(1 c50 (,1(6 e+52O 026206P

TPU e+5202620(1

SU

f,3/2,'( |(//(1 '(6 o(16&+(1 (17+$/7(1 ,1 ,+5(0 |(//.(51 VX e+5202620(1\ TT c872620(13$$5( 81' T i(6&+/(&+76&+5202620(1 Ji212620(1KP f$6 *5?M(5( '(5 i(6&+/(&+76&+5202620(1 :,5' 0,7 z 81' '$6 ./(,1(5( 0,7 { %(=(,&+1(7P g,1( :(,%/,&+( |(//( (17+>/7 =:(, zOe+5202620(1N :>+5(1' (,1( 0>11/,&+( |(//( (,1 zO 81' (,1 {Oe+5202620 $8):(,67P u(,7 '(1 YR(5 l$+5(1 :(5'(1 &<72*(1(7,6&+( d>1'(581*67(&+1,.(1 =85 e+5202620(1$1$/<6( (,1*(6(7=7P j,(5%(, :(5'(1 ',( e+5202620(1 0,7 &+(0,6&+(1 u8%67$1=(1 62 %(+$1'(/7N '$M $/7(51,(5(1' +(//( 81' '81./( d$1'(1 (17/$1* '(5 e+5202620(1 (5=(8*7 :(5'(1P d(, '(5 g567(//81* (,1(6 m$5<2*5$006 :(5'(1 ',( e+5202620(1 1$&+ i5?M(N n$*( '(6 e(17520(56 81' d$1'(1)>5%81* 3$$5:(,6( *(25'1(7 81' 921 S %,6 TTN %(=,(+81*6:(,6( 0,7 z 81' { 180(5,(57 Jc%%P TPWKP c%%,/'81* TPX =(,*7 $0 d(,63,(/ (,1(6 e+52026206 S ',( 817(56&+,('/,&+(1 d$1'(10867(5 1$&+ iON tO 81' eOd>1'(581*P

c%%P TPW e+5202620(16$7= (,1(6 o$11(6P f,( c%%,/'81* =(,*7 (,1( f$567(//81* '(6 d$1O '(10867(56 1$&+ i,(06$Oh>5%81*P

f,( d>1'(581*67(&+1,.(1 0$&+(1 (,1 )@5 -('(6 e+5202620 63(=,76&+(6 h>5%(O 0867(5 6,&+7%$5 81' 6,1' '$+(5 =85 &<72*(1(7,6&+(1 d(857(,/81* &+5202620$/(5 x(5>1'(581*(1 6(+5 +,/)5(,&+P g,1( e+5202620(1%$1'( +$7 '$%(, ',( i5?M( 921 81*()>+5 SR o,//,21(1 p8./(27,'(1 JSR o(*$%$6(13$$5(1N o%3KN 'P+P 0,7 j,/)( &<72*(1(7,6&+(5 d>1'(581*7(&+1,.(1 .?11(1 185 5(/$7,9 *52%( x(5>1'(581*(1 '(5 e+5202620(1 (5.$117 :(5'(1P

SV

T o2/(.8/$5( c1$720,( Chromosom 1

G

R

C

c%%P TPX c1)>5%81* 921 e+5202620 S 0,7 '(5 .219(17,21(//(1 i,(06$ o(7+2'( JiOd>1O '(581*K 62:,( '(1 0(7+2',6&+(1 x$5,$17(1 '(5 tOd>1'(581* J5(9(56( f$567(//81* 921 e+52O 02620(15(*,21(1N ',( 1$&+ '(5 iOd>1'(581* 81*()>5%7 %/(,%(1K 81' eOd>1'(581* J*(=,(/7( o$5.,(581* '(6 j(7(52&+520$7,16 ,1 '(5 e(17520(5Ot(*,21KP f,( 6&+(0$7,6&+( f$567(//81* '(6 e+52026206 (17635,&+7 '(5 iOd>1'(581*P d(,63,(/+$)7 :,5' ,0 d(5(,&+ '(5 .85=(1 81' /$1*(1 e+5202620(1$50( *(=(,*7 Ju75,&+/,1,(KN '$M (,1( '81.(/*()>5%7( d$1'( 1$&+ iOh>5O %81* (,1(0 81*()>5%7(1 d(5(,&+ '(5 tOd>1'(581* (17635,&+7P

QMRMP b(2/-/3/-%.!"%22!4)/.%. p250$%:(,&+81*(1 ,1 |$+/N i5?M( 2'(5 h250 921 e+5202620(1 .?11(1 $/6 3$O 7+2/2*,6&+ $1*(6(+(1 :(5'(1P i/(,&+=(,7,* 08M -('2&+ +(5$86*(67(//7 :(5'(1N '$M c120$/,(1 '(6 m$5<27<36 ./,1,6&+ *(*(%(1(1)$//6 92//.200(1 81$85>//,* %/(,%(1 .?11(1P c8) '(5 $1'(5(1 u(,7( 58)(1 &<72*(1(7,6&+ )(6767(//%$5( e+5202620(1$12O 0$/,(1 ,1 9,(/(1 h>//(1 .203/(;( u<1'520( +(5925P d('(1.7 0$1 ',( o(1*( *(O 1(7,6&+(5 k1)250$7,21N ',( (,1(5 x(5>1'(581* 817(5:25)(1 6(,1 08MN %(925 6,( &87* 0(+5(5( 3+<6,2/2*,6&+( m?53(5)81.7,21(1 2'(5 m?53(56<67(0( %(7525(1 6,1'P c120$/,(1 '(6 m$5<27<36 /$66(1 6,&+ ,1 =:(, i5833(1 817(57(,/(1\ $K 180(5,6&+( 81' %K 6758.785(//( e+5202620(1$120$/,(1P c//( x(5>1'(581*(1N %(, '(1(1 ',( e+5202620(1=$+/ '(6 ',3/2,'(1 0(16&+/,&+(1 e+5202620(16$7=(6 *5?M(5 2'(5 ./(,1(5 $/6 VX ,67N =>+/(1 =8 '(1 180(5,6&+(1 e+5202620(1$120$/,(1P f$ -('(6 e+5202620 81' -('( &+5202620$/( t(*,21 817(56&+,('/,&+( g5%,1)250$7,21(1 %(O +(5%(5*7N +>1*7 ',( ./,1,6&+( u<03720$7,. 0$M*(%/,&+ 921 '(5 n2.$/,6$7,21 '(5 x(5>1'(581* $%P f85&+ x(59,(/)$&+81*(1 Jr2/<620,(1K 2'(5 h(+/(1 Jo212620,(1K (,1(6 2'(5 0(+5(5(5 e+5202620(1 .?11(1 180(5,6&+( e+5202620(1$%(55$7,21(1 Jc1(8O 3/2,',(K +(5925*(58)(1 :(5'(1P f$6 ./,1,6&+( g56&+(,181*6%,/' />M7 6,&+ 9(5087/,&+ $8) i(1'26,6(5(.7( J(,1)$&+( 2'(5 '5(,)$&+( i(1'26,6 $167$77 '(5 =:(,)$&+(1K =8O 5@&.)@+5(1P f$6 r$5$',*0$ '(5 180(5,6&+(1 e+5202620(1$%(55$7,21 67(//7 ',( v5,O 620,( '(6 e+52026206 TS Jf2:1 u<1'520K '$5P f(5 m$5<27<3 :,5' ,1 ',(6(0 h$// $/6 VYN zz 2'(5 z{N 1TS %(6&+5,(%(1P f$6 f2:1 u<1'520 ,67 ',( +>87*67( $//(5 c1(83/2,',(1 JSATBSRRR i(%857(1K 81' .2007 %(, $//(1 (7+1,6&+(1 i5833(1 925P y>+5(1' '$6 ./,1,6&+( g56&+(,181*6%,/' 7<3,6&+ ,67N %/(,%7 '(5=(,7 12&+ 81*(O

TPU e+5202620(1

SW

./>57N :(6+$/% (,1 '5,77(6 e+5202620 TS J%=:P :(/&+( i(1( $8) ',(6(0 e+5202620K )@5 (,1( 62 :(,75(,&+(1'( ./,1,6&+( u<03720$7,. 9(5$17:257/,&+ ,67P o$1 :(,M ,1O =:,6&+(1 $8) i581' &<72*(1(7,6&+(5 c1$/<6(1 (,1(5 ./(,1(1 |$+/ 921 r$7,(17(1N %(, '(1(1 185 (,1 v(,/ '(6 e+52026206 TS '5(,)$&+ 925/,(*7N '$M ',( 9(5$17:257/,&+(1 i(1( ,0 d(5(,&+ '(6 /$1*(1 c506 921 e+5202620 TS JTS4TTK /2.$/,6,(57 6,1'P f(5 m$5<27<3 VWN zRN '$6 +(,M7 '$6 h(+/(1 (,1(6 i(6&+/(&+76&+52026206 ,1 $//(1 m?53(5=(//(1N 67(//7 ',( '(5=(,7 (,1=,* %(.$117( /(%(16)>+,*( c1(83/2,',( 0,7 :(1,*(5 $/6 VX e+5202620(1 '$5P f(5 r+>127<3 %(, (,1(0 i(127<3 921 VWN zR Jv851(5 u<1'520K ,67 :(,%/,&+N -('2&+ 6,1' ',( %(7525(1(1 r$7,(17,11(1 81)58&+7%$5 81' ./(,1:@&+6,*P c8&+ ,0 m217(;7 0$/,*1(5 g5.5$1.81*(1 .$11 (6 =8 180(5,6&+(1 c1(83/2,',(1 ,1 (,1=(/1(1 m?53(5=(//(1 .200(1P k0 i(*(16$7= =8 '(1 180(5,6&+(1 x(5>1'(581*(1 %(75(5(1 6758.785(//( c%(55$O 7,21(1 v(,/$%6&+1,77( (,1=(/1(5 e+5202620(1P w17(5 '(1 u758.785$120$/,(1 6,1' f(/(7,21(1N f83/,.$7,21(1N v5$16/2.$7,21(1 81' k19(56,21(1 ',( +>87*67(1P d(, '(5 f(/(7,21 81' '(5 f83/,.$7,21 ,67 ',( i(6$070(1*( &+5202620$/(5 fpc 9(5O >1'(57N %(, '(5 J%$/$1&,(57(1K v5$16/2.$7,21 81' k19(56,21 *(:?+1/,&+ 1,&+7P c86 02/(.8/$50(',=,1,6&+(5 u,&+7 62// +(5925*(+2%(1 :(5'(1N '$M $//( u758.785$120$O /,(1 d58&+67(//(1 $8):(,6(1N %(, '(1(1 NN1(8( p$&+%$56&+$)769(5+>/71,66(DD *(6&+$)O )(1 :(5'(1 J6,(+( c%%P TPYKP

normales Chromosom "A"

Deletion "A"

Duplikation "A"

normales Chromosom "B"

Inversion "A"

"A"

Translokation "B"

c%%P TPY u&+(0$7,6&+( f$567(//81* (,1,*(5 &+5202620$/(5 u758.785$120$/,(1P f,( *(.(11O =(,&+1(7(1 d(5(,&+( '(6 4 c506 ',(6(5 %(,'(1 e+5202620(1 ',(1(1 '(5 q5,(17,(581*P f,( r)(,/( :(,6(1 $8) '(1 921 (,1(5 u758.785$120$/,( %(7525(1(1 d(5(,&+ '(6 e+52026206 +,1P

SX

T o2/(.8/$5( c1$720,(

f$'85&+ .?11(1 ',( m21752//(/(0(17( (,1=(/1(5 i(1( ,+5(1 g,198M $8) ,+5 |,(/O *(1 9(5/,(5(1 81'B2'(5 $1'(5( i(1( 817(5 ,+5( t(*8/$7,21 *(5$7(1P k0 g1'(5(.7 ,67 '(5 1250$/( c%/$8) (,1(5 *(67(8(57(1 g;35(66,21 '(5 g5%,1)250$7,21 *(67?57N :$6 =80 v(,/ :(,75(,&+(1'( m216(48(1=(1 J=PdP (,1( v8025(17:,&./81*K 1$&+ 6,&+ =,(+(1 .$11P f$5@%(5 +,1$86 :,5' ,1 =81(+0(1'(1 o$M( ',( d('(8781* (,1=(/1(5N ,1 9,(/(1 h>//(1 ./(,1(5 f(/(7,21(1 ,0 t$+0(1 '(5 ./,1,6&+(1 j80$1*(1(7,. 25(16,&+7/,&+P c/6 (,1 ./$66,6&+(6 d(,63,(/ *,/7 '$6 0,7 o,1'(5:8&+6N c',326,7$6 81' *(,67,*(5 t(O 7$5',(581* (,1+(5*(+(1'( r5$'(5Oy,//, u<1'520N '$6 '85&+ (,1( f(/(7,21 (,1(6 &6,21(1 :85'(1 $8&+ %(,0 y,//,$06Od(85(1 JY4SSK 2'(5 %(,0 n$1*(5Oi,(',21 u<1'520 JZ4TTK %(2%$&+7(7P

QMRMQ l/,%+5,!2% b94/'%.%4)+ f85&+ ',( g,1)@+581* '(5 h/825(6=(1= ,1 6,78 j<%5,',6,(581* JhkujK g1'( '(5 ZR(5 l$+5( .2117( ',( f,$*1267,. &+5202620$/(5 x(5>1'(581*(1 :(6(17/,&+ (5:(,7(57 :(5'(1P f,( hkujOv(&+1,. 9(5%,1'(7 &<72*(1(7,6&+( 81' 02/(.8/$5*(1(7,6&+( c5O %(,760(7+2'(1 81' (50?*/,&+7 (,1( )$5%,*( f$567(//81* $86*(:>+/7(5 e+5202620(1 81' e+5202620(1$%6&+1,77( ,0 h/825(6=(1=Oo,.526.23P x(5*/,&+(1 0,7 .219(1O 7,21(//(1 d>1'(581*67(&+1,.(1 .$11 '85&+ ',( hkujOc1$/<6( (,1 %,6 =8 7$86(1')$&+ +?+(5(6 c89?681*69(50?*(1 ,0 d(5(,&+ :(1,*(5 .% (5=,(/7 :(5'(1P o,7 j,/)( ',(6(5 o(7+2'( ,67 (6 $8&+ 0?*/,&+ ',( &+5202620$/( j(5.81)7 .203/(; =86$00(1*(O 6(7=7(5 e+5202620(1$120$/,(1 J62*(1$117(5 o$5.(5&+5202620(1K 81' v5$16/2O .$7,21(1 =8 %(67,00(1P f85&+ '(1 g,16$7= $86*(:>+/7(5 fpcOu21'(1 /$66(1 6,&+ 63(=,76&+( e+5202620(19(5>1'(581*(1 =8'(0 ,1 '(5 k17(53+$6( 1$&+:(,6(1P y,( $//( j<%5,',6,(581*67(&+1,.(1 %(58+7 $8&+ ',( hkuj c1$/<6( $8) '(5 h>O +,*.(,7 921 fpc 6,&+ ,0 (,1=(/675>1*,*(1 |867$1' 0,7 (,1(0 .203/(0(17>5(1 fpcOu75$1* =8 (,1(0 '233(/675>1*,*(1 o2/(.@/ =86$00(1=8/$*(51P f,( j<%5,O ',6,(581* '(5 u21'( (5)2/*7 '$%(, ,1 6,78 ',5(.7 $8) '(0 e+5202620(1O %=:P |(//O .(5135>3$5$7 '(6 r$7,(17(1P f$6 x(5)$+5(1635,1=,3 ,67 ,1 c%%,/'81* TPZ 6&+(0$7,6&+ '$5*(67(//7P l( 1$&+ h5$*(67(//81* .?11(1 9(56&+,('(1( fpcOu21'(1 =85 j<%5,',6,(581* (,1O *(6(7=7 :(5'(1P r5,1=,3,(// 817(56&+(,'(7 0$1 '$%(, =:,6&+(1 *(1O %=:P /2&8663(=,O 76&+(1 fpcOu21'(1N ',( 817(5 *((,*1(7(1 j<%5,',6,(581*6%(',1*81*(1 185 $8) (,1O (0 63(=,76&+(1 e+5202620(1$%6&+1,77 +<%5,',6,(5(1N 81' fpcOu21'(1N ',( 1(%(1 &+5202620(163(=,76&+(1 fpcOc%6&+1,77(1 $8&+ 8%,48,7>5 ,0 i(120 925.20O 0(1'( 5(3(7,7,79( u(48(1=$%6&+1,77( J=PdP c/8Ou(48(1=(1K (17+$/7(1P f85&+ (,1(1 %(56&+8M 810$5.,(57(5 5(3(7,7,9(5 fpc ,0 j<%5,',6,(581*6$16$7= .?11(1 ',(6( u(48(1=(1 817(5'5@&.7 :(5'(1P h@5 ',(6( $/6 NN&+5202620( 3$,17,1*DD %(=(,&+1(7( v(&+1,. 67(+(1 +(87( &+5202620(1O63(=,76&+( fpcOd,%/,27+(.(1N ',( ',( fpc (,1(6 .203/(77(1 0(16&+/,&+(1 e+52026206 (17+$/7(1N =85 6(/(.7,9(1 c1)>5%81* ,1',9,'8(//(5 e+5202620(1 =85 x(5)@*81*P fpcOu21'(1 )@5 e+5202620(1$50( %,6 +,1 =8 (,1=(/1(1 e+5202620(1%$1'(1 J/ SR o%3K .?11(1 0,7 j,/)( 921 o,O .52',66(.7,21 81' $16&+/,(M(1'(5 o,.52./21,(581* %=:P c03/,7.$7,21 0,77(/6 ret

TPU e+5202620(1

SY

Fluorochrom-markierte DNA-Sonde

chromosomaler DNA-Einzelstrang

Chromosom

c%%P TPZ u&+(0$7,6&+( f$567(//81* '(5 h/825(6=(1= ,1 6,78 j<%5,',6,(581* JhkujK\ f85&+ j,7=('(1$785,(581* ,67 '(5 fpcOf233(/675$1* (,1(6 e+52026206 81' (,1(5 fpcOu21'( =80 g,1=(/675$1* $8)*(6&+02/=(1P f,( 0,7 (,1(0 h/825(6=(1=)$5%6725 0$5.,(57( fpcOu21'( +<%5,',6,(57 $1 ',( .203/(0(17>5( d$6(16(48(1= '(5 &+5202620$/(1 fpc 81' ,67 $16&+/,(O M(1' ,0 h/825(6=(1=0,.526.23 $/6 u,*1$/ $8) %(,'(1 e+520$7,'(1 '(6 o(7$3+$6(&+5202O 6206 6,&+7%$5P

Jr2/<0(5$6( m(77(15($.7,21K +(5*(67(//7 :(5'(1P m/(,1(5( fpcOd(5(,&+( .?11(1 0,7 e260,'O JURAVW .%K 2'(5 r+$*(1 %=:P r/$60,'Ou21'(1 J. SR .%K 0$5.,(57 :(5O '(1 J6,(+( m$3P VPSPSKP p(8(5',1*6 :(5'(1 $8&+ .@167/,&+( e+5202620(1 :,( rce JrS %$&7(5,23+$*( $57,7&,$/ &+5202620(KN dce J%$&7(5,$/ $57,7&,$/ &+5202620(K 2'(5 {ce J<($67 $57,7&,$/ &+5202620(K $/6 m/21,(581*69(.725(1 (,1*(6(7=7P u,( +$%(1 '(1 x257(,/N '$M 6(+5 *52M( fpcOh5$*0(17( JSRRATRRR .%K $8)*(1200(1 :(5'(1 .?11(1P h@5 ',( c86:(5781* '(5 hkujOg;3(5,0(17( :(5'(1 ,1 =81(+0(1O '(0 o$M( eefO J&+$5*( &283/(' '(9,&(OK m$0(5$6 81' e20387(5Or52*5$00( =85 ',*,7$/(1 d,/'%($5%(,781* 9(5:(1'(7P g,1,*( d(,63,(/( 62//(1 ',( ',$*1267,6&+( t(/(9$1= '(5 hkujOc1$/<7,. 9(5'(87/,O &+(1P k0 t$+0(1 '(5 r5>1$7$/',$*1267,. :,5' u&+:$1*(5(1 =80 c866&+/8M (,1(5 e+5202620(167?581* '(6 m,1'(6 (,1( e+5202620(1',$*1267,. 1$&+ e+25,21O %,236,( 2'(5 h58&+7:$66(5381.7,21 $1*(%27(1P f$6 g5*(%1,6 (,1(5 62/&+(1 w17(5O 68&+81* /,(*7 ,1 '(5 t(*(/ 1$&+ =:(, %,6 '5(, y2&+(1 925P o,77(/6 hkuj .$11 ',(6( |(,763$11( )@5 ',( $0 +>87*67(1 %(2%$&+7(7(1 180(5,6&+(1 e+5202620(19(5>1O '(581*(1 :,( v5,620,( TSN v5,620,( SU 2'(5 v5,620,( SZ '(87/,&+ $8) =:(, v$*( 9(5.@5=7 :(5'(1N '$ 2+1( m8/7,9,(581* '(5 |(//(1 (,1( k17(53+$6(Of,$*1267,. ',5(.7 $0 |(//.(51 '85&+*()@+57 :(5'(1 .$11P c%%,/'81* TP[ =(,*7 '(1 p$&+:(,6 (,1(6 f2:1 u<1'5206 $1 81.8/7,9,(57(1 h58&+7:$66(5=(//.(51(1P f,( fpcOu21'( )@5 e+5202620 TS =(,*7 '5(, 63(=,76&+( j<%5,',6,(581*66,*1$/( ,0 |(//.(51P c//(5',1*6 62//7( ',(6(5 u&+1(//7(67 185 %(, *(O =,(/7(5 k1',.$7,21667(//81* (,1*(6(7=7 :(5'(1N '$ (5 ,0 i(*(16$7= =85 .219(17,21(//(1 e<72*(1(7,. 185 ',( 63(=,76&+ 817(568&+7(1 180(5,6&+(1 c%(55$7,21(1 (5)$M7N -(O '2&+ .(,1(1 %(5%/,&. @%(5 327(17,(//( c120$/,(1 '(5 e+5202620(1=$+/ 2'(5 O6758.785 %(,0 m,1' 9(50,77(/7P o,77(/6 hkuj /$66(1 6,&+ $8&+ 6758.785(//( e+5202620(1$%(55$7,21(1 6&+1(// 81' (,1)$&+ ',$*1267,=,(5(1P e+5202620(163(=,76&+( fpcOd,%/,27+(.(1 :(5'(1 =80

SZ

T o2/(.8/$5( c1$720,(

c%%P TP[ |:(,)$5%(1Oj<%5,',6,(581* $1 81.8/7,9,(57(1 h58&+7:$66(5=(//.(51(1 (,1(6 m,1'(6 0,7 f2:1 u<1'520 Jk17(53+$6(Oe<72*(1(7,.KP f,( 0,7 (,1(0 527(1 h/825(6=(1=)$5%6725 0$5O .,(57( fpcOu21'( )@5 e+5202620 SU =(,*7 T j<%5,',6,(581*66,*1$/(N ',( 0,7 (,1(0 *5@1(1 h/825(6=(1=)$5%6725 0$5.,(57( fpcOu21'( )@5 e+5202620 TS =(,*7 U j<%5,',6,(581*66,*1$/( ,0 |(//.(51P

p$&+:(,6 921 v5$16/2.$7,21(1 Jc%%P TPSRK 81' k16(57,21(1 9(5:(1'(7N r52%(1 )@5 &+5202620$/( u8%5(*,21(1 :(5'(1 =80 p$&+:(,6 921 f83/,.$7,21(1N k19(56,21(1 81' f(/(7,21(1 Jc%%P TPSSK =85 j<%5,',6,(581* (,1*(6(7=7P x25 $//(0 ',( g5.(1181* 68%0,.526.23,6&+(5 f(/(7,21(1 ,67 )@5 ',( |825'181* =8 %(67,007(1 o,.52'(/(O 7,216Ou<1'520(1 81' )@5 ',( *(1(7,6&+( d(5$781* '(5 %(7525(1(1 h$0,/,(1 921 d(O '(8781*P c0 d(,63,(/ '(5 zO&+5202620$/ 5(=(66,9 9(5(5%7(1 o86.(/'<67523+,( f8O &+(11( JfofK 62// ',(6 (;(03/$5,6&+ $8)*(=(,*7 :(5'(1 J6,(+( m$3P WPSPTKP y,5'

c%%P TPSR p$&+:(,6 (,1(5 %$/$1&,(57(1 v5$16/2.$7,21 7J[]SRKP |:(,)$5%(1Oj<%5,',6,(581* 0,7 (,1(5 e+5202620 [O63(=,76&+(1 J527( h/825(6=(1=K 81' (,1(5 e+5202620 SRO63(=,76&+(1 J*5@1( h/825(6=(1=K r52%(P f,( r)(,/( =(,*(1 $8) ',( v5$16/2.$7,216352'8.7( =:,6&+(1 (,1(0 e+5202620 [ 81' (,1(0 e+5202620 SRP

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X

PAR 1

Y sry

xist

PAR 2

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TPV p8./(,16>85(1

TW

c8&+ ,1 ',(6(0 h$//( (17*(+(1 %(67,007( d(5(,&+( :,( ',( 36(8'2$872620$/(1 t(O *,21(1 '(5 k1$.7,9,(581*P f,( 0,7 (,1(5 %(5=$+/ 921 zOe+5202620(1 9(5%81'(1( i(1'26,69(56&+,(%81* 0$1,)(67,(57 6,&+ (%(1)$//6 ./,1,6&+N %(,63,(/:(,6( %(,0 m/,O 1()(/7(5 u<1'520 JVYN zz{K '85&+ (,1(1 j2&+:8&+6 81' k1)(57,/,7>7P c86*(+(1' 920 zOk1$.7,9,(581*6=(17580 @%(5=,(+7 ',( ;,67 tpc '$6 zOe+5202620 81' ,1O '8=,(57 '85&+ ',5(.7( k17(5$.7,21 0,7 &+5202620$/(1 u758.785(1 :(,7(5( o2',7O .$7,21(1 :,( fpcOo(7+7 81' .?11(1 ,1 '(5 k17(53+$6( &<72/2*,6&+ $/6 i(O 6&+/(&+76&+520$7,1 2'(5 d$55Om?53(5 $0 m(515$1' 6,&+7%$5 *(0$&+7 :(5'(1P w17(5 '(1 0(+5 $/6 TR i(1(1 '(6 {Oe+52026206 71'(1 6,&+ (,1,*( 0,7 zO&+52O 02620$/(1 j202/2*(1] ',( 0(,67(1 i(1( 6,1' $%(5 {O63(=,76&+P j,(5=8 =>+/7 '$6 ,1 810,77(/%$5(5 p$&+%$56&+$)7 '(5 36(8'2$872620$/(1 t(*,21 S *(/(*(1( 65< i(1N '$6 )@5 ',( g17:,&./81* '(6 0>11/,&+(1 i(6&+/(&+7(6 $866&+/$**(%(1' ,67P g6 .2',(57 (,1(1 v5$16.5,37,216)$.725N '(5 :>+5(1' '(5 g0%5<2*(1(6( ',( w0:$1'/81* '(5 ,1',5(5(17(1 i21$'(1$1/$*(1 ,1 v(67,6*(:(%( 81' ',( t(*5(66,21 '(5 o@//(56&+(1 i>1*( 67(8(57P h(+/7 65< 2'(5 ,67 ',(6(6 i(1 087,(57N 62 (1767(+7 (,1 q9$5P p250$O /(5:(,6( :,5' '(5 65< n2&86 1,&+7 ,1 ',( +202/2*( r$$581* '(5 z 81' { e+5202O 620(1 :>+5(1' '(5 o(,26( (,1%(=2*(1P g5)$M7 ',(6(5 r52=(M $%(5 (,10$/ (,1 *5?O M(5(6 i(%,(7N '$11 .$11 %(, (,1(0 &5266,1*O29(5 '$6 65< i(1 $8) (,1 zOe+5202620 @%(575$*(1 :(5'(1P k1 ',(6(0 h$// .?117(1 m,1'(5 (,1(6 %(7525(1(1 o$11(6 7527= zzOm$5<27<36 (,1(1 0>11/,&+(1 r+>127<3 (17:,&.(/1 JzzOo$11K] 80*(.(+57 :@5'( '$6 h(+/(1 '(6 65< i(16 $8) '(0 {Oe+5202620 =8 (,1(0 :(,%/,&+(1 r+>O 127<3 0,7 z{Oe+5202620(1 )@+5(1 Jz{Oh5$8KP

QMS m5+,%).3;52%. f(5 925$1*(+(1'( c%6&+1,77 %(6&+5(,%7 ',( /,&+70,.526.23,6&+ (5.(11%$5( q5*$O 1,6$7,2166758.785 '(5 f(62;<5,%218./(,16>85( JfpcKN '$6 e+5202620P f,( )2/*(1O '(1 c%6&+1,77( :(5'(1 6,&+ '(1 =:(, d(67$1'7(,/(1 921 e+5202620(1 1>+(5 =8O :(1'(1N 1>0/,&+ '(5 fpc 81' '(1 &+5202620$/(1 r527(,1(1P q)70$/6 /$66(1 6,&+ ,1 '(5 d,2/2*,( .203/(;( h81.7,21675>*(5 $8) 5(/$7,9 :(1,*(N (,1)$&+( i581'%$867(,1( =85@&.)@+5(1P u2 %(67(+7 '(5 *(1(7,6&+( d$83/$1 $//(5 n(O %(:(6(1 $86 185 9,(5 9(56&+,('(1(1 d$867(,1(1N p8./(27,'( *(1$117P f,( fpc ,67 (,1( m(77( /,1($5 0,7(,1$1'(5 9(5.1@3)7(5 p8./(27,'(N '(5(1 (;$.7( t(,+(1)2/*( '(1 w17(56&+,(' 921 (,1(0 r527(,1 =80 $1'(5(1N /(7=7(1'/,&+ 62*$5 921 gP &2/, =80 j202 6$3,(16 $860$&+7P

QMSMP b(%-)3#(%2 `5&"!5 6/. cm` 5.$ qm` l('(6 p8./(27,' 6(7=7 6,&+ $86 (,1(0 |8&.(502/(.@/N (,1(5 25*$1,6&+(1 d$6( 81' (,1(5 r+263+$7*5833( =86$00(1 Jc%%P TPSXKP f$6 |8&.(502/(.@/ 817(56&+(,'(7 6,&+ %(, fpcO 81' tpcOp8./(27,'(1 ,1 185 (,1(5 r26,7,21P k1 %(,'(1 h>//(1 +$1'(/7 (6 6,&+ 80 (,1(1 eW |8&.(5N (,1( r(1726(P y,( c%%,/'81* TPSX =(,*7N +$7 ',( t,%26(

TX

T o2/(.8/$5( c1$720,( NH2

Adenin N1 HC

2

C 6

5C

N

3

4

9

N

C

7

8C

Base

N

O --O

P O--

O

5´

CH2

O

4´

H

1´

H

H

3´

OH Phosphat

H

2´

OH Ribose

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$/6 |8&.(5%(67$1'7(,/ '(5 t,%218./(,16>85( (,1( qjOi5833( ,1 '(5 TIOr26,7,21N :>+5(1' ',( f(62;<5,%26( '(5 f(62;<5,%218./(,16>85( ,1 '(5 TI r26,7,21 (,1 y$6O 6(56725$720 $8):(,67P f,( 25*$1,6&+( d$6( 9(50,77(/7 ',( w17(56&+(,'%$5.(,7 '(5 9,(5 d$867(,1( 921 fpc 81' tpcP f,( '5(, d$6(1 c'(1,1 JcKN i8$1,1 JiK 81' e<726,1 JeK .200(1 62:2+/ ,1 fpc $/6 $8&+ ,1 tpc p8./(27,'(1 925P w5$&,/ JwK 71'(7 6,&+ 185 ,1 tpcN '(66(1 0(7++5(1' c'(1,1 81' i8$1,1 $86 f233(/5,1*(1N r85,1(1N %(67(O +(1 Jr85,1%$6(1KP f$ '(5 |8&.(5%(67$1'7(,/ 81' ',( r+263+$7*5833( %(, $//(1 p8O ./(27,'(1 .2167$17 6,1'N :(5'(1 ',( p8./(27,'( 0,7 '(1 */(,&+(1 d8&+67$%(1 JcN iN eN vN wK :,( ',( ,1 ,+1(1 (17+$/7(1(1 d$6(1 $%*(.@5=7P h2/*/,&+ ,67 $86 (,1(0 d8&+67$%(1.@5=(/ 1,&+7 (56,&+7/,&+N 2% 921 '(5 d$6( 2'(5 921 '(0 '$=8 *(+?5,*(1 p8./(27,' ',( t('( ,67P g,1( g,1+(,7 $86 (,1(5 d$6( 81' (,1(5 r(1726( %(=(,&+1(7 0$1 $/6 p8./(26,'N p8.(26,'( 0,7 (,1(5 r+263+$7*5833( $/6 p8./(27,'(P f,( r+263+$7*5833( ,67 $86 =:(, i5@1'(1 :,&+7,*P |80 (,1(1 67(//7 6,( '$6 d,1O '(*/,(' =:,6&+(1 =:(, %(1$&+%$57(1 p8./(27,'(1 '$5N =80 $1'(5(1 9(50,77(/7 6,( '(1 6$85(1 e+$5$.7(5 '(5 p8./(,16>85(1P f,( r+263+$7*5833( 9(5%,1'(7 '$6 eU m2+/(16725$720 '(6 925$1*(+(1'(1 |8&.(56 0,7 '(0 eW m2+/(16725$720 '(6 1$&+)2/*(1'(1 J6,(+( c%%P TPSYKP o$1 635,&+7 '(6+$/% 921 (,1(5 WIOUI r+263+2',(O 67(5%,1'81*P |:$1*6/>87* +$%(1 %(, (,1(5 )$'(1)?50,*(1 m(77( '$6 m23)O 81' '$6 u&+:$1=18./(27,' 185 (,1(1 p$&+%$51P f$6 m23)18./(27,' 75>*7 ,1 ',(6(0 h$// ',( r+263+$7*5833( $0 eW c720 6(,1(5 r(1726( J0$1 635,&+7 '(6+$/% 920 WIOg1'( '(6 fpcO 2'(5 tpcOo2/(.@/6KN '$6 u&+:$1=18./(27,' +$7 (,1( )5(,( qjOi5833( $0 eU c720 '(6 |8&.(56 J'(6+$/% UIOg1'(KP y(11 |(//(1 fpc 2'(5 tpc 6<17+(7,6,(5(1N ',(1(1 ',( -(:(,/,*(1 v5,3+263+$7( '(5 p8./(27,'(N $/62 'cvrN 'evrN 'ivrN 'vvr %=:P cvrN evrN ivr 81' wvr $/6 c86*$1*6%$867(,1(P g,1( 1(8( r+263+2',(67(5%,1'81* =:,6&+(1 =:(, p8./(2O

TPV p8./(,16>85(1

TY

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P

O

O H2C 5´

H

C

O H

H

H

3´

O --O

H O Phosphodiesterbindung

P O H2C 5´

H

A

O H

H

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3´

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H

P

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H

G

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OH

H

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7,'(1 :,5' 817(5 c%63$/781* 921 =:(, r+263+$75(67(1 '(6 v5,3+263+$76 (567(//7P u2 :$&+6(1 62:2+/ fpc $/6 $8&+ tpc u75>1*( 920 WIO =80 UIOg1'( J6,(+( m$3P UPS 81' UPXPSKP p8./(27,'( (5)@//(1 =:(, m5,7(5,(1N ',( :,&+7,* 6,1'N :(11 k1)250$7,21 921 (,1(5 |(//*(1(5$7,21 *(187=7 81' $1 v2&+7(5*(1(5$7,21(1 :(,7(5*(*(%(1 :(5'(1 62//P |80 (,1(1 08M ',( k1)250$7,21 6&+1(// 81' =89(5/>66,* $%*(/(6(1 J'(.2',(57K :(5'(1 .?11(1N =80 $1'(5(1 08M '(5 k1)250$7,21675>*(5 =89(5/>66,* .23,(57 81' $1 ',( v2&+7(5=(//(1 :(,7(5*(*(%(1 :(5'(1P f(5 u&+/@66(/ =85 g5)@//81* %(,'(5 g5)25'(5O 1,66( /,(*7 ,1 '(5 h>+,*.(,7 '(5 d$6(1N 63(=,76&+ 0,7(,1$1'(5 ,1 y(&+6(/:,5.81* 75(7(1 =8 .?11(1P |:,6&+(1 i8$1,1 81' e<726,1 .?11(1 6,&+ '5(, y$66(56725%[email protected]

TZ

T o2/(.8/$5( c1$720,( Wasserstoffbrückenbindung O N Guanin

N

N

H N HN

N Adenin

N

N

(Desoxy-)Ribose

N H

O

Cytosin

N

(Desoxy-)Ribose

(Desoxy-)Ribose HN

H

HN

H N

O N

H O

(CH3) Uracil (Thymin)

N

(Desoxy-)Ribose

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QMSMQ r%+5.$;23425+452 $%2 cm` fpc (;,67,(57 ,0 |(//.(51 1,&+7 $/6 g,1=(/)$'(1N 621'(51 $/6 f233(/675$1*P f,( %(6&+5,(%(1(1 y$66(56725%5@&.(1%,1'81*(1 =:,6&+(1 '(1 d$6(1 '(5 (,1=(/1(1 p8O ./(27,'( +$/7(1 ',( =:(, g,1=(/675>1*( =86$00(1P f(5 (,1( u75$1* 9(5/>8)7 ,1 WI =8 UI t,&+781*N '(5 $1'(5( $17,3$5$//(/ '$=8 ,1 UI =8 WI t,&+781*P d$6,(5(1' $8) '(5 u3(=,77>7 '(5 d$6(13$$581* /(*7 ',( p8./(27,'6(48(1= '(6 (,1(1 u75$1*(6 ',( p8O ./(27,'6(48(1= '(6 r$571(5675$1*(6 *(1$8 )(67P c%%P TPS[ u758.785 '233(/+(/,.$/(5 fpcP J$K g,1( $17,3$5$//(/( fpc f233(/+(/,; ,67 '$5O 7 *(67(//7P f$6 d$1' 6<0%2/,6,(57 '$6 i(5@67 $86 |8&.(5O 81' r+263+$75(67(1N ',( d$6(1 =(,*(1 1$&+ ,11(1 81' %,/'(1 .203/(0(17>5( y$66(56725%5@&.(1%,1'81*(1 $86P J%K f233(/+(/,.$/( fpc J+,(5 $/6 h$'(1 '$5*(67(//7K :,&.(/7 6,&+ =:(,)$&+ 80 2.7$0(5( j,6721.(51( J3p8O ./(2620KP l('(6 p8./(2620 $662=,,(57 0,7 (,1(0 j,6721 jS o2/(.@/P p8./(2620(1 25*$O 1,6,(5(1 6,&+ ,1 (,1(5 u758.785 +?+(5(5 q5'181* 0,7 UR10 f85&+0(66(5N '(0 u2/(12,'P J&K x21 /,1.6 1$&+ 5(&+76 ,67 (,1( fpc f233(/+(/,; 0,7 =81(+0(1' +?+(5(5 q5*$1,6$7,2166758.O 785 6<1237,6&+ $%*(%,/'(7P

T[

30 nm

TPV p8./(,16>85(1

OctamerHistonkern 10 nm

3`

5`

Histon H1

T A A T G C C

Nucleosom

C G A T

3`

-f.

-h.

DNA

5`

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7,.(/1 $/62 48$6, 80 (,1( NNu<0%,26(DD 921 tpc 81' r527(,1(1P g,1 :(,7(5(6 o(5.O 0$/ 9,(/(5 tpr6 ,67 ',( *(5,1*( n>1*( '(6 tpcOo2/(.@/6 921 2)7 :(1,*(5 $/6 TRR p8./(27,'(1P f,( t,%218./(23527(,1 r$57,.(/ '(6 |(//.(516 :(5'(1 ,1 =:(, j$837O *5833(1 817(57(,/7N ',( +1tpr6 81' ',( 61tpr6 JNNu18536DDKP f,( +1tpr6 J+(7(O 52/2*286 18&/($5 5,%218&/(23527(,1 3$57,&/(6K (17+$/7(1 x25678)(1 '(5 0tpc 81' $/6 r527(,1$17(,/ (,1(1 )81.7,21(// 12&+ :(1,* '(71,(57(1 m203/(; $86 0(+5 $/6 TR r527(,1(1P f,( 35>O0tpc r52=(66,(581* J6,(+( m$3P UPTK 92//=,(+7 6,&+ ,1 ',(6(1 +1tpr6P f,( u18536 J60$// 18&/($5 5,%218&/(23527(,1 3$57,&/(K 6,1' %(66(5 &+$5$.7(5,6,(57P f(5 p$0( '(5 61tpr6 /(,7(7 6,&+ 921 '(5 m@5=( '(5 tpcOd(67$1'7(,/( $% JXR %,6 TSW p8./(27,'(KN ',( $8M(5'(0 6(+5 w5,',1O5(,&+ 6,1'P c86 ',(6(0 i581'( :(5'(1 ',( 9(56&+,('(1(1 61tpr6 1$&+ ,+5(1 tpcOd(67$1'7(,/(1 wSN wT (7&P %(1$117P u2 6,1' ',( wSN wTN wVN wW 81' wX 61tpr6 =80 d(,63,(/ $1 '(5 63>7(5 12&+ *(1$8(5 =8 %(635(&+(1'(1 t(,)81* 921 0tpcN '(0 u3/(,M(1N %(7(,/,*7 J6,(+( m$3P UPTPUKP f,( r527(,1.20321(17( '(5 61tpr6 %(67(+7 $86 0(+5(5(1 18./(>5(1 r527(,1(1P

R l/,%+5,!2-%$):).)3#(% o(93)/,/')% 5.$ a)/#(%-)%

f,(6(6 m$3,7(/ %(6&+5(,%7N :,( ',( ,0 i(120 (,1(5 -('(1 |(//( +,17(5/(*7( k1)250$O 7,21 '$=8 ',(17N =(//8/>5( h81.7,21(1 81' '$0,7 ',( h81.7,21(1 (,1(6 *(6$07(1 q5*$1,6086 =8 75$*(1 81' =8 67(8(51P f,( fpc 6(/%67 +$7 .(,1( g;(.87,9)81.7,21N 621'(51 ',(17 NN185DD $/6 k1)250$7,21663(,&+(5P f$+(5 :,5' (5/>87(57N :,( ',(6(5 k1O )250$7,21663(,&+(5 ,0 t$+0(1 '(5 |(//352/,)(5$7,21 $1 v2&+7(5=(//(1 :(,7(5*(*(%(1 JfpcOt(3/,.$7,21 81' |(//7(,/81*KN ,1 )81.7,2167@&+7,*(0 |867$1' (5+$/7(1 Jfpc t(3$5$785K 81' $/6 o$75,=( =85 u<17+(6( 921 tpc6 *(187=7 :,5' Jv5$16.5,37,21KP c8M(5'(0 :,5' ',6.87,(57N :,( u7?581*(1 '(5 fpcOt(3/,.$7,21N t(3$5$785 81' v5$16.5,37,21 817(56&+,('/,&+(1 g5.5$1.81*(1 =8 i581'( /,(*(1P g%(162 :,5' '$5O *(67(//7N :,( ',( '85&+ v5$16.5,37,21 (1767$1'(1(1 r5,0>575$16.5,37( 6(48(17,(//( t(,)81*66&+5,77( '85&+/$8)(1 81' 6&+/,(M/,&+ (,1 |86$00(163,(/ 0(+5(5(5 5(,)(5 tpc6 =85 u<17+(6( 921 r527(,1(1 (5)25'(5/,&+ ,67P

DNA

(DNA Rekombination) Transkription

mRNA

prä-mRNA Reifung (RNA Editierung)

Zellkern

nukleo-cytoplasmatischer Transport (mRNA Lokalisierung)

Kernpore

Protein

Translation

„Funktion”

mRNA Abbau

Cytoplasma

c%%P UPS u&+(0$ '(6 =(//8/>5(1 k1)250$7,2169866(6 81' '(5 g;35(66,21 921 u758.785*(1(1P n,1.6\ k1 $//(1 |(//(1 ',(17 fpc $/6 3(50$1(17(5 u3(,&+(5 *(1(7,6&+(5 k1)250$7,21P f,( v5$16.5,37,21 (,1(5 0tpc )@+57 $/6 75$16,(17( |:,6&+(1678)( =85 u<17+(6( 921 r527(,1(1N ',( ,+5(56(,76 h81.7,21(1 (1=<0$7,6&+(5 p$785 2'(5 ,0 t$+0(1 '(5 6758.785(//(1 q5*$1,6$7,21 (,1(5 |(//( $86@%(1P t(&+76\ i(1(7,6&+( k1)250$7,21 :,5' '85&+ '(1 x25*$1* '(5 v5$16.5,3O 7,21 921 '(5 fpc $%*(58)(1P f$6 f,$*5$00 =(,*7 ',( c%)2/*( 9(56&+,('(1(5 u&+5,77( ,0 t$+0(1 '(5 i(1(;35(66,21P

UX

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

f$ ',( fpc ,0 |(//.(51 /2.$/,6,(57 ,67 81' ',( r527(,16<17+(6( Jv5$16/$7,21K ,0 e<723/$60$ 67$7771'(7N :,5' (,1 c%6&+1,77 $8&+ ',( %,',5(.7,21$/(1 v5$163257925O *>1*( '85&+ ',( m(51325(1 ',6.87,(5(1P k0 $//*(0(,1(1 :(5'(1 =8(567 ',( (,1=(/1(1 u&+5,77( '(5 i(1(;35(66,21 %(6&+5,(%(1N 81' '$11 ,0 )2/*(1'(1 t(*8/$7,216925O *>1*( $1 $86*(:>+/7(1 d(,63,(/(1 ',6.87,(57P f,(6( d(,63,(/( 62//(1 +(/)(1 =8 (5./>O 5(1N :,( |(//(1 $%+>1*,* 921 ,+5(5 i(:(%(=8*(+?5,*.(,7N ,+5(0 f,5(5(1=,(581*6O *5$' 2'(5 0(7$%2/,6&+(1 g5)25'(51,66(1 ,+5( i(1(;35(66,2160867(5 9(5>1'(51 81' $13$66(1 .?11(1 81' :,( ',( 3$7+2/2*,6&+ 9(5>1'(57( g;35(66,21 (,1=(/1(5 2'(5 0(+5(5(5 i(1( 856>&+/,&+ 9,(/(1 (5(5%7(1 81' (5:25%(1(1 g5.5$1.81*(1 =8 i581'( /,(*(1P c%%,/'81* UPS *,%7 (,1( %(56,&+7 @%(5 ',( 9(56&+,('(1(1 u&+5,77( '(5 i(1O (;35(66,21P

RMP s2!.3+2)04)/. f,( v5$16.5,37,21 67(//7 '(1 (567(1 u&+5,77 ,0 r52=(66 '(5 g;35(66,21 921 i(1(1 '$5N $/62 '(0 c%58)(1 '(5 ,1 ',(6(1 fpcOc%6&+1,77(1 *(63(,&+(57(1 *(1(7,6&+(1 k1)250$7,21P v5$16.5,37,21 ,67 '(71,(57 $/6 w06&+5(,%81* 921 i(1(1 ,1 tpcP |8 d(*,11 '(6 v5$16.5,37,216925*$1*(6 08M '(5 $86)@+5(1'( g1=<0.203/(; $1 ',( 5,&+7,*( r26,7,21 ,0 i(1 *(%5$&+7 :(5'(1 81' (,1 u75$1* $/6 o$75,=( )@5 '(1 c8)%$8 '(6 (,1=(/675>1*,*(1 tpcOo2/(.@/6 925%(5(,7(7 :(5'(1N ,1'(0 ',( fpcO f233(/+(/,; $8)*(6&+02/=(1 :,5'P g567 '$11 .?11(1 ',( (567(1 p8./(27,'( '(6 i(16 ,1 tpc 80*(6&+5,(%(1 :(5'(1P f,(6(5 r52=(66 :,5' $/6 v5$16.5,37,216,1,7,$7,21 %(=(,&+1(7P f,( g5(.7,9,7>7 '(5 k1,7,$7,21 ,67 ,0 :(6(17/,&+(1 )@5 ',( g5,=,(1= '(5 v5$16.5,37,21 (,1(6 i(16 9(5$17:257/,&+ J5$7( /,0,7,1* 67(3KP u20,7 71'(7 ',( t(O *8/$7,21 +$8376>&+/,&+ $8) '(5 g%(1( '(5 v5$16.5,37,216,1,7,$7,21 67$77P f,( x(5/>1*(581* '(6 v5$16.5,37(6 :,5' $/6 g/21*$7,21 %(=(,&+1(7P c8&+ ',( g)O 7=,(1= '(5 g/21*$7,21 921 v5$16.5,37(1 .$11 ,1 '(5 |(//( (5+(%/,&+ 9$5,,(5(1P c8)O %$8(1' $8) '(0 r5,1=,3 '(5 d$6(13$$581* :>&+67 '(5 tpcOu75$1* ,1 WA B UA t,&+O 781*P g5 ,67 '(0 75$16.5,%,(57(1 fpcOu75$1* Jo$75,=(K .203/(0(17>5 81' )2/*/,&+ ,1 6(,1(5 p8./(27,'6(48(1=N %,6 $8) '(1 )@5 tpc &+$5$.7(5,67,6&+(1 vBw c867$86&+N 0,7 '(0 1,&+7O75$16.5,%,(57(1 fpcOu75$1* ,'(17,6&+P i581'6>7=/,&+ :,5' 185 (,1 u75$1* (,1(6 i(16 75$16.5,%,(57N -('2&+ .?11(1 ',(6 -( 1$&+ c865,&+781* '(5 i(1( 817(56&+,('/,&+( u75>1*( '(5 fpcOf233(/+(/,; 6(,1P h@5 ',( u(48(1= (,1(6 i(16 :,5' ,1 '(5 n,7(5$785 *(:?+1/,&+ ',( u(48(1= '(6 1,&+775$16.5,%,(57(1 fpc u75$1*(6 $1*(*(%(1P f$ 921 ',(6(0 u75$1* ',( r527(,16(48(1= $1+$1' '(6 *(1(7,6&+(1 e2'(6 $%*(/(,7(7 :(5'(1 .$11 J6P 2PKN :,5' (5 $8&+ $/6 NNu(16(Ou75$1*DD %(=(,&+1(7P g,1( NNc17,6(16(OtpcDD %(6,7=7 '(01$&+ ',( u(48(1= '(6 75$16.5,%,(57(1 fpc u75$1*(6N 81' 6,( +$7 ',( h>+,*.(,7 0tpc6 0,7 +2+(5 u3(=,77>7 =8 %,1'(1P f,(6( v$76$&+( 0$&+7 6,&+ ',( o2/(.8/$5( o(',=,1 ,0 (;3(5,0(17(//(1 62:,( ,0 ',$*1267,6&+(1 81' 7+(5$3(87,6&+(1 d(5(,&+ =8 p87=(N 80 v5$16.5,37( %(67,007(5 |,(/*(1( 63(=,O 76&+ $167(8(51 =8 .?11(1P f(5 t()(5(1=381.7 )@5 ',( p80(5,(581* '(5 p8./(27,'( (,1(6 i(16 ,67 ',( '(0 (567(1 t,%218./(27,' '(6 tpcOu75$1*(6 (17635(&+(1'( d$6(P f,(6( :,5' 0,7 1S %(=(,&+1(7P x21 '257 :,5' ,1 t,&+781* '(5 v5$16.5,37,21N 'P +P ,1 UAOt,&+781*N :(,O 7(5*(=>+/7P i(16(48(1=(1 WA =80 v5$16.5,37,21667$57 :(5'(1 (17635(&+(1' 1(*$7,9

UPS v5$16.5,37,21

--3 C

--2 --1 +1 +2 +3 G T A G C

G

A

UY

nicht transkribierter DNA-Strang

T

G

5´

C

C G A

Transkript

RNA Polymerase 5' -- A -- G -- C -- G -- A -- U --

3´

G C A T C G --3 --2 --1 +1 +2 +3

C

T

A

C

G

G

C

T

A

T

G

A

T

C

G

C

T

A

C

T

A

G

C

G

C 3´ 5´ G

transkribierter DNA-Strang

TS

c%%P UPT p80(5,(581* '(5 p8./(27,'( ,1 (,1(5 v5$16.5,37,216(,1+(,7P f$5*(67(//7 ,67 (,1 fpcOf233(/675$1*N '(5 ,0 d(5(,&+ '(6 v5$16.5,37,2167$57(6 JvuK $8)*(6&+02/=(1 ,67P x21 '(0 '85&+ ',( tpcOr2/<0(5$6( 352'8=,(57(1 v5$16.5,37 .200(1 ',( (567(1 6(&+6 p8./(27,'( =85 f$567(//81*P

180(5,(57 Jc%%P UPTKP o,7 '(5 92//67>1',*(1 w06&+5,)7 '(6 i(16 ,1 tpc :,5' '(5 v5$16.5,37,216925*$1* %((1'(7P f,(6(5 u&+5,77 :,5' $/6 v(50,1$7,21 %(=(,&+1(7P c86 '(5 2%,*(1 f$567(//81* :,5' '(87/,&+N :$580 '(5 g1=<0.203/(; '(5 v5$16.5,37,21 $/6 fpcO$%+>1*,*( tpcOr2/<0(5$6( O2'(5 .85= $/6 tpcOr2/<0(5$6(O %(=(,&+1(7 :,5'P y(,/ -('( .(51+$/7,*( 620$7,6&+( |(//( 816(5(6 q5*$1,6086 0,7 '(0 */(,&+(1 u$7= $1 i(1(1 $86*(67$77(7 ,67 Jc861$+0(1 67(//(1 ',( 5(.20%,1$7,216$.7,9(1 n<03+2O &<7(1 '$5N 6,(+( m$3P UPWKN 08M *(:>+5/(,67(7 6(,1N '$M ',( g;35(66,21 817(56&+,('O /,&+(5 i(1( =8 %(67,007(1 |(,7(1 $1O 81' $%*(6&+$/7(7 :(5'(1 .$11 81' '$5@%(5 +,1$86 ',( g;35(66,216+?+( =:,6&+(1 '(1 g;75(0(1 9$5,$%(/ 5(*8/,(5%$5 ,67P E D

A

B

A

B

C

POL II

C

Steuerregion

transkribierte Region upstream

TS +1

downstream

c%%P UPU u&+(0$7,6&+( f$567(//81* '(5 i(16758.785P f(5 v5$16.5,37,21667$57 JvuK 817(57(,/7 (,1 i(1 ,1 (,1( $%:>576 J'2:1675($0K /,(*(1'(N 75$16.5,%,(57( t(*,21 81' ,1 (,1( $8):>576 J83675($0K /,(*(1'( u7(8(55(*,21P k1 '(5 u7(8(55(*,21 6,1' (,1=(/1( &,6O$*,(5(1'( g/(0(17( 0,7 75$16O$*,(5(1'(1 h$.725(1 '$5*(67(//7P

UZ

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

c8) v5$16.5,37,216(%(1( :,5' ',( .255(.7( i(1(;35(66,21 '85&+ '$6 .203/(;( |86$00(163,(/ =:(,(5 m20321(17(1 *$5$17,(57 Jc%%P UPUKP g,1(56(,76 6,1' ',(6 ',( 62*(1$117(1 u7(8(5(/(0(17( '(5 i(1(N ',( 6,&+ 7<3,6&+(5:(,6( 2%(5+$/% J(1*/P\ 83O 675($0KN 'P +P ,1 WAOt,&+781* 920 v5$16.5,37,21667$57 (,1(6 i(16 %(71'(1P c1'(O 5(56(,76 6,1' ',(6 t(*8/$7253527(,1.203/(;(N ',( @%(5 ',(6( u758.785(/(0(17( $1 =8 75$16.5,%,(5(1'( i(1( 5(.587,(57 :(5'(1 81' ',( g5,=,(1= '(5 v5$16.5,37,21 326,7,9 2'(5 1(*$7,9 %((,19866(1 .?11(1P f,( u7(8(5(/(0(17( :(5'(1 $8&+ $/6 &,6O$*,(5(1'( g/(0(17( J&,6O$&7,1* (/(0(176K 81' ',( t(*8/$7253527(,1( $/6 75$16O$*,(5(1'( h$.O 725(1 J75$16O$&7,1* )$&7256K %(=(,&+1(7P f$ ',(6(1 %(,'(1 m20321(17(1 ',( $//(6(176&+(,'(1'( t2//( %(, '(5 t(*8/$7,21 '(6 v5$16.5,37,216925*$1*(6 =8)>//7N :,5' ',(6(6 m$3,7(/ ,1 6(,1(0 :(,7(5(1 x(5/$8) $0 d(,63,(/ '(5 3527(,1.2',(5(1'(1 i(1(N 'P +P tpcOr2/<0(5$6( kk 75$16.5,%,(57(5 i(1(N '$6 |86$00(1:,5.(1 &,6O$*,(5(1'(5 g/(0(17( 81' 75$16O$*,(5(1'(5 h$.725(1 '(7$,/,(57(5 %(6&+5(,%(1P f,( '85&+ tpcOr2/<0(5$6(1 k 81' kkk '85&+*()@+57( v5$1O 6.5,37,21 '(5 5tpcO %=: 7tpcOi(1( J6,(+( m$3P TPVK %(58+7 $8) >+1/,&+(1 r5,1O =,3,(1] ,+5( d(621'(5+(,7(1 62//(1 -('2&+ $1 ',(6(5 u7(//( 81%(5@&.6,&+7,*7 %/(,%(1P

RMPMP c)% r4%5%2%,%-%.4% $%2 qm`Lo/,9-%2!3% hh 6%2-)44%,4%. f%.%802%33)/. y,( 2%(1 %(5(,76 $1*('(87(7N %(71'(1 6,&+ ',( u7(8(5(/(0(17( '(5 '85&+ tpcO r2/<0(5$6( kk 75$16.5,%,(57(1 i(1( J,0 )2/*(1'(1 $/6 r2/ kk i(1( %(=(,&+1(7K ,1 '(5 t(*(/ ,1 (,1(0 :(1,*( m,/2%$6(1 80)$66(1'(1 d(5(,&+ 2%(5+$/% '(6 v5$16.5,3O 7,21667$57(6P u7(8(5(/(0(17( 6,1' 7<3,6&+(5:(,6( XASR %3 .85=( fpcOc%6&+1,77(N 921 '(1(1 0$1&+0$/ :(1,*(5 $/6 =(+1N ,1 $1'(5(1 h>//(1 $%(5 $8&+ 0(+5 $/6 UR ,1 m20%,1$7,21 925/,(*(1 .?11(1P f,( i(6$07+(,7 '(5 u7(8(5(/(0(17( (,1(6 i(16 :,5' $/6 u7(8(55(*,21 2'(5 r5202725 %(=(,&+1(7P Jw17(5 '(0 d(*5,5 NNr5202725DD +$7 0$1 ,1 '(5 x(5*$1*(1+(,7 2)70$/6 ',( 80 '(1 v5$16.5,37,21667$57 /,(*(1'(1 u7(8(5(/(0(17( =86$00(1*()$667P f,(6( g/(0(17( :(5'(1 +(87( %(66(5 $/6 NN%$6$/( r5202725(/(0(17(DD %(=(,&+1(7 J6P 8PKKP f85&+ '(7$,//,(57( u(48(1=O 81' o87$7,216O $1$/<6(1 921 r5202725(1 817(56&+,('/,&+(5 r2/ kk i(1( ,67 (6 *(/81*(1N (,1=(/1( u7(8(5(/(0(17( ,1 ,+5(5 d$6(1$%)2/*( 81' ,1 ,+5(5 d('(8781* )@5 ',( i(1(;35(66,21 *(1$8 =8 %(6&+5(,%(1P f,(6( c1$/<6(1 (5/$8%(1 (,1( i5833,(581* 817(56&+,('/,&+(5 u7(8(5/(0(17( 1$&+ ,+5(5 y(57,*.(,7 )@5 '(1 v5$16.5,37,216925*$1*P

RMPMPMP a!3!,% o2/-/4/2%,%-%.4% f(5 r5202725 (17+>/7 '5(, 817(56&+,('/,&+( i5833(1 921 u7(8(5(/(0(17(1P f,( (567( i5833( %(67(+7 $86 '(1 %$6$/(1 J=(175$/(1K r5202725(/(0(17(1 Jc%%P UPVKP |8 ,+1(1 *(+?5(1 ',( vcvcOd2;N ',( (7:$ TWAUR %3 2%(5+$/% '(6 v5$16.5,37,21667$57(6 /,(*7P f(5 p$0( /(,7(7 6,&+ 921 '(5 p8./(27,'6(48(1= ',(6(6 g/(0(17(6 $% Jm216(1686\ vcvc$B7c$B7KP f(5 =:(,7( x(575(7(5 ',(6(5 i5833( ,67 '$6 k1,7,$725Og/(0(17N :(/&+(6 ,1 6(,1(5 d$6(1$%)2/*( :(1,*(5 *87 '(71,(57 ,67 $/6 ',( vcvcOd2;N '$6 $%(5 ,00(5 (,1( %(621'(56 3<5,0,',15(,&+( |86$00(16(7=81* $8):(,67 81' 67(76 @%(5 '(0 v5$1O 6.5,37,21667$57381.7 =(175,(57 ,67P f$6 f2:1675($0 u(48(1&( g/(0(17 ,67 (,1 .@5=O

UPS v5$16.5,37,21

Steuerregion

Exon I

Exon II

U[

Exon III

basale Promotorregion

tccgacgggTATAAAagggtaagtcgcgttccgtcTCACTCTCTg TATA-Box

Inr-Element

c%%P UPV u.,==,(581* '(5 %$6$/(1 r52027255(*,21 ,0 i(1.217(;7P k1 '(5 2%(5(1 j>/)7( '(5 c%%,/'81* ,67 (,1 i(1 0,7 v5$16.5,37,21667$57 JBKN g;216758.785(1 62:,( '(5 u7(8(55(*,21 $%*(%,/'(7P f,( %$6$/( r52027255(*,21 %(71'(7 6,&+ 810,77(/%$5 925 '(0 v5$16.5,37,21667$57P f,(6( ,67 ,1 '(5 817(5(1 c%%,/'81*6+>/)7( $/6 p8./(27,'6(48(1= '$5*(67(//7P i52M( d8&+67$%(1 +(%(1 ',( vcvcOd2; 81' '$6 k1,7,$725Og/(0(17 Jk15K +(5$86P

/,&+ (17'(&.7(6N 6(/7(1(5 925.200(1'(6 %$6$/(6 r5202725(/(0(17 (,1,*(5 vcvcO d2;O/26(5 i(1(P c//( %$6$/(1 r5202725(/(0(17( ',(1(1 35,0>5 '(5 n2.$/,6,(581* '(6 v5$16.5,3O 7,21667$57(6P f,( n2.$/,6,(581* '(6 v5$16.5,37,21667$57381.7(6 :,5' ,0 :(6(17/,&+(1 '$'85&+ (55(,&+7N '$M '(5 ',( v5$16.5,37,21 ,1,7,,(5(1'( g1=<0.203/(; 1(%(1 '(5 tpcOr2/<0(5$6( $8&+ ',( fpcOd,1'81*63527(,1( '(5 %$6$/(1 r5202725(/(0(17( J:,( =P dP '$6 vcvcO%,1'(1'( r527(,1N 6P 8PK (17+>/7P %(5 ',(6( d,1'81*63527(,1( :,5' '(5 g1=<0.203/(; $1 '(1 v5$16.5,37,21667$57381.7 +(5$1*()@+57P o$1&+( i(1( (17+$/7(1 =:(, 2'(5 '5(, )81.7,21(//( vcvcOd2;(1N $1'(5( r52O 02725(1 -('2&+ .(,1(6 '(5 J%(.$117(1K %$6$/(1 u7(8(5(/(0(17(P k1 62/&+(1 h>//(1 :,5' ',( v5$16.5,37,21 $1 08/7,3/(1 u7$57381.7(1 ,1,7,,(57N ',( '$11 1,&+7 6(/7(1 @%(5 (,1( t(*,21 921 &$P SRR %3 9(5675(87 /,(*(1P f(5 x257(,/ (,1'(87,* '(71,(57(5 v5$16.5,37,21667$57381.7( /,(*7 ,1 '(0 %(:8M7(1 g,1O 2'(5 c866&+/,(M(1 921 u(O 48(1=$%6&+1,77(1 '(5 WAO1,&+775$16/$7,(57(1 t(*,21 (,1(6 v5$16.5,37(6 JWAOwvtKP f$O '85&+ (5*(%(1 6,&+ t(*8/$7,2160?*/,&+.(,7(1 '(5 i(1(;35(66,21 :,( ',( k17(*5$7,21 326775$16.5,37,21$/(5 u7(8(5(/(0(17( ,1 ',( WAOwvt 2'(5 ',( c167(8(581* 817(5O 6&+,('/,&+(5 v5$16/$7,21667$57381.7( J6,(+( m$3P UPVPTKP g6 ,67 ,17(5(66$17N '$M i(1( 2+1( %$6$/( r5202725(/(0(17( 2)7 62*(1$117( e3iOk6/$1'6 $8):(,6(1 81' =(//7<3O 8163(=,76&+ 81' .2167,787,9 (;35,0,(57 :(5'(1 J6P 8PKP |86$00(1*(1200(1 /$66(1 ',( d(2%$&+781*(1 '(1 u&+/8M =8N '$M %$6$/( r5202725(/(0(17( '(1 v5$16.5,3O 7,21667$57 %(, '(5 ,1 |(,7 81' t$80 .203/(; 5(*8/,(57(1 i(1(;35(66,21 '(71,(5(1P

RMPMPMQ o2/8)-!,% o2/-/4/2%,%-%.4% f,( =:(,7( i5833( '(5 u7(8(5(/(0(17(N ',( 62*(1$117(1 352;,0$/(1 r5202725(/(O 0(17(N %(71'(7 6,&+ ,1 (,1(5 t(*,21N ',( 6,&+ %,6 =8 :(1,*(1 +81'(57 d$6(13$$5(1 2%(5+$/% '(5 vcvcOd2; (5675(&.7 Jc%%P UPWKP f,( %(, :(,7(0 +>87*67(1 ',(6(5 g/(O

VR

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

Steuerregion

Exon I

Exon II

Exon III

proximale Promotorregion

TTTCGCGC

ATTTGCAT

GGGCGG

CCAAT

E2F

Oktamer

SP-1

CTF C/EBP CPI-3

c%%P UPW q5*$1,6$7,21 '(5 352;,0$/(1 r52027255(*,21 ,0 i(1.217(;7P c16&+/,(M(1' $1 ',( %$6$/( r52027255(*,21 ,67 +,(5 ,1 '(5 2%(5(1 d,/'+>/)7( ',( 352;,0$/( r52027255(*,21 (,1(6 i(16 6&+(0$7,6&+ '$5*(67(//7P k1 '(5 817(5(1 d,/'+>/)7( 6,1' %(,63,(/+$)7 (,1,*( v5$16.5,37,216O )$.725(1 0,7 k+5(1 63(=,76&+(1 g5.(1181*6(48(1=(1 %(1$117P

0(17( 6,1' ',( ieOd2; 81' ',( eccvOd2;P f,( ieOd2; (17+>/7 ',( u(48(1= iiieii 81' ',(6 2)7 ,1 08/7,3/(1 m23,(1P f$6 o27,9 :,5' 921 '(0 18./(>5(1 h$.725 urOS *(%81'(1P f(5 p$0( eccvOd2; *,%7 ',( m216(16866(48(1= ',(6(6 g/(0(176 :,'(5P g6 .$11 921 9(56&+,('(1(1 18./(>5(1 h$.725(1 (5.$117 :(5'(1P c1'(56 $/6 ',( vcvcOd2; 2'(5 '$6 k1,7,$725 g/(0(17 .?11(1 ieO 81' eccvO d2;(1 ,11(5+$/% '(5 352;,0$/(1 r52027255(*,21 %(75>&+7/,&+ ,1 ,+5(5 g17)(5181* 920 v5$16.5,37,21667$57 9$5,,(5(1N ,1 08/7,3/(1 m23,(1 352 i(1 925.200(1 81' ,1 %(,'(1 q5,(17,(581*(1 $.7,9 6(,1P u,( 6,1' $//(5',1*6 ,1 (,1(0 *5?M(5(1 c%67$1' 920 v5$16.5,37,21667$57 J921 =P dP 0(+5 $/6 (,1(5 m,/2%$6(K 1,&+7 0(+5 )81.7,21(//P f,(6 0$&+7 '(1 :(6(17/,&+(1 w17(56&+,(' =8 '(1 ',67$/(1 r5202725(/(0(17(1 $86 J6P 8PKP ieO 81' eccvOd2;O%,1'(1'( r527(,1( .200(1 8%,48,7>5 925 81' :(5'(1 .2167,787,9 (;35,0,(57P o$1 :(,MN '$M ',(6( 352;,0$/(1 g/(0(17( ,1 (567(5 n,1,( )@5 ',( g5(.7,9,7>7 '(5 v5$16.5,37,216,1,7,$7,21 9(5$17:257/,&+ 6,1'N 2+1( '$%(, (,1( +2&+63(=,76&+( t(*8/$7,21 '(5 i(1( =8 (50?*/,&+(1P p(%(1 ',(6(1 %(,'(1 352727<3,6&+(1 352;,0$/(1 r5202725(/(0(17(1 *,%7 (6 =$+/O 5(,&+( :(,7(5( u7(8(5(/(0(17( ',(6(5 m$7(*25,(P c1'(56 $/6 ieO 81' eccvOd2;(1 .?11(1 $%(5 =P dP q.7$0(5ON cvhON ph;$dO 2'(5 gThOg/(0(17( 1,&+7 185 ',( i581'O $.7,9,7>7 (,1(6 r52027256 (5+?+(1N 621'(51 6,( 75$*(1 $8&+ ',5(.7 =85 63(=,76&+(1 t(*8/$7,21 '(5 i(1(;35(66,21 %(,P u2 ,67 '$6 gThOg/(0(17 7<3,6&+(5:(,6( ,1 62/&+(1 i(1(1 $1=875(5(1N '(5(1 g;O 35(66,21 ,0 x(5/$8) '(6 |(//=<./86 5(*8/,(57 :,5' Jc%%P UPXKP c8) ',(6( y(,6( :,5' ',( g;35(66,21 921 i(1(1N '(5(1 r52'8.7( /(',*/,&+ ,0 t$+0(1 '(5 fpcOt(3/,O .$7,21 %(1?7,*7 :(5'(1N 185 .85= 925 '(0 d(*,11 81' :>+5(1' '(5 fpcOu<17+(6(O r+$6( '(5 |(//( *(67(,*(57P g,1 d(,63,(/ )@5 (,1 62/&+(6 i(1 ,67 '$6 e<&/,1Og i(1N '$6 ,1 6(,1(0 352;,0$/(1 r5202725$%6&+1,77 1(%(1 '(1 gThOg/(0(17(1 $8&+ 32O 6,7,9( u7(8(5(/(0(17( %(6,7=7N ',( '(0 r5202725 (,1( i581'$.7,9,7>7 9(5/(,+(1P y(5O '(1 ',(6( u7(8(5(/(0(17( 087,(57N 9(5/,(57 '(5 r5202725 6(,1( i581'$.7,9,7>7P y(5O '(1 +,1*(*(1 ',( gThOg/(0(17( $86*(6&+$/7(7N %/(,%7 =:$5 ',( i581'$.7,9,7>7 '(6

UPS v5$16.5,37,21

VS

Aktivität

E2F-Aktivator Komplex

E2F-Repressor Komplex

Expressionshöhe

Cyclin E-Promotor Cyclin E-Promotor ∆ E2F

GO / G1

S

c%%P UPX i5$3+,6&+( f$567(//81* '(5 c.7,9,7>7 '(6 e<&/,1Og r52027256 ,1 c%+>1*,*.(,7 921 gThOh$.725(1P f,( c.7,9,7>7 '(6 e<&/,1 g r52027256 :,5' ,1 (,1(0 (1* %(*5(1=7(1 h(167(5 $0 %(5*$1* '(5 |(//=<./863+$6(1 iS 81' u *(67(,*(57P g,1 e<&/,1 g r5202725 0,7 '(/(7,(57(1 gThOd,1'81*667(//(1 VgTh =(,*7 (,1( .2167$17 +2+( g;35(66,21 2+1( :(6(17/,&+( =(//=<./866O 3(=,76&+( t(*8/$7,21P k0 2%(5(1 v(,/ '(5 c%%,/'81* :,5' ',(6(0 g;35(66,2160867(5 ',( c.O 7,9,7>7 921 gThOc.7,9$725O %=:P gThOt(35(6625.203/(;(1 ,0 |(//=<./86 *(*(1@%(5*(67(//7P

r52027256 (5+$/7(1N $%(5 ',( t(*8/$7,21 ,0 x(5/$8) '(6 |(//=<./86 (17)>//7P f,( gThO g/(0(17( 5(*8/,(5(1 620,7 ',( g;35(66,21 '(6 e<&/,1Og i(16N ,1'(0 6,( ',( i581'O $.7,9,7>7 '(6 r52027256 ,1 '(1 (17635(&+(1'(1 r+$6(1 '(6 |(//=<./86 02'8/,(5(1P f,(6( t(*8/$7,21 :,5' @%(5 ',( ,0 |(//=<./86 =(,7/,&+ %(*5(1=7( x(5)@*%$5.(,7 %(O 67,007(5 gThOr527(,1.203/(;( (55(,&+7 Jc%%P UPXKP f(5 =8*581'( /,(*(1'( o(&+$O 1,6086 62// %(, '(5 d(635(&+81* '(5 t(*8/$7,21 '(6 |(//=<./86 1>+(5 %(75$&+7(7 :(5'(1 J6,(+( m$3P UPXPTKP f,(6(6 d(,63,(/ 62// 9(5'(87/,&+(1N '$M $//( &,6O 81' 75$16O$*,(5(1'(1 m20321(17(1 (,1(6 r52027256 $/6 )81.7,21(//( g,1+(,7 %(75$&+7(7 :(5'(1 0@66(1P r5202725(/(O 0(17( %(6,7=(1 .(,1( v5$16.5,37,216$.7,9,7>7 3(5 6(] (567 ',( x(5)@*%$5.(,7 81' c1O %,1'81* $.7,9(5 75$16O$*,(5(1'(5 h$.725(1 9(5/(,+(1 r5202725(1 0,7 817(56&+,('O /,&+(1 m20%,1$7,21(1 &,6O$*,(5(1'(5 g/(0(17( (,1 63(=,76&+(6 g;35(66,2160867(5P

RMPMPMR c)34!,% o2/-/4/2%,%-%.4% Gd.(!.#%2H d,6+(5 ,67 '(5 r5202725 $/6 ',( t(*,21 (,1(6 i(16 925*(67(//7 :25'(1N ',( 6,&+ ,1 WIOt,&+781* /@&.(1/26 $1 '(1 75$16.5,%,(57(1 c17(,/ (,1(6 i(16 $16&+/,(M7P f(0*(O *(1@%(5 6,1' ',67$/( r5202725(/(0(17( u7(8(5(/(0(17(N ',( 6,&+ ,1 *5?M(5(5 g17O )(5181* =80 v5$16.5,37,21667$57381.7 %(71'(1P f$%(, ,67 (6 *581'6>7=/,&+ 81(5+(%O /,&+N 2% 6,( 2%(5+$/% 2'(5 817(5+$/% '(6 v5$16.5,37,21667$57(6 /,(*(1P f,( h>+,*.(,7N i(1(;35(66,21 75$16.5,37,21(// @%(5 (,1( *52M( f,67$1= =8 %((,1O 9866(1N ,67 '(5 :(6(17/,&+( w17(56&+,(' =:,6&+(1 352;,0$/(1 81' ',67$/(1 r5202O 725(/(0(17(1P f$ '$6 x25.200(1 ',(6(5 t(*8/$725(/(0(17( 0,7 (,1(0 6(+5 *52M(1

VT

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

v$%P UPS d,1'81*6(/(0(17( 921 g1+$1&(51 0,7 ,+5(1 g5.(1181*66(48(1=(1P NNpDD 67(+7 )@5 -('(6 0?*/,&+( p8./(27,'P d,1'81*6(/(0(17

g5.(1181*66(48(1=

u(580 t(63216( g/(0(17

eecvcvvcii

crOS JhquBlwpK

vicevec

i/8.2.257,.2,' t(63216( g/(0(17

viivceccvivvev

j,7=(6&+2&.Og/(0(17

eppiccppveeppi

gvuBrwPk

icccippicc

gOd2; J=P dP o{eK

eceivi

c167,(* '(5 v5$16.5,37,216$.7,9,7>7 '(5 tpcOr2/<0(5$6( (,1+(5*(+(1 .$11N :(5'(1 ',(6( g/(0(17( $8&+ $/6 g1+$1&(5 %(=(,&+1(7P y,( ',( %,6+(5 %(6352&+(1(1 r5202O 7256758.785(1 67(//(1 $8&+ g1+$1&(5 d,1'81*667(//(1 )@5 t(*8/$7253527(,1( '$5P f$O %(, (17+>/7 (,1 g1+$1&(5 A :,( '(5 352;,0$/( r5202725$%6&+1,77 A 0(+5(5( d,1O '81*667(//(1 )@5 75$16O$*,(5(1'( h$.725(1P k1 v$%(//( UPS 6,1' u7(8(5(/(0(17( %(O .$117(5 g1+$1&(5 81' ',( '$=8*(+?5,*(1 h$.725(1 $8)*()@+57P f,( g;,67(1= ',67$/(5 u7(8(5(/(0(17( ,1 (,1(5 g17)(5181* 921 %,6 =8 0(+5(5(1 =(+1 m,/2%$6(1 =80 v5$16.5,37,21667$57 J2'(5 ,1 k175216758.785(1 921 i(1(1K />M7 9(5087(1N '$M 9,(/( >+1/,&+ 326,7,21,(57( u7(8(5(/(0(17( %,6+(5 81(17'(&.7 *(%/,(O %(1 6,1'P g1+$1&(5 :,5.(1 i(1O8163(=,76&+P u,( .?11(1 (;3(5,0(17(// 2+1( h81.O 7,2169(5/867 921 (,1(5 v5$16.5,37,216(,1+(,7 $8) (,1( $1'(5( @%(575$*(1 :(5'(1P p$&+ '(0 -(7=,*(1 y,66(1667$1' (17)$/7(1 6,( ,+5( y,5.81* ,0 *(120,6&+(1 m217(;7 $8) '(1 $0 1>&+67(1 *(/(*(1(1 %$6$/(1 r5202725.203/(;P f,67$/( u7(8(5(/(0(17(N ',( ',( g;35(66,21 921 i(1(1 5('8=,(5(1N $%(5 $162167(1 1$&+ '(0 y,5.35,1=,3 921 g1+$1&(51 $*,(5(1N :(5'(1 $/6 u,/(1&(5 %(=(,&+1(7P g,1( %(621'(5( h250 (,1(5 ',67$/(1 u7(8(5(,1+(,7 ,67 )(51(5 ',( n2.86.21752//5(*,21 JnetK '(6 tOi/2%,1*(1.203/(;(6P f,( net %(6,7=7 =$+/5(,&+( u7(8(5(/(0(17(N ',( ',( 817(56&+,('/,&+(1 i(1( '(6 i/2%,1*(1.203/(;(6 $86 6(+5 *52M(5 g17)(5181* J# SR .%K ',5(5(1=,(// 5(*8/,(5(1P g,1( )2/*(15(,&+( m203/,.$7,21 '(5 8163(=,76&+(1 y,5.:(,6( 921 g1+$1&(5(/(O 0(17(1 .(11(1 :,5 $86 '(5 02/(.8/$5(1 q1.2/2*,(P u2 .$11 (6 %(, %(67,007(1 v5$16/2.$7,21(1 2'(5 '(5 k16(57,21 3529,5$/(5 fpc =8 '(5 $57,7=,(//(1 |86$00(1O )@+581* 921 g1+$1&(5(/(0(17(1 81' r5272Oq1.2*(1(1 .200(1 J6,(+( m$3P XPTPTKP g,1 (,1'58&.692//(6 d(,63,(/ 67(//(1 *(1(7,6&+( u8%)250(1 '(6 d85.,77On<03+206 '$5N :2 (6 '85&+ &+5202620$/( v5$16/2.$7,21 J7JZ]SVKK =8 (,1(5 5>80/,&+(1 c11>O +(581* '(6 i(16 )@5 '(1 35272O21.2*(1(1 y$&+67806)$.7256 o{e 81' '(6 k*jO g1+$1&(56 ,1 dO|(//(1 .2007P f$5$86 5(68/7,(57 ',( %(5(;35(66,21 '(6 6758.785(// 9?//,* 819(5>1'(57 *(%/,(%(1(1 o{e r527(,16N :$6 (,1(1 .217,18,(5/,&+(1 r52/,)(O 5$7,21667,08/86 )@5 ',( %(7525(1(1 |(//(1 %('(87(7 J6,(+( m$3P XPTPVKP g,1 :,&+7,*(6 e+$5$.7(5,67,.80 921 g1+$1&(5O%,1'(1'(1 h$.725(1 ,67 ,+5( k1O '8=,(5%$5.(,7P u20,7 (50?*/,&+(1 g1+$1&(5 ',( g;35(66,21 (,1(6 i(16 6&+1(// 81'

UPS v5$16.5,37,21

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POL II

CTD

In vitro Transkription

BTF

SWI/ SNF BTF

Core-Enzym

--

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+ nackte DNA

Core-Enzym + basale TF + SWI/SNF

+ chromatinisierte DNA

Holo-Enzym + regulative TF

+ + + chromatinisierte DNA

SRB/Mediator regulative TF

SWI/ SNF

BTF

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UPS v5$16.5,37,21

TATA TFIID

TFIID TATA TFIIA TFIIB TFIID TFIIA

TFIIB

TATA POL II TFIIF

Mediator/ SRB

POL II

TFIID TFIIA

TFIIF

TFIIB

TATA TFIIE TFIIH

Mediator/ SRB

POL II

TFIID TFIIA

TFIIF

TFIIB

TATA

TFIIE TFIIH

A

RN

POL II

TFIID TATA

PP

TFIIA

TFIIB

PP

Mediator/ SRB

TFIIF

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VY

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RMPMQMR q%'5,!4)6% s2!.3+2)04)/.3&!+4/2%. "%34)--%. $)% q!4% $%2 s2!.3+2)0L 4)/.32%).)4))%25.' f,( :,&+7,*67( h81.7,21 5(*8/$7,9(5 vh ,67 ',( o2',7=,(581* '(5 k1,7,$7,2165$7( '(5 v5$16.5,37,21P f$5@%(5 +,1$86 .?11(1 5(*8/$7,9( vh $%(5 $8&+ '(1 g/21*$7,216O 6&+5,77 '(5 v5$16.5,37,21 %((,19866(1 J6,(+( m$3P UPSPWKP g567 '85&+ '$6 |86$00(1O :,5.(1 817(56&+,('/,&+(5 m20%,1$7,21(1 5(*8/$7,9(5 vh $1 (,1(0 r5202725 :,5' ',( h(,1$%67,0081* '(5 v5$16.5,37,2165(*8/,(581* ,1 |(,7 81' t$80 (50?*/,&+7P w0 ',(6( c8)*$%( (5)@//(1 =8 .?11(1N 0@66(1 5(*8/$7,9( vh 0,1'(67(16 =:(, h>O +,*.(,7(1 %(6,7=(1\ ',( 63(=,76&+( g5.(1181* 81' d,1'81* 921 u7(8(5(/(0(17(1 81' ',( )81.7,21(//( c1%,1'81* $1 '$6 j2/2Orqn kkOg1=<0P 1

437 DNA-Bindung

Dimerisierung

Aktivierung

(a)

Aktivierung

Dimerisierung

(b)

DNA-Bindung

Adapter

Aktivierung POL II

Adapter

(c)

POL II

DNA-Bindung

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WR

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

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2

37

28 42

10 3

22

1 58

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UPS v5$16.5,37,21

WS

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L LZ-Protein I

LZ-Protein II

L L L L

Dimerisierungsdomäne

L L L L L DNA-Bindungsdomäne

L L L L L L L L L

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WT

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

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UPS v5$16.5,37,21

WU

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Glukokortikoide Kernmembran HSP90

GR

P300

F J

Verlust der Transaktivierung

P300 F J

Transaktivierung

Transaktivierung GRE

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WV

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H3

H3

H2A

H4

Nukleosom – Aufsicht – ohne DNA

H4

H2B

(a)

H3 --

H4

--

H4

H2B ---

+

+ --

+ -(b)

H3 H2A

--H2B

+

--

-+

--

--

--

– Seitenansicht – mit DNA-Faden

---

+

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H

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C

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CH2

H

CH2

Lysin

CH3

C

CH2

CH2

CH2

CH2

+ NH3

N

O

CH3

C

H

O

Acetylgruppe

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-regulativer TF (a)

HAT Ac

Ac

Ac

+

POL II aktivierender TF (b)

Ac

Ac

Ac

HDAC

-reprimierender TF (c)

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POL II

HSP 70

(a)

TFIIH P

P

P

P

POL II

regulative TF (b) Elongin ELL

TFIIF

TEF – b POL II

(c)

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UPS v5$16.5,37,21

XS

'(6 18./(2620$/(1 d/2&.6P f$=8 :,5' '(5 675(M,1'8=,(57( 5(*8/$7,9( vhN '$6 j,7=(O 6&+2&.3527(,1 81' (,1 p8./(2620O02'8/,(5(1'(5 g1=<0.203/(; %(1?7,*7 J6,(+( c%%P UPSX$KP j,(5 6&+(,17 6,&+ $/62 (,1 5(*8/$7,9(6 o20(17 '(5 v5$16.5,37,216,1,O 7,$7,21 :,('(5=871'(1P g,1 o(5.0$/ $1'(5(5 5(*8/$7,9(5 vhN ',( ,1 '(5 g/21*$7,216.21752//( (,1( t2//( 63,(/(1 J=P dP NN6$85(DD J$=,'(K v5$16$.7,9$725(1 :,( gTh 81' '$6 j(53(69,5863527(,1 xrSX 62:,( '$6 jkx vcvOr527(,1KN ,67 ',( c662=,,(581* ',(6(5 h$.725(1 0,7 (,1(5 evfOm,1$6( :,( =P dP vhkkj Jc%%P UPSX%KP x25 '(0 j,17(5*581' '(5 2%(1 %(5(,76 %(6&+5,(%(1(1 h81.7,21 '(5 evfOr+263+25+1/,&+ :,( vhkkjO 6&+(,1(1 6,( ',5(.7 0,7 '(5 i(1(6( 2'(5 r52*5(66,21 921 m5$1.+(,7(1 $662=,,(57 =8 6(,1P v5$1O 6.5,37,216$.7,9(6 g/21*,1 ,67 (,1 75,0(5(5 m203/(; $86 '(1 w17(5(,1+(,7(1 cN d 81' eP f$6 921 j,33(/On,1'$8 v802568335(66253527(,1 JxjnK $17$*21,6,(57 ',( h250$7,21 '(6 g/21*,1.203/(;(6P k67 xjn $%(5 ,1 v8025(1N :,( =P dP '(0 m/$5O =(//,*(1 p,(5(178025N 087,(57N .$11 (6 ',(6( h81.7,21 1,&+7 0(+5 $86)@+5(1P f,(6(5 d()81' ,03/,=,(57 (,1( 0?*/,&+( d('(8781* 921 xjn %(, '(5 t(*8/$7,21 '(5 v5$1O 6.5,37,216(/21*$7,21N 2%:2+/ :(,7(5(N 75$16.5,37,216)5(0'( h81.7,21(1 '(6 g/21O *,1OxjnOm203/(;(6 J,16%(621'(5( ,1 '(5 t(*8/$7,21 '(6 r527(,1$%%$86K 1,&+7 $86O *(6&+/266(1 :(5'(1 .?11(1P f$5@%(5 +,1$86 ,67 '$6 gnnOS i(1 $1 '(5 i(1(6(B r52*5(66,21 921 u8%)250(1 '(5 $.87(1 0<(/2,6&+(1 n(8.>0,( %(7(,/,*7N '(11 '(5 gnnSOi(1/2.86 .2117( $/6 d58&+381.7 (,1(5 v5$16/2.$7,21 J7JSS]S[KJ4TU]3SUPSKK ,'(17,7=,(57 :(5'(1P q%:2+/ $8&+ ,1 ',(6(1 h>//(1 ',( y,5.:(,6( '(5 (1767(+(1'(1 h86,2163527(,1( 1,&+7 %(.$117 ,67N *,%7 (6 620,7 %(5(,76 =:(, j,1:(,6( $8) (,1( 0?*O /,&+( x(5%,1'81* 921 g/21*$7,216)$.725(1 81' '(5 g1767(+81*Br52*5(66,21 921 v8O 025(1P k0 i(*(16$7= =8 r52.$5<217(1N %(, '(1(1 %(5(,76 9,(/( f(7$,/6 @%(5 ',( v(50,O 1$7,21 '(5 v5$16.5,37,21 %(.$117 6,1'N /,(*7 ',(6(5 x25*$1* %(, (8.$5<217(1 |(//(1 12&+ 6(+5 ,0 f81.(/1P u2 6,1' :('(5 &,6O$*,(5(1'( g/(0(17( 12&+ 75$16O$*,(5(1'( h$.725(1 '(5 v(50,1$7,21 '(71,7,9 ,'(17,7=,(57 :25'(1P f(0 ccvcccOu(48(1=O 027,9 ,0 UAOd(5(,&+ 921 i(1(1 62:,( '(5 J$%5837(1 f(3+263+25/7,*( o2',7=,(581* 921 v5$16.5,37,216)$.725(1 ,67N ',( (6 (,1(5 %(*5(1=7(1 |$+/ 921 r527(,1(1 (50?*/,&+7N v5$16.5,37,21 $8) 6&+,(5 81(1'/,&+ 9,(/(1 y(*(1 =8 5(*8/,(5(1P k1 '(5 x,(/)$/7 62/&+(5 t(*8/$7,2160?*/,&+.(,7(1 /,(*7 (,1( d$6,6 )@5 ',( g17:,&./81* 81' c8)5(&+7(5+$/781* +2&+.203/(;(5 q5*$1,60(1P

XT

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

RMQ qm` o2/:%33)%25.' c1)$1* '(5 XR(5 l$+5( :85'( *(=(,*7N '$M 0J(66(1*(5K tpc6 $/6 d27(168%67$1=(1 =:,6&+(1 i(1(1 ,0 |(//.(51 81' r527(,16<17+(6( ,0 e<723/$60$ )81*,(5(1P f$%(, 6,1' 0tpc6 .(,1( (;$.7(1 m23,(1 ,+5(5 i(1(N '$ ',( 35,0>5(1 v5$16.5,37,216O 352'8.7(N ',( 35>O0tpc6N 6,&+ ,1 0(+5(5(1 c63(.7(1 921 '(1 75$16/$7,2165(,)(1N &<723/$60$7,6&+(1 0tpc6 817(56&+(,'(1P g,1( 35>O0tpc 08M =81>&+67 $0 m23)O JWIK 81' u&+:$1=O JUIK O(1'( 62:,( ,1 '(5 o,77( 9(5>1'(57 :(5'(1N %(925 6,( $86 '(0 |(//.(51 ,16 e<723/$60$ 75$163257,(57 :,5'P f,(6( '5(, t(,)81*66&+5,77( +(,M(1 e$33,1*N r2/<$'(1O0tpc J'(0 m23)K (1=<0$7,6&+ (,1 &+(0,6&+ 02',7=,(57(6 p8./(27,' J(,1( m$33(K $8)*(6(7=7P f,( r2/<$'(11*7P d(,0 u3/(,M(1 :(5'(1 ',( 62*(1$117(1 k175216 $86 '(0 k11(5(1 '(5 35>O0tpc (;$.7 $86*(6&+1,77(1 81' ',( 9(5%/(,%(1'(1 g;216 0,7 ,+5(1 g1'(1 :,('(5 9(5.1@3)7P g%(162 :,( '$6 e$33,1*N ',( r2/<$'(1
DNA Primärtranskript

Terminationsstellen

Intron Transkription + Capping

Cap 5´

3´ Polyadenylierung

5´

A (100-250) 3'

Prä-mRNAReifung

RNA-Spleißen reife mRNA

5´ Cap-Struktur

A (100-250)

3´

Poly-A-Schwanz

c%%P UPSY t(,)81*66&+5,77( '(5 (8.$5<27,6&+(1 r5>O0tpcP f,(6( r52=(66,(581* 71'(7 ,0 |(//.(51 67$77N :2%(, (,1 %,2/2*,6&+ $.7,9(6N 5(,)(6 0tpcOo2/(.@/ (1767(+7N '$6 '$11 ,16 e<723/$60$ 75$163257,(57 :,5'P f$6 921 '(5 tpcOr2/<0(5$6( kk 6<17+(7,6,(57( r5,0>575$1O 6.5,37 (5675(&.7 6,&+ 921 '(5 WAOe$36758.785N ',( ,1 '(5 5(,)(1 tpc (17+$/7(1 %/(,%7N %,6 =8 (,1(0 921 0(+5(5(1 $/7(51$7,9(1 UAOp8&/(27,'(1N ',( 581' RNWAT .% 67520$%:>576 921 '(5 r2/<$'(1575$16.5,37 :,5' $1 '(5 r2/<$'(18*(7,(5(1 &$P TWRN %(, k16(.7(1 &$P SWR 81' %(, j()( &$P SRR cOt(67( /$1*P

UPT tpc r52=(66,(581*

XU

RMQMP b!00).' c85>//,*(5:(,6( %(*,117 ',( v5$16.5,37,21 (,1(6 i(16 ,1 0(+5 $/6 [W @ $//(5 h>//( 0,7 (,1(0 r85,1Op8./(27,' J0(,67(16 cKN '$6 921 r<5,0,',1(1 80*(%(1 ,67P f,( +>87*67( u(48(1= ,67 eOcOvN :2%(, c '$6 (567( ,1 '(5 35>O0tpc 925.200(1'( p8./(27,' ,67P f,(6(6 (567( tpcOp8./(27,' %(=(,&+1(7 0$1 $8&+ $/6 '(1 v5$16.5,3O 7,21667$57N '(5 $/6 t()(5(1=381.7 )@5 ',( p80(5,(581* '(5 p8./(27,'( (,1(6 i(16 ',(17P k0 2%,*(1 d(,63,(/ (17635>&+( '$6 e '(5 r26,7,21 OSN 81' v J%=:P wK :>5( 1TP d(,0 e$33,1* :,5' ,1 (,1(5 =:(,6787*(1 t($.7,21 '(0 1S p8./(27,' '(5 35>O 0tpc 12&+ :>+5(1' '(6 v5$16.5,37,216925*$1*6 (,1 ivr ,1 (,1(5 NN9(5'5(+7(1DD WIOWIOd,1'81* $1*()@*7P f$1$&+ :,5' ',(6(6 ivr '85&+ (,1( YOo(7+1',*7P g,1( 62/&+( e$3Ou758.785 (5)@//7 0(+5(5( c8)*$%(1P u,( 9(5%(66(57 ',( g5,=,(1= '(6 u3/(,M(16 '(5 35>O0tpc 81' 9(50,77(/7 ',( k17(5$.7,21 '(5 5(,)(1 0tpc 0,7 v5$163257(502/(.@/(1 )@5 '(1 18./(2O&<723/$60$7,6&+(1 g;3257P c8M(5'(0 (5+?+7 ',( e$3Ou758.785 ',( u7$%,/,7>7 5(,)(5 0tpc6 81' 63,(/7 %(, '(5 0tpc v5$16/$7,21 (,1( :,&+7,*( t2//(P f,( 0(',=,1,6&+( d('(8781* '(6 e$33,1* :,5' =P dP ,0 t$+0(1 '(5 r2/,29,586,1)(.7,21 %(621'(56 '(87/,&+\ f,( tpc '(6 r2/,29,586 %(1?7,*7 )@5 (,1( (5,=,(17( v5$16/$7,21 .(,1( 7<3,6&+( e$3Ou758.785P g,1( 9,5$/( r527($6( ,1$.O 7,9,(57 (,1(1 '(5 e$3O%,1'(1'(1 =(//8/>5(1 v5$16/$7,216)$.725(1 81' 352*5$00,(57 ',( y,576=(//( '$'85&+ '(5$57 80N '$M 6,( +$8376>&+/,&+ ',( 9,5$/( tpc $8) m267(1 '(5 (,*(1(1 0tpc 75$16/$7,(57P f,(6( u75$7(*,( (50?*/,&+7 (6 '(0 x,586N $8&+ 2+1( (,*(1( t,%2620(1 (,1( (5,=,(17( v5$16/$7,21 9,5$/(5 r527(,1( $8) m267(1 '(5 v5$16O /$7,21 =(//8/>5(5 r527(,1( =8 (5=,(/(1P

RMQMQ o/,9!$%.9,)%25.' g%(162 :,( '$6 WAOg1'( '(5 35>O0tpc 02',7=,(57 :,5'N (5+>/7 $8&+ '$6 UAOg1'( (,1 326775$16.5,37,21(//(6 c1+>1*6(/N '(1 r2/<JcKOu&+:$1=P c%*(6(+(1 921 (,1,*(1 j,6721O.2',(5(1'(1 81' '(1 0,72&+21'5,$/(1 0tpc6 817(5/,(*(1 $//( =(//8/>5(1 0tpc6 '(5 r2/<$'(15( r2/<JvKOt(*,21N 621'(51 (5 :,5' ,0 |(//.(51 921 (,1(0 @%(55$6&+(1' .203/(;(1 r52=(66,(581*6$33$5$7 $1*(+>1*7N '(5 $8&+ ',( r2/<JcKO r2/<0(5$6( (,16&+/,(M7 Jc%%P UPSZKP f,( t(,)81* '(6 UAOg1'(6 (,1(5 35>O0tpc 92//=,(+7 6,&+ 1$&+ d((1',*81* '(5 v5$16.5,37,21 '85&+ ',( tpcOr2/<0(5$6( kk ,1 =:(, J(;3(5,0(17(//K 921(,1$1'(5 75(11%$5(1 u&+5,77(1P |8(567 :,5' (,1 .85=(6 u7@&. '(6 UAOg1'(6 '85&+ ',( g1'25,O %218./($6($.7,9,7>7 (,1(6 o8/7,3527(,1.203/(;(6 $%*(6&+1,77(1P c16&+/,(M(1' :,5' 921 '(5 r2/<JcKOr2/<0(5$6( 817(5 o,7$5%(,7 (,1(6 =:(,7(1 o8/7,3527(,1.203/(;(6 ',(6(0 9(5.@5=7(1 UAOg1'( '(5 r2/<JcKOu&+:$1= $1*(+>1*7 Jc%%P UPSZKP f$)@5 6,1' 925 $//(0 =:(, u7(8(581*6O 81' g5.(1181*6(/(0(17( '(5 35>O0tpc 9(5$17:257/,&+N ',( ',( u&+1,7767(//( 9$1.,(5(1P c/6 (,1( 127:(1',*( m20321(17( )@5 %(,'( v(,/6&+5,7O 7( 67(+7 '$6 r2/<JcKOu,*1$/ )(67P f,( j(;$18./(27,'6(48(1= ccBwwccc %(71'(7 6,&+ (7:$ SRAUR p8./(27,'( WA 921 '(5 u&+1,7767(//( 81' '$0,7 '(0 d(*,11 '(6 r2/<JcKOu&+:$1=(6P o87$7,21(1 ,1 ',(6(5 +2&+.216(59,(57(1 g5.(1181*66(48(1= .?11(1 ',( c86%,/'81* (,1(6 .255(.7(1 UAOg1'(6 9(5+,1'(51 81' 620,7 =8 u7?581*(1

XV

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

5´

5´ 3´

nicht-transkribierter DNA-Strang Poly-ASignal

prä-mRNA

G/U-reiches Element

AAUAAA

G/U

POL II 5´

transkribierter DNA-Strang

Terminierungssignal CPSF 100 30 73 160

5´

3´

AAUAAA

prä-mRNA

50 77

82

PAP

CSTF

64 G/U

3´ CF I/CF II

endonucleolytischer Schnitt AAAAAAAA

AA

A

AA

PAB II

A

CPSF

AA AAAAAAA

A

3´

A

PAP

A

AA

AA

AAUAAA

5´

AA

AA

A AAAAAAAAAA

AA

A

10 – 30 Nukleotide 5´

AAUAAA

AAAAAAAAAn 3´ Poly-A-Schwanz

c%%P UPSZ c%/$8) '(5 r2/<$'(1O0tpcP f,( v(50,1,(581* '(5 v5$16.5,3O 7,21 81' ',( r2/<$'(1+(5 (5./>57P

'(5 i(1(;35(66,21 )@+5(1P g,1(6 921 =$+/5(,&+(1 d(,63,(/(1 '$)@5 %,(7(7 (,1( x$5,O $17( '(5 sOv+$/$66>0,(N %(, '(5 '$6 r2/<JcKOu,*1$/ '(6 sOi/2%,1 i(16 =8 ccvcci 087,(57 ,67 81' ,0 e<723/$60$ .(,1( 5(,)( sOi/2%,1 0tpc 925*()81'(1 :,5'P f$6 =:(,7( g/(0(17 ,67 :(1,*(5 67$5. .216(59,(57N iwO5(,&+N 81' (7:$ TRAVR p8./(27,'( UA 921 '(5 u&+1,7767(//( /2.$/,6,(57P f$6 |86$00(163,(/ %(,'(5 g/(0(17( %=:P '(5

UPT tpc r52=(66,(581*

XW

'$5$1 %,1'(1'(1 h$.725(1 (5/$8%(1 ',( /2.$/( f(71,7,21 '(5 u&+1,7767(//( 81' %(O (,19866(1 620,7 ',( u7>5.( '(6 r2/<JcKOu,*1$/6P }+1/,&+ '(5 e$3Ou758.785 ,67 $8&+ '(5 r2/<JcKOu&+:$1= )@5 0(+5(5( c63(.7( '(6 0tpc o(7$%2/,6086 921 d('(8781*P u2 :85'( (,1 326,7,9(5 g,198M $8) '(1 18./(2O&<723/$60$7,6&+(1 v5$163257 62:,( ',( u7$%,/,7>7 '(5 0tpc *(=(,*7P d(66(5 '(71,(57 ,67 ',( h81.7,21 '(6 r2/<JcKOu&+:$1=(6 )@5 ',( v5$16/$7,21 ,0 e<723/$60$P f257 67,08/,(5(1 ',( e$3Ou758.785 81' '(5 r2/<JcKOu&+:$1= 6<1(5*,67,6&+ ',( v5$16O /$7,216,1,7,$7,21P u2 ,67 (6 1,&+7 9(5:81'(5/,&+N '$M ',( t(*8/$7,21 '(5 n>1*( '(6 r2/<JcKOu&+:$1=(6 ,0 e<723/$60$ $/6 :,&+7,*(5 o(&+$1,6086 *(187=7 :,5'N 80 ',( v5$16/$7,216(5,=,(1= 921 0tpc6 =8 5(*8/,(5(1 J6,(+( m$3P UPVPTKP c1$/2* =80 u3/(,M(1 *,%7 (6 $8&+ %(, '(5 r2/<$'(1//(1 (;,67,(5(1 0(+5(5( ccvcccOu,*1$/( ,1 '(5 UIO t(*,21 '(6 %(75(5(1'(1 i(16P f,5(5(17,(//( p87=81* '(5 $/7(51$7,9(1 u,*1$/( .$11 =85 g;35(66,21 921 0tpcOo2/(.@/(1 0,7 817(56&+,('/,&+(1 r527(,1O.2',(5(1'(1 u(48(1=(1 )@+5(1P g,1 d(,63,(/ )@5 ',(6(1 v<3 3267O75$16.5,37,21$/(5 i(15(*8/$7,21 %,(7(1 ',( k0081*/2%8/,1( '(5 o m/$66(P x21 ',(6(1 k0081*/2%8/,1(1 (;,67,(5(1 (,1( =(//0(0%5$167>1',*( 81' (,1( 6(=(51,(57( h250N ',( 6,&+ $0 &$5%2;<7(50,1$/(1 g1'( '(6 r527(,16 817(56&+(,'(1 Jc%%P UPS[KP c8) >+1/,&+( y(,6( :(5'(1 $8&+ 920 e$/&,721,1*(1 ,1 '(5 u&+,/''5@6( 81' ,0 i(+,51 817(56&+,('/,&+( r527(,1( (;35,O 0,(57P c%*(6(+(1 921 '(5 3+<6,2/2*,6&+(1 d('(8781* '(6 r2/<JcKOu&+:$1=(6 (5?51(7 6(,1( g;,67(1= (,1( 35$.7,6&+( o?*/,&+.(,7 =85 t(,1,*81* 921 0tpc6N =P dP )@5 ',( m/21,(581* 921 &fpc Jm$3P VPXPSKP

Poly-A-Signal (schwach)

Poly-A-Signal (stark)

lgM-Gen

lgMs Exons

lgMm

lgMm

membranständige lgMm prä·mRNA

lgMs

lgMm

lgMm

lgMm mRNA

lgMs

sezernierte lgMs mRNA

lgMs

lgMm lgMm

AAAA

AAAA…

(CSTF limitierend)

AAAA

(CSTF nicht limitierend)

c%%P UPS[ c/7(51$7,9( m21752//( '(5 r2/<$'(11',*( Jk*o0K 81' 6(=(51,(57( Jk*o6K h250(1 '(6 r527(,16P f,( 0(0%5$167>1',*( h250 6&+/,(M7 T g;216 (,1N ',( '(1 k*o6 )(+/(1P y(11 =81>&+67 '(5 euvh J&/($9$*( 67,08/$7,1* )$&725N 6,(+( c%%P UPSZK /,0,7,(5(1' ,67N :,5' '$6 6&+:$&+(N WA *(/(*(1( r2/<JcK u,*1$/ @%(5*$1*(1P f,( k*o0 g;216 :(5'(1 '$11 '85&+ u3/(,M(1 (,1*(O 6&+/266(1P d(, +?+(5(1 m21=(175$7,21(1 921 euvh :,5' '$6 6&+:>&+(5( r2/<JcK u,*1$/ *(O 187=7N 81' (,1( k*o6 .2',(5(1'( 0tpc (5=(8*7P f,(6 ,67 (,1 *87(6 d(,63,(/ '$)@5 :,( x(5O >1'(581*(1 ,1 '(5 c.7,9,7>7 *(1(5(//(5 h$.725(1 =85 t(*8/$7,21 63(=,76&+(5 i(1( %(,75$*(1 .?11(1P

XX

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

RMQMR r0,%)J%. g,1 x(5*/(,&+ 5(,)(5 0tpc6 81' ,+5(5 =8*(+?5,*(1 i(1( =(,*7N '$M (,1 i(1 +>87* '85&+ u(48(1=(1 817(5%52&+(1 :,5'N ',( 6,&+ 1,&+7 ,1 '(5 5(,)(1 0tpc :,('(571'(1 Jc%%P UPSYKP f,( c%6&+1,77( (,1(6 i(16N ',( ,1 '(5 5(,)(1 0tpc 5(35>6(17,(57 6,1' +(,M(1 g;216N ',( '$=:,6&+(1 *(6&+2%(1(1 u(48(1=(1 %(=(,&+1(7 0$1 $/6 k175216P |8(567 :,5' ',( 35>O0tpc $/6 92//67>1',*( m23,( '(6 i(16 $/6 x25678)( 75$1O 6.5,%,(57] $16&+/,(M(1' (1767(+7 ',( 5(,)( 0tpc '85&+ j(5$866&+1(,'(1 '(5 k175216P f$ ',( 0tpc %(, '(5 r527(,16<17+(6( 75,3/(77:(,6( $%*(/(6(1 :,5' J6,(+( m$3P UPVPTKN 0@66(1 ',( k175216 (;$.7 (;=,',(57 81' %(1$&+%$57( g;216 0,7(,1$1'(5 9(5%81'(1 :(5'(1P NNk557@0(5DDN %(, '(1(1 (,1 g;21 (,1 p8./(27,' =8 .85= 2'(5 =8 /$1* *(5,(7(N :@5'(1 =8 (,1(5 x(56&+,(%81* '(6 n(6(5$67(56 )@+5(1P

RMQMRMP d802%33)/. !.$%2%2 qm`3 d(, '(5 )2/*(1'(1 $86)@+5/,&+(1 f,6.866,21 '(5 t(,)81*66&+5,77( 921 35>O0tpc6 62// 1,&+7 @%(56(+(1 :(5'(1N '$M )@5 '(1 .255(.7(1 c%/$8) '(5 i(1(;35(66,21 :(,7(5( h$0,/,(1 921 tpc o2/(.@/(1 81%(',1*7 %(1?7,*7 :(5'(1P f$=8 =>+/(1 ',( h$0,/,(1 '(5 7J5$16)(5Ktpc6N '(5 5J,%2620$/(1K tpc6N '(5 6J0$//K1J8&/($5K tpc6 62:,( '(5 6J0$//K1J8./(K2J/$5K tpc6P f,( d(7(,/,*81* (,1,*(5 61tpc6 $0 c8)%$8 '(6 )81.7,21(//(1 u3/(,M26206 :,5' *(1$8(5 %(6&+5,(%(1P c8M(5'(0 6,1' 61tpc6 81' 612tpc6 )@5 ',( r52=(66,(581* 81' t(,)81* '(5 5,%2620$/(1 tpc6 921 d('(8781*N ',( 6,&+ ,1 (,1(5 63(=,(//(1 t(*,21 '(6 |(//.(516 $%63,(/7N '(0 p8./(2/86P 5tpc6 %,/'(1 =86$00(1 0,7 '(1 5,%2620$/(1 r527(,1(1 '(1 v5$16/$7,216$33$5$7N ',( t,%2620(1P y,( ,0 m$3,7(/ UPVPT 12&+ $86)@+5/,&+ %(6&+5,(%(1 :(5'(1 :,5'N 63,(/(1 ',( 7tpc6 %(, '(0 v5$16O /$7,216925*$1* (%(1)$//6 (,1( =(175$/( t2//(P

RMQMRMQ l%2+-!,% 6/. d8/.3 5.$ h.42/.3 f,( 3527(,1O.2',(5(1'( k1)250$7,21 '(5 0(,67(1 i(1( ,67 $8) '(5 fpc 81' $8) '(0 r5,0>575$16.5,37 ',6.217,18,(5/,&+ $1*(25'1(7 81' ,0 $//*(0(,1(1 '85&+ 0(+O 5(5( k175216 817(5%52&+(1N '(5(1 |$+/ @%(5 YW 352 i(1 %(75$*(1 .$11P g6 *,%7 $//(5',1*6 $8&+ ,17521/26( i(1( J=P dP $/3+$O 81' %(7$Ok17(5)(521KP f,( n>1*( (,1O =(/1(5 k175216 9$5,,(57 =:,6&+(1 (,1(0 o,1,080 921 (7:$ WR %,6 =8 @%(5 SRN p8O ./(27,'(1 J=P dP c32/,323527(,1 dSRRN h$.725 xkkkN f<67523+,1N v,7,1KP k0 x(5*/(,&+ '$=8 0,M7 '$6 .@5=(67( %,6/$1* '(71,(57( g;21 Y p8./(27,'(N ',( />1*67(1 @%(5 YRRRP f,( />1*67(1 5(,)(1 0tpc o2/(.@/( 6,1' 0(+5 $/6 WR RRR p8./(27,'( /$1*P c86 ',(6(1 |$+/(1 :,5' '(87/,&+N '$M '(5 u3/(,MOc33$5$7N '$6 u3/(,M2620N 0$1&+0$/ *52M( f,67$1=(1 =:,6&+(1 =:(, %(1$&+%$57(1 g;216 @%(5:,1'(1 08MP k175216 0@66(1 0,7 +?&+67(5 r5>=,6,21 $86*(6&+1,77(1 :(5'(1P f,( 817(56&+,('O /,&+(1 n>1*(1 921 k175216 81' g;216 6&+/,(M(1 $%(5 (,1(1 6,03/(1 o(M0(&+$1,6O 086 $86P y,&+7,* )@5 '(1 o(&+$1,6086 '(6 u3/(,M(16 6,1' '$+(5 tpcOg5.(1181*6O 6(48(1=(1N ',( $0 WAOg;21Bk17521 %(5*$1* Ju3/(,M'2125KN $0 UAOg1'( '(6 k175216 Ju3/(,M$.=(3725KN ,11(5+$/% '(6 k175216 Jx(5=:(,*81*6381.7K 62:,( ,11(5+$/% '(6

UPT tpc r52=(66,(581*

XY

Intron 5' Exon 1

AG GUAAGU SpleißDonor

UACUAAC* Verzweigungspunkt

PynAG G Spleiß-Akzeptor mit Polypyrimidinstrang

GAAGAGA

3'

SpleißEnhancer

c%%P UPTR e+$5$.7(5,67,6&+( u(48(1=0(5.0$/( 921 k175216P f,( '$5*(67(//7(1 m216(16866(O 48(1=(1 ,11(5+$/% (,1(6 k175216 %=:P '(5 k17521Bg;21O%(5*>1*( 6,1' )@5 '(1 x25*$1* '(6 u3/(,M(16 921 d('(8781*P f$6 iwBci o27,9 :85'( :(*(1 6(,1(5 )$67 SRR@,*(1 m216(59,(581* )(77 *('58&.7P f,( $1'(5(1 u(48(1=027,9( 6,1' :(1,*(5 675(1* .216(59,(57P f$6 " +,17(5 '(5 u(48(1= '(6 x(5=:(,*81*6381.7(6 %('(87(7N '$M (6 6,&+ +,(5%(, 80 ',( ,1 u$&&+$520<&(6 &(5(9,6,$( *()81'(1( u(48(1= +$1'(/7P k175216 921 u>8*(5=(//(1 :(,6(1 (,1( 9(5:$1'7(N $%(5 :(1,*(5 675(1* .216(59,(57( u(48(1= $0 x(5=:(,*81*6381.7 $8)P

UAOg;216 Ju3/(,MOg1+$1&(5 2'(5 g;21Og1+$1&(5 *(1$117K /2.$/,6,(57 6,1' 81' $/6 u3/(,M6,*1$/( ',(1(1P c%%,/'81* UPTR 9(5$16&+$8/,&+7 ',(6( *(0(,16$0(1 o(5.0$/( 9(56&+,('(1(5 k175216P o87$7,21(1N ',( 62/&+( g5.(1181*66(48(1=(1 =(567?5(1 %=:P $1 )$/6&+(1 u7(//(1 .5(,(5(1 )@+5(1 =8 $%(55$17(0 u3/(,M(1P u2 ,67 (6 1,&+7 9(5:81'(5/,&+N '$M (7:$ SW @ $//(5 3$7+2/2*,6&+(1 o87$7,21(1 =8 u3/(,M'()(.7(1 '(5 %(7525(1(1 i(1( )@+O 5(1P d(, 9,(/(1 r$7,(17(1 0,7 r+(11'(581* 9(5+,1'(57 ',( .255(.7( g5.(1181* '(6 k17521O %(*,116 81' )2/*/,&+ ',( t(,)81* (,1(5 .255(.7 *(63/(,M7(1 0tpcP c%*(6(+(1 921 o87$7,21(1N ',( 3+<6,2/2*,6&+( u3/(,M6,*1$/( 3$7+2/2*,6&+ 9(5>1'(51N *,%7 (6 '$5O @%(5 +,1$86 d(,63,(/(N %(, '(1(1 '85&+ o87$7,21(1 1(8( u3/(,M6,*1$/( (1767(+(1P u2:2+/ %(,0 TSOj<'52;87*67(1 i581' )@5 '$6 $'5(12*(1,7$/( u<1'520K $/6 $8&+ %(, (,1,*(1 h250(1 '(5 tOv+$/$66>0,( )@+5(1 o87$7,21(1 ,1O 1(5+$/% 921 k175216 =85 3$7+2/2*,6&+(1 c.7,9,(581* 921 u3/(,M6,*1$/(1P f$'85&+ :,5' '$6 (,*(17/,&+( k17521 )$/6&+ 5(6(=,(57N 62 '$M ',( &<723/$60$7,6&+( 0tpc 1,&+7 0(+5 ,1 '$6 3+<6,2/2*,6&+( r527(,1 75$16/$7,(57 :(5'(1 .$11P d(, '(1 u3/(,MOg1+$1&(51 %=:P g;21Og1+$1&(51 +$1'(/7 (6 6,&+ 80 )$.8/7$7,9( u3/(,M6,*1$/(P y>+5(1' (;21,6&+( u3/(,MOg1+$1&(5 %(, k175216 0,7 ./$66,6&+(1 m21O 6(1686Ou3/(,M6,*1$/(1 .$80 (,1( t2//( 63,(/(1N .?11(1 6,( =85 c.7,9,(581* 5(/$7,9 6&+:$&+(5 ,17521,6&+(5 u3(,M$.=(37256(48(1=(1 (,1(6 WAO*(/(*(1(1 k175216 ',(1(1P f$6 *(6&+,(+7 925 $//(0 '$'85&+N '$M g;21Og1+$1&(5 63(=,(//( r527(,1( %,1'(1N ',( ',( c1%,1'81* '(6 u3/(,M$33$5$76 $1 '$6 k17521 )?5'(51 81' 67$%,/,6,(5(1 J6P 8PKP y(5'(1 62/&+( *(:?+1/,&+ 385,15(,&+(1 g;21Og1+$1&(5 '85&+ o87$7,21(1 ,1$.7,O 9,(57N .2007 (6 (%(1)$//6 =8 )(+/(5+$)7(0 u3/(,M(1P d(621'(56 ,17(5(66$17( d(,63,(/( 67(//(1 '$%(, x(5>1'(581*(1 '$5N %(, '(1(1 ',( o87$7,21 (,1(5 NNy2%%/(326,7,21DD J6,(+( m$3P UPVPTK ,1 (,1(0 3527(,1.2',(5(1'(1 g;21 1,&+7 =8 (,1(5 9(5>1'(57(1 c0,O 126>85(6(48(1= )@+57N 621'(51 =8 )(+/*(63/(,M7(1 0tpc6N ',( $8) 087,(57(1 g;21O g1+$1&(56(48(1=(1 %(58+(1P f$6 +(,M7N '$M (,1( g;21Og1+$1&(5087$7,21 3$7+2O /2*,6&+(1 y(57 +$7N 2%*/(,&+ ',( .2',(57( c0,126>85(6(48(1= 35,0>5 1,&+7 9(5>1'(57 ,67P f85&+ $%(55$17(6 u3/(,M(1 .2007 (6 /(7=7/,&+ '2&+ =8 (,1(5 (5+(%/,&+ 9(5>1'(57(1 u(48(1= '(6 5(,)(1 u3/(,M352'8.7(6P |8 62/&+(1 g;21Og1+$1&(5087$7,21(1 =>+/(1 8P $P x(5>1'(581*(1 '(5 r253+2%,/,12*(1'($0,1$6( 35>O0tpc %(, '(5 r253+<5,$

XZ

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

,17(50,77(16 2'(5 '(5 h80$5O0tpc %(, '(5 +(5(',7>5(1 v<526,1>0,( v<3 SP

RMQMRMR `5&"!5 $%3 r0,%)J/3/-3 m/$66,6&+( (1=<0$7,6&+( m$6.$'(1 :,( =P dP '(5 e,75$7=<./86 :(5'(1 921 r527(,1(1 .$7$/<6,(57P k0 i(*(16$7= '$=8 :,5' '(5 0(+56787*( r52=(M '(6 u3/(,M(16 921 tpcB r527(,1 m203/(;(1 $86*()@+57P y,( 6&+21 .85= (5:>+17N =>+/(1 ',(6( tpcBr527(,1 U1 snRNP

U2 snRNP

U2AF GUC CAUUCA I I I I I I I I I C A G GU A A G U Exon 1

5´

AUGAU I I I I I UACUA

IAI

G I C

Py

CAGG Exon 2

Verzweigungspunkt + U5, U4/U6

G A C 1 on Ex

UACUA C II A G AU UGA

Py

UACUA C II A G AU UGA

Py

CAGG Exon 2

CAG

CAG G Exon 1 Exon 2

Assemblierung des Spleißosoms

Schritt 1 = Ausbildung der Lassostruktur = 1. Transesterifizierung

Schritt 2 = Zusammenspleißen des Exons, Freisetzung des Lariats = 2. Transesterifizierung

c%%P UPTS c%/$8) '(6 u3/(,M(16 (,1(5 35>O0tpcP |81>&+67 :,5' (,1 wS 61tpr 81' wT 61tpr (,16&+/,(M(1'(5 u3/(,M2620.203/(; $1 '(5 35>O0tpc $66(0%/,(57N wS 61tpc 187=7 '$%(, .203/(0(17>5( d$6(13$$581* 0,7 '(5 .216(59,(57(1 u3/(,M'21255(*,21P wT 61tpc +<%5,',6,(57 $0 x(5=:(,*81*6381.7 81' 326,7,21,(57 (,1 NNcDD )@5 '(1 SP u&+5,77 '(6 u3/(,M(16P g,1( 3<5,0,',15(,&+( u(48(1= ,1 '(5 p>+( '(6 u3/(,M$.=(37256 :,5' 921 wTch JwT $8;,/,$5< )$&725K *(%81'(1N :$6 ',( wT 61tpr d,1'81* 67$%,/,6,(57P p$&+ t(.587,(581* '(6 62*(1$117(1 wVBwWBwX v5,O61tprN :,5' ,0 SP u3/(,M6&+5,77 ,1 (,1(5 v5$16(67(5,7=,(581*65($.7,21 '$6 WAO g1'( '(6 k175216 920 x(5=:(,*81*6381.7 817(5 c86%,/'81* (,1(5 n$6626758.785 $77$&.,(57P k0 TP u&+5,77 $77$&.,(57 '$6 )5(,( WAOg;21 ',( u3/(,M$.=(372567(/(N :$6 =85 35>=,6(1 n,*,(581* %(,'(5 g;216 81' '(5 h5(,6(7=81* '(6 k175216 ,1 h250 (,1(5 n$6626758.785 )@+57P

UPT tpc r52=(66,(581*

X[

m203/(;( =85 h$0,/,( '(5 61tpr6N '(5 60$// 18&/($5 5,%218&/(23527(,1 3$57,&/(6P f,(6( 61tpr6 %(67(+(1 $86 -(:(,/6 (,1(0 .85=(1 tpcOo2/(.@/ '(5 wOm/$66( J62 %(1$117 :(,/ ,+5( u(48(1=(1 6(+5 w5,',1O5(,&+ 6,1'K 81' 0(+5(5(1 18./(>5(1 r52O 7(,1(1P k16*(6$07 6,1' )@1) 9(56&+,('(1( 61tpr6 $1 '(5 +>87*67(1 h250 '(6 u3/(,M(16 %(7(,/,*7\ wSN wTN wVBwX 81' wW 61tpr6P k0 (567(1 u&+5,77 '(5 k17521(5.(1181* %,1'(7 '$6 wS 61tpr $1 '$6 WAOg1'( '(6 k175216 Jc%%P UPTSKP g6 187=7 ',( m20O 3/(0(17$5,7>7 '(5 wS tpc =85 WAOu3/(,M.216(1686Ot(*,21 '(5 35>O0tpc $86N ',( $8&+ '$6 .216(59,(57( NNiwDD '(6 k175216 0,7(,16&+/,(M7P f$*(*(1 :,5' '$6 UIOg1'( '(6 k175216 =8(567 921 (,1(0 r527(,1N wTchN *(%81'(1P c16&+/,(M(1' %,1'(7 '$6 wT 61tpr 81*()>+5 TRAXR p8./(27,'( 920 UAOg1'( '(6 k175216 (17)(517 $1 '(1 x(5=:(,*81*6381.7 ,1 '(5 p>+( '(6 62*(1$117(1 r2/<3<5,0,',1675$1*(6N *()2/*7 921 wVBwX 61tpr6 J%(,'( 6,1' '85&+ y$66(56725%5@&.(1 0,7(,1$1'(5 9(5%81'(1K 81' '(0 wW 61tprP p$&+'(0 '$6 u3/(,M2620 92//67>1',* =86$00(1*()@*7 ,67N :,5' '$6 k17521 ,1 =:(, u&+5,77(1 $86*(6&+1,77(1P |8(567 .2007 (6 ,1 (,1(5 &+(0,6&+(1 w0/$*(581*65($.7,21 Jv5$16(67(5,7=,(581*K =8 (,1(5 x(5.1@3)81* '(6 (567(1 p8./(27,'6 '(6 k175216 0,7 '(0 x(5=:(,*81*6381.7 817(5 c86%,/'81* (,1(5 n$6626758.785 Jn$5,$7KP f$%(, :,5' '$6 WAOg;21 $%*(75(117N $%(5 920 u3/(,M2620 '$5$1 *(+,1'(57 NN'$921=86&+:,00(1DD Ju&+5,77 SN c%%P UPTSKP c16&+/,(M(1' $77$&.,(57 '$6 g1'( ',(6(6 )5(,(1 WAOg;216 ',( u3/(,M$.=(372567(//(P k1 (,1(5 =:(,7(1 v5$16(67(5,7=,(581*65($.7,21 9(5%,1'(1 6,&+ ',( %(,'(1 g;216 35>O =,6( 0,7(,1$1'(5 81' 6(7=(1 '$6 *(6$07( NNk17521/$662DD )5(, Ju&+5,77 TN c%%P UPTSKP f$6 9(5%/(,%(1'( k17521 :,5' ,0 |(//.(51 $%*(%$87P c86 '(0 c%/$8) '(5 u3/(,MO 5($.7,21 :,5' (56,&+7/,&+N '$M ',( d(7(,/,*81* 921 tpcOo2/(.@/(1 $0 u3/(,M2620 6,1192// ,67N :(,/ '$'85&+ ',( m203/(0(17$5,7>7 =:,6&+(1 p8./(27,'6(48(1=(1 '(6 k175216 %=:P '(6 g;21OBk17521O %(5*$1*6 81' '(5 w tpc6 =85 *(1$8(1 g5.(1181* 63(=,76&+(5 g5.(1181*66,*1$/( $86*(187=7 :(5'(1 .$11P

RMQMRMS `,4%2.!4)6%3 5.$ 2%'5,)%24%3 r0,%)J%. c/7(51$7,9(6 u3/(,M(1 ,67 (,1 0(',=,1,6&+ :,&+7,*(6 d(,63,(/ )@5 ',( 9,(/)>/7,*( p87=81* '(6 k1)250$7,216*(+$/76 *(1(7,6&+(1 o$7(5,$/6P |$+//26( h>//( $/7(51$7,9(1 u3/(,M(16 0(16&+/,&+(5 35>O0tpc6 6,1' %(6&+5,(%(1P q)7 :,5' 921 (,1(0 i(1 (,1( '(71,(57( 35>O0tpc 75$16.5,%,(57N ',( ,+5(56(,76 ,1 925*(*(%(1(5 h250 352=(66,(57 81' 6&+/,(M/,&+ ,1 (,1 %(67,007(6 r527(,1 75$16/$7,(57 :,5' Jc%%P UPSKP f,(6(5 c%/$8) +$77( =8 '(5 62*(1$117(1 NNg,1 i(1 A (,1 r527(,1 j<327+(6(DD *()@+57P c/7(51$7,9(6 u3/(,O M(1 67(//7 -('2&+ (,1(1 '(5 i5@1'( '$5N :(6+$/% ',(6(5 j<327+(6( +(87( (+(5 +,O 6725,6&+(5 y(57 =8.2007P d(,0 $/7(51$7,9(1 u3/(,M(1 :,5' (,1( 35>O0tpc 0,7 0(+O 5(5(1 k175216 81' g;216 62 *(63/(,M7N '$M =:(, J2'(5 0(+5(5(K 817(56&+,('/,&+( 5(,)( 0tpcOu3(=,(6 '$5$86 (1767(+(1 Jc%%P UPTTKP f,( 9(56&+,('(1(1 0tpc6 .?11(1 6,&+ ,1 '(5 |$+/ ,+5(5 3527(,1O.2',(5(1'(1 g;216 2'(5 ,1 '(5 r26,7,21 '(6 v5$16/$O 7,21667$57 2'(5 O67236,*1$/6 817(56&+(,'(1P |8:(,/(1 &2O(;,67,(5(1 $/7(51$7,9 *(63/(,MO 7( 0tpc6 ,1 '(16(/%(1 |(//(1N 2)70$/6 71'(1 6,&+ $%(5 $8&+ *(:(%(63(=,76&+( 2'(5 ',5(5(1=,(581*6$%+>1*,*( $/7(51$7,9( u3/(,M0867(5P f,( g;,67(1= $/7(51$7,9(5 u3/(,M)250(1 (,1(5 %(67,007(1 0tpc %('(87(7 -('2&+ 1,&+7 =:$1*6/>87*N '$M '$6 u3/(,M(1 ',(6(5 0tpc $8&+ 5(*8/,(57 ,67P g,1 ,17(5(66$17(6 d(,63,(/ )@5 $/7(51$7,9(6

YR

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( mRNA I (1+2+3) Alternative 1

ungespleißte prä-mRNAs

Exon 1

Exon 2

Intron

Intron

Exon 3

Alternative 2 mRNA II (1+3)

c%%P UPTT c/7(51$7,9(6 u3/(,M(1P k1 '(5 o,77( ,67 ',( 81*(63/(,M7( 35>O0tpc '$5*(67(//7P f,( '$5@%(5 %=:P '$5817(5 $%*(%,/'(7(1 u3/(,M925*>1*( )@+5(1 =85 c86%,/'81* 921 =:(, 81O 7(56&+,('/,&+(1 0tpc6 Ji(*(1:$57 921 g;21 TKP

u3/(,M(1 %,(7(7 '$6 %&/O; i(1N 921 '(0 =:(, $/7(51$7,9 *(63/(,M7( 0tpc x$5,$17(1 ,1 817(56&+,('/,&+(1 |(//(1 *(%,/'(7 :(5'(1P g,1( u3/(,M9$5,$17(N ',( %&/O;/ 0tpcN .2',(57 )@5 (,1 />1*(5(6 r527(,1 '$6 (%(162 :,( '$6 9(5:$1'7( denOT $17,$32372O 7,6&+( y,5.81* +$7P k0 i(*(16$7= '$=8 $17$*21,6,(57 '$6 920 $/7(51$7,9(1 u3/(,MO 352'8.7 (1767$1'(1( .@5=(5( r527(,1 denOzu ',( $17,$323727,6&+( y,5.81* 921 denOTP y,( 0$1 (5:$57(1 :@5'(N (1767(+7 ',( %&/O;/ 0tpc 925 $//(0 ,1 /$1*/(%,*(1 32670,727,6&+(1 |(//(1 :,( '(1(1 '(6 i(+,516N :>+5(1' ',( %&/O;6 0tpc 925:,(O *(1' ,1 |(//(1 0,7 +2+(5 w06$7=5$7( :,( n<03+2=<7(1 (;35,0,(57 :,5'P f$6 u3/(,M(1 .$11 62:2+/ '85&+ 326,7,9( $/6 $8&+ '85&+ 1(*$7,9( u,*1$/( 5(*8/,(57 :(5'(1P r26,7,9( u3/(,M5(*8/$7,21N 'P +P ',( c.7,9,(581* (,1(6 $1 6,&+ 6&+:$&+(1 u3/(,M6,*1$/6N 71'(7 925 $//(0 '85&+ ',( c1%,1'81* u(5,1 JuKO 81' c5*,1,1 JtKO 5(,&+(5 c.7,9$7253527(,1( J62*(1$117( ut r527(,1(K $1 (;21,6&+( u3/(,M(1+$1&(5 67$77P g,1 d(,63,(/ '$)@5 %,(7(7 '$6 |(//2%(59>&+(1$'+>6,21602/(.@/ efVVP f,( efVV 35>O0tpc .$11 $8) 9,(/)>/7,*( y(,6( $/7(51$7,9 *(63/(,M7 :(5'(1P k17(5(6O 6$17(5:(,6( .255(/,(5(1 %(67,007( u3/(,M)250(1 0,7 '(5 g;35(66,21 %(67,007(5 ut r527(,1(N ',( 6,&+ :,('(580 *(+>8)7 ,1 %(67,007(1 v8025=(//(1N 1,&+7 $%(5 '(1 9(5:$1'7(1 1,&+7O0$/,*1(1 |(//(1 :,('(571'(1P j(7(52/2*( g;35(66,21 ',(6(5 u3/(,M9$5,$17(1 @%(5)@+57 1,&+7O0(7$67$6,(5(1'( |(//,1,(1 ,1 0(7$67$6,(5(1'( |(//(1P f,(6( (;3(5,0(17(//(1 d()81'( /(*(1 1$+(N '$M $/7(51$7,9(6 u3/(,M(1 81' ',( g;O 35(66,21 %(67,007(5 ut r527(,1( 352)81'(1 g,198M $8) '$6 0(7$67$7,6&+( r27(17,$/ (,1,*(5 v8025=(//(1 $86@%(1 .?11(1N 81' '$M 6,&+ ',( k17(5$.7,21 ',(6(5 ut r527(,1( 0,7 (;21,6&+(1 g1+$1&(51 '(5 efVV 0tpc *(*(%(1(1)$//6 $/6 1(8$57,*( c16$7=O 381.7( )@5 3+$50$.2/2*,6&+( k17(59(17,21 (,*1(1 .?117(1P p(*$7,9( u3/(,M5(*8/$7,21 :,5' '85&+ r527(,1( 9(50,77(/7N ',( ,1 '(5 p>+( '(5 u3/(,M'2125O 2'(5 c.=(37256,*1$/( %,1'(1 81' .203(7,7,9 '(1 |8*$1* (66(17,(//(5 u3/(,M)$.725(1 9(5+,1'(51P g,1 ,17(5(66$17(6 d(,63,(/ '$)@5 71'(7 6,&+ %(, '(5 h58&+7O 9,(*( f52623+,/$ 0(/$12*$67(5P j,(5 :,5' .(,1( *(5,1*(5( g176&+(,'81* $/6 NN0>11O /,&+ 2'(5 :(,%/,&+DD '85&+ $/7(51$7,9(6 u3/(,M(1 *()>//7 Jc%%P UPTUKP f$6 r527(,1 u(;O /(7+$/ JuznK :,5' 185 ,1 :(,%/,&+(1 g0%5<26 (;35,0,(57P g6 +$7 ',( c8)*$%(N '$6 u3/(,M(1 '(5 ,1 %(,'(1 i(6&+/(&+7(51 *(%,/'(7(1 75$ 35>O0tpc 62 =8 5(*8/,(5(1N '$M 185 ,1 :(,%/,&+(1 g0%5<26 vtc r527(,1 75$16/$7,(57 :(5'(1 .$11P d(, :(,%O /,&+(1 g0%5<26 %,1'(7 uzn ,1 '(5 p>+( '(5 u3/(,M$.=(372567(//( '(6 k175216 S 81' 817(5'5@&.7 ',( g5.(1181* ',(6(5 u3/(,M$.=(372567(//(P f$+(5 :,5' %(, :(,%/,&+(1

UPT tpc r52=(66,(581*

YS

SXL Protein Transformer prä-mRNA

1

2

3

]

1

3

^

1

2

]TRA-Protein 3

kein TRA-Protein

Stop-Codon Stop-Codon

c%%P UPTU t(*8/,(57(6N $/7(51$7,9(6 u3/(,M(1 ,1 '(5 6(;8(//(1 f,5(5(1=,(581* %(, f52623+,/$ 0(/$12*$67(5P f$6 v5$16)250(5 JvtcK r527(,1 %(67,007 ',( :(,%/,&+( g17:,&./81*P f,( 75$ 35>O0tpc :,5' $%(5 %(, %(,'(1 i(6&+/(&+7(51 75$16.5,%,(57P c866&+/$**(%(1' ,67 ',( g;O 35(66,21 (,1(6 tpcO%,1'(1'(1 5(*8/$725,6&+(1 r527(,16N 6(;O/(7+$/ JuznKN '$6 185 ,1 :(,%O /,&+(1 g0%5<21(1 6<17+(7,6,(57 :,5'P f$6 )@+57 '$=8N '$M (,1( 352;,0$/( u3/(,M$.=(372567(//( 817(5'5@&.7 :,5' 81' 67$77'(66(1 (,1( :(,7(5 UAO*(/(*(1( u7(//( *(187=7 :,5'P f,(6( .@5=(5( 0tpc .2',(57 )@5 '$6 vtc r527(,1P d(, 0>11/,&+(1 g0%5<26 :,5' (,1 ./(,1(5(6 k17521 5(6(=,(57N 62 '$M ,0 g;21 (,1 v5$16/$7,2166723&2'21 (,1*(6&+/266(1 :,5'P h2/*/,&+ .$11 .(,1 vtc r527(,1 *(%,/'(7 :(5'(1P

g0%5<26 '$6 g;21 S ',5(.7 $1 '$6 g;21 U *(63/(,M7P f$6 @%(563581*(1( g;21 T :,5' %(, 0>11/,&+(1 h/,(*(1(0%5<26 0,7(,1*(6&+/266(1P f$ (6 (,1 v5$16/$7,2166723O &2'21 (17+>/7N :,5' %(, ',(6(1 0>11/,&+(1 g0%5<26 ',( v5$16/$7,21 (,1(6 .203/(77(1 vtc r527(,16 J.2',(57 921 '(1 g;216 SN U 81' VK 9(5+,1'(57P v527= =$+/5(,&+(5 d(,63,(/( 5(*8/,(57(1 u3/(,M(16 %(, 0(16&+/,&+(1 i(1(1 6,1' ',( o(&+$1,60(1 %,6/$1* 12&+ 1,&+7 62 *87 9(567$1'(1 :,( =P dP %(, '(5 h58&+79,(*(P f,(6( d(,63,(/( 817(5675(,&+(1 (%(162 :,( =8 $%(55$17(0 u3/(,M(1 )@+5(1'( o87$7,21(1 %(, 0(16&+/,&+(1 g5%(5.5$1.81*(1 ',( .5,7,6&+( t2//( '(6 u3/(,M925O *$1*6 %(, '(5 i(1(;35(66,21P

RMQMRMT q)"/:9-% m/$66,6&+( g1=<0( Jd,2.$7$/<6$725(1K 6,1' r527(,1(P f,( g17'(&.81*N '$M (,1,*( 1$7@5/,&+ 925.200(1'( tpc6 (%(1)$//6 $/6 d,2.$7$/<6$725(1 )81*,(5(1 .?11(1 :$5 '$+(5 @%(55$6&+(1'P k1 c1/(+181* $1 ./$66,6&+( r527(,1(1=<0( :(5'(1 ',(6( .$O 7$/<7,6&+(1 tpc6 $/6 t,%2=<0( %(=(,&+1(7P t,%2=<0( +$%(1 ',( h>+,*.(,7N ',( t(O $.7,216*(6&+:,1',*/(,7 (,1(5 %,2&+(0,6&+(1 t($.7,21 (5+(%/,&+ =8 %(6&+/(81,*(1N 6(/%67 819(5>1'(57 $86 (,1(0 .$7$/<7,6&+(1 |<./86 +(5925=8*(+(1 81' '(6+$/% 0(+O 5(5( 62/&+(5 |<./(1 '85&+/$8)(1 =8 .?11(1P h(51(5 =(,&+1(1 6,( 6,&+ '85&+ +2+( u8%675$7O 81' r52'8.763(=,77>7 $86N 81' 67(//(1 +,16,&+7/,&+ ',(6(5 m5,7(5,(1 (&+7( tpcO}48,9$/(17( =8 r527(,1(1=<0(1 '$5P v+(25,(1 921 '(5 g1767(+81* '(6 n(%(16 $8) '(5 g5'( :85'(1 '85&+ ',( g17'(&.81* 921 t,%2=<0(1 1$&++$/7,* %((,198M7P o$1 */$8%7N '$M ',( %,2/2*,6&+( y(/7 925 '(5 g1767(+81* 921 |(//(1 (,1( NNtpcO y(/7DD *(:(6(1 6(,1 .?117(N ,1 '(5 62:2+/ ',( p8./(,16>85(O7<3,6&+( h81.7,21 '(5 k1)250$7,21663(,&+(581* $/6 $8&+ ',( m$7$/<6( 0(7$%2/,6&+(5 x25*>1*( 921 tpcO o2/(.@/(1 $86*()@+57 :25'(1 6(,P r+<6,2/2*,6&+ 925.200(1'( t,%2=<0( 9(5:(1'(1 tpc6 $/6 u8%675$7( )@5 u3$/O 781*65($.7,21(1 921 r+263+2',(67(5%,1'81*(1P f,( k17(5$.7,21 (,1(6 t,%2=<06 0,7

YT

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( Hammerhead Ribozym (allgemein)

I I I I

Hammerhead Ribozym (spezifisch)

5' A C C G U A I I I I I 3' U G G C A A A G C A G G A G

G A C U 3' I I I I C U G A 5' C U G A A G G U U C C G U

3' N N N C A A A G C A G G A G

N N N N 5' C U G A A G G U U C C G U

I I I I

Zielsequenz

c%%P UPTV u3(=,76&+(6 g,16&+1(,'(1 921 tpc u(48(1=(1 '85&+ NN+$00(5+($'DD t,%2=<0(P f,(6( t,%2=<0( %(67(+(1 $86 (,1(5 t(*,21N ',( 6,&+ 0,77(/6 d$6(13$$581* 63(=,76&+ $1 (,1( |,(/6(48(1= $1/$*(57 Lppp $8) '(5 5(&+7(1 u(,7( '(5 c%%PK 81' '(0 .$7$/<7,6&+(1 m(51N '(66(1 u(48(1= )81.7,21(// :,&+7,* ,67P f(5 r)(,/ $8) '(5 /,1.(1 u(,7( '(5 c%%P ,'(17,7=,(57 ',( u&+1,7767(//( '(6 NN+$00(5+($'DD t,%2=<06N '$6 6(,1(1 p$0(1 921 '(5 j$00(5.23)O >+1/,&+(1 u758.785 '(6 g1=<0Ou8%675$7.203/(;(6 $%/(,7(7P

6(,1(0 u8%675$7 71'(7 =81>&+67 '85&+ d$6(13$$581* 67$77N :$6 6(,1( +2+( u3(=,77>7 (5./>57P r+<6,2/2*,6&+ 9(50,77(/1 t,%2=<0( =P dP ',( t(,)81* 921 7tpc x25678)(1 J'85&+ ',( 62*(1$117( tp$6( rK 2'(5 .?11(1N >+1/,&+ '(0 u3/(,M2620N $8&+ '$6 c866&+1(,'(1 63(=,(//(5 k175216 J=P dP 921 '(5 TXu 5tpc %(, v(75$+<0(1$K .$7$O /<6,(5(1P p(%(1 ,+5(5 3+<6,2/2*,6&+(1 d('(8781* :(5'(1 t,%2=<0( ,1 '(5 o2/(O .8/$50(',=,1 $/6 0?*/,&+( v+(5$3(87,.$ ',6.87,(57N 925 $//(0 ',( 5(/$7,9 ./(,1(1 JURAWR p8./(27,'(K NNj$00(5.23)DD J+$00(5+($'K 81' NNj$$51$'(/DD J+$,53,1K t,O %2=<0(P f,( d(621'(5+(,7 ',(6(5 t,%2=<0( /,(*7 '$5,1N '$M 6,( 35,1=,3,(// *(*(1 -('( %(/,(%,*( tpc u(48(1= 0,7 +2+(5 u3(=,77>7 *(5,&+7(7 :(5'(1 .?11(1 Jc%%P UPTVKP f$6 +(,M7N '$M 0$1 *581'6>7=/,&+ 63(=,76&+( t,%2=<0( =85 |(567?581* 9,5$/(5 tpc6 Jjkx 81' $1'(5(KN 0tpc6 087,(57(5 q1.2*(1( J:,( '$6 detOcdn h86,2163527(,1 %(, '(5 r+,/$'(/3+,$ e+5202620O326,7,9(1 n(8.>0,(N 6,(+( XPVPTK 2'(5 '(6 oft J08/7, '58* 5(6,67$1&(K r527(,16 7+(5$3,(5(6,67(17(5 v8025(1 (,16(7O =(1 .?117(P f$=8 :>+/7 0$1 (,1( )@5 ',( |,(/Otpc 0?*/,&+67 63(=,76&+( u(48(1= 81' 6<17+(7,6,(57 (,1 +$00(5+($' t,%2=<0 0,7 '$=8 .203/(0(17>5(1 d,1'($50(1 Jc%%P UPTVKP

RMQMS -qm` d$)4)%25.' g,1( u21'(5)250 '(5 0tpc r52=(66,(581* 67(//7 ',( 0tpc g',7,(581* '$5P u,( %(75,57 925 $//(0 (,1( ./(,1( J$%(5 :,&+7,*(K i5833( 18./(>5(5 0tpc6 %(, u>8*(51 62:,( 9(56&+,('(1( 0,72&+21'5,$/( 0tpc6 %(, r5272=2(1 :,( v5<3$12620(1 81' n(,6+0$1,$N ',( ,1 '(5 r$5$6,72/2*,( (,1( :,&+7,*( t2//( 63,(/(1P d(, '(5 0tpc g',7,(581* :,5' ',( *(120,6&+ .2',(57( u(48(1= (,1(5 tpc 1$&+ ,+5(5 v5$16.5,37,21 (1=<0$7,6&+ 9(5>1'(57N 62 '$M ',( (',7,(57( tpc (,1 $1'(5(6 r527(,1 .2',(57 $/6 ',( 1,&+7(',7,(57( x25678)(P

UPT tpc r52=(66,(581*

YU

RMQMSMP -qm` d$)4)%25.' $52#( a!3%.5-7!.$,5.' e B w g',7,(581*\ f$6 0(16&+/,&+( c32/,323527(,1 dVZ :,5' 921 g17(52&<7(1 6(O =(51,(57 81' %,/'(7 (,1(1 d(67$1'7(,/ '(5 e++5(1' '$6 c32/,32O 3527(,1 dSRR ,1 '(5 n(%(5 *(%,/'(7 :,5' 81' =85 nfnOh5$.7,21 *(+?57P f,( pO v(50,1, %(,'(5 r527(,1( 6,1' 6(48(1=,'(17,6&+N '$6 ./(,1(5( c32/,323527(,1 dVZ (17O 635,&+7 VZ @ '(6 *5?M(5(1 Jc%%P UPTWKP f,( 0tpc6 %(,'(5 r527(,1( 6,1' 1$+(=8 6(48(1=,'(17,6&+N 817(56&+(,'(1 6,&+ -('2&+ ,0 p8./(27,' XXXXN '$6 %(, '(5 dSRR 0tpc (,1 e ,67 J(17635(&+(1' '(5 fpc u(48(1=KN %(, '(5 dVZ 0tpc -('2&+ (,1 wP f,(6(5 u(48(1=817(56&+,(' %(58+7 $8) '(5 (1=<0$7,6&+(1 f($0,1,(581* '(6 %(O 75(5(1'(1 e<726,16 =8 w5$&,/N ',( =85 w0:$1'/81* (,1(6 i/87$0,1Oe2'216 JeccK ,1 (,1 u723&2'21 JwccK )@+57P y,( (5.(117 '$6 '$)@5 9(5$17:257/,&+(N ,0 |(//.(51 /2.$/,6,(57( g1=<0 JcrqdgeOSK (;$.7 ',(6(6 p8./(27,' XXXX 81' 817(56&+(,'(7 (6 921 '(1 9,(/(1 $1'(5(1 e<726,1(1 ',(6(5 81' $1'(5(5 0tpc6a g176&+(,'(1' '$)@5 ,67 (,1( 63(=,76&+( u(48(1= 921 SS p8./(27,'(1N ',( 6,&+ ,1 810,77(/%$5(5 p>+( '(5 g',7,(581*667(//( %(71'(7 81' 921 crqdgeS (5.$117 :,5'P 6666 CAA

TAA

apo-bGen 5´

apo-bmRNA

3´

5´

Leber

keine Editierung

CAA

UAA

1

An

Exon 26 Editierung durch Darm APOBEC-1 CAA UAA 5´

4536

Proteine NH2

COOH APO-B100

1

UAA

An

2152

NH2

COOH APO-B48

c%%P UPTW g',7,(581* '(5 c32OdSRR 0tpc *(1(5,(57 (,1( 02',7=,(57( c32OdVZ 0tpc ,1 ,17(67,1$/(1 |(//(1P k1 '(5 n(%(5 :,5' '$6 c32OdSRR r527(,1 921 VWUX c0,126>85(1 n>1*( 6<17+(7,6,(57 J/,1.6KP k0 f$50 :,5' '$6 ecc v5,3/(77 J:$6 )@5 ',( TSWTPOc0,126>85( .2',(57 '85&+ g',7,(581* '(6 NNeDDOp8./(27,'6 XXXX ,1 (,1 NNwDD ,1 (,1 wcc u723&2'21 80*(:$1'(/7 J5(&+76KP f$)@5 ,67 '$6 g1=<0 crqdgeOS 9(5$17:257,&+P f$6 $8) VZ @ 6(,1(5 n>1*( 9(5.@5=7( c32OdVZ r527(,1 :,5' 620,7 (;35,0,(57P

f,( 3+<6,2/2*,6&+( d('(8781* ',(6(6 g',7,(581*60(&+$1,6086 :,5' $1 75$16*(1(1 o>86(1 '(87/,&+N ',( crqdgeOS ,1 '(5 n(%(5 @%(5(;35,0,(5(1 81' '$+(5 .(,1 c32O /,323527(,1 dSRR %,/'(1 .?11(1P f,(6( v,(5( /(,'(1 $1 (,1(5 h(77/(%(5 0,7 n(%(5O 7%526(P g,1 =:(,7(6 d(,63,(/ )@5 ',( e B w g',7,(581* 71'(7 6,&+ %(, '(5 1)S 0tpcN '(5(1 i(1352'8.7 %(, '(5 p(8527%520$726( 921 t(&./,1*+$86(1 087,(57 ,67P u(O 48(1=9(5*/(,&+( '(5 1)S 0tpc =:,6&+(1 v8025(1 81' 819(5>1'(57(0 i(:(%( )$1O '(1 (,1(1 (5+?+7(1 r52=(176$7= (',7,(57(5 tpc ,0 v8025*(:(%(P f,( h5$*( '(5 m$86$/,7>7 ,67 +,(5 12&+ 1,&+7 *(./>57P

YV

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

c B k g',7,(581*\ f,( g;35(66,21 9(56&+,('(1(5 w17(5(,1+(,7(1 '(6 i/87$0$75(O =(37256 Ji/8tKN (,1(6 :,&+7,*(1 t(/$,66&+$/7(56 %(, '(5 u,*1$/@%(575$*81* ,0 i(+,51N :,5' (%(1)$//6 '85&+ tpc g',7,(581* .21752//,(57P f,( fpc u(48(1= *,%7 ,1 (,1(5 )@5 ',( e$T1r(50($%,/,7>7 '(6 t(=(37256 .5,7,6&+(1 v5$160(0%5$1'20>1( (,1 i/87O $0,1 JeciK 925N '$6 -('2&+ %(, (,1,*(1 w17(5(,1+(,7(1 '85&+ (,1 c5*,1,1 (56(7=7 ,67P f,(6( c%:$1'/81* %(58+7 $8) '(5 f($0,1,(581* '(6 c'(126,1 ,1 (,1 k126,1 Jeci B ekiKN :$6 920 t,%2620 $/6 i JeiiK *(/(6(1 :,5'P f$6 )@5 ',(6(1 1(8O 52%,2/2*,6&+ :,&+7,*(1 x25*$1* 9(5$17:257/,&+( g1=<0 9(50,77(/7 ',( f($0,1,(581* 921 c'(126,1(1 ,1 '233(/675>1*,*(5 tpcP d(, '(0 (17635(&+(1'(1 g',7,(581*6O 925*$1* '(5 i/8tOd 0tpc ,67 '(5 .5,7,6&+( g',7,(581*6%(5(,&+ 0,7 (,1(5 k17521O 6(48(1= *(3$$57N 62 '$M ',( 35>O0tpc 925 '(0 u3/(,M(1 (',7,(57 :(5'(1 08MP y(,7(5(N :(1,*(5 *87 &+$5$.7(5,6,(57( d(,63,(/( 921 0tpc g',7,(581* 6,1' (,1( c0,1,(581* Jw B eK %(, '(5 y,/0678025 JyvK 0tpc 62:,( (,1 w B c g56$7= %(, '(5 sOi$/$&726,'$6( 0tpcP

RMQMSMQ -qm` d$)4)%25.' $52#( tLh.3%24)/.%. 5.$ c%,%4)/.%. "%) o2/4/:/%. g;75(0( d(,63,(/( 921 0tpc g',7,(581* :85'(1 %(, 9(56&+,('(1(1N 920 0,72O &+21'5,$/(1 i(120 .2',(57(1 0tpc6 %(, v5<3$12620(1 81' n(,6+0$1,$ (17'(&.7P j,(5 :(5'(1 =80 v(,/ +81'(57( 921 w6 ,1 ',( 1,&+7 (',7,(57( tpc $1 0(+5(5(1 u7(//(1 ,16(5,(57 2'(5 $86 ,+5 '(/(7,(57N 62 '$M 6,&+ ',( *(120,6&+( u(48(1= 81' ',( u(48(1= '(5 (',7,(57(1 0tpc %,6 =85 w1.(117/,&+.(,7 ,+5(5 ',5(.7(1 x(5:$1'6&+$)7 817(56&+(,'(1 .?11(1N 81' 62:2+/ '$6 v5$16/$7,21667$57&2'21 JcwiKN ',( v5$16O /$7,2166723&2'216 JwccN wicN wciK $/6 $8&+ ',( c0,126>85(6(48(1= (567 '85&+ g',7,(581* )(67*(/(*7 :(5'(1 Jc%%P UPTXKP g,1 >+1/,&+(5 x25*$1* ,67 %(, u>8*(5=(//(1 1,&+7 %(.$117P f$ ',(6( g',7,(581* %(,63,(/6:(,6( -('2&+ )@5 ',( g55(*(5 '(5 ,1 '(1 v523(1 :(,7 9(5%5(,7(7(1 u&+/$).5$1.+(,7 2'(5 '(5 e+$*$6 g5.5$1.81* 81%(',1*7 (5)25'(5/,&+ ,67N +257 0$1N 63(=,76&+( o(',.$0(17( *(*(1 '(1 g',7,(581*6$33$5$7 (17:,&.(/1 =8 .?11(1P f(5 g',7,(581*60(&+$1,6086 %$6,(57 $8) '(5 g;,67(1= ./(,1(5 tpc6 J&$P WRAYR p8./(27,'(KN ',( 6,&+ 0,7 (,1(5 .85=(1N .203/(0(17>5(1 u(48(1= $1 ',( 1,&+7 (',O 7,(57( 2'(5 7(,/(',7,(57( 0tpc $1/$*(51N 81' $16&+/,(M(1' &$P URAVR p8./(27,'( .203/(0(17>5 =85 *(:@16&+7(1 u(48(1= $8):(,6(1P f,(6( tpc6 ',(1(1 $/62 $/6 k1)250$7,216*(%(5 )@5 '(1 (1=<0$7,6&+(1 g',7,(581*6925*$1* 81' +(,M(1 NN*8,'( tpc6DDP f,(6( *8,'( tpc6 9(50,77(/1 =81>&+67 ',( (1'218./(2/<7,6&+( u3$/781* '(5 =8 (',7,(5(1'(1 tpcN 81' %(67,00(1 '$11 ',( *(1$8( |$+/ '(5 (,1=8)@*(1'(1 2'(5 '(5 =8 '(/(7,(5(1'(1 p8./(27,'( '85&+ (,1( w5,'*7 (,1(1 u&+:$1= $86 (,1,*(1 w6N '(66(1 d('(8781* 12&+ 1,&+7 *$1= $8)*(./>57 ,67P |85 92//67>1',*(1 g',7,(581* (,1(5 0tpc 6,1' 0(+5(5( *8,'( tpc6 127:(1',*N ',( *(0(,16$0 '(1 *(6$07(1 =8 (',7,(5(1'(1 d(5(,&+ $%'(&.(1P

UUGGAGUUAUAGAAUAAGAUCAAAU. . . 3´ 5´ . . . AAAGAGCAGGAAAGGUUAGGGGGAGGAGAGAAGAAAGGGAAAGUUGUGAUUUUGGAGUUAUAG I : I I I I I I I I I I guide G C C U C AAUAU C AUAUAGG 5´ 3´ UUUUUUUUUUUUAUUAAUAGUAUAGUGACAGUUUUAGACUAAGCAAU AAGCCUCAAUAUC RNA U-Schwanz Information Anker

c%%P UPTX tpc g',7,(581* %(, v5<3$12620$ %58&(,P f,( 1,&+7 (',7,(57( cvr$6( X 35>O0tpc ,67 2%(1 $%*(%,/'(7P f85&+ j<%5,',6,(581* '(5 c1.(56(48(1= (,1(5 NN*8,'( tpcDD :,5' k1O )250$7,21 =85 g',7,(581* ,1 h250 921 g,1)@*81*(1 Jm/(,1%8&+67$%(1 0,7 r)(,/.23)K 81' f(/(7,21(1 Ju7(51&+(1 0,7 r)(,/(1K 921 NNwDD6 %(5(,7*(67(//7P f,(6( g,1)@*81*(1 81' f(/(7,21(1 9(5>1'(51 ',( (',7,(57( J817(1K ,0 x(5*/(,&+ =85 1,&+7O(',7,(57(1 J2%(1K tpc *581'/(*(1'P

5´ . . . AAAGAGCAGGAAAGGUUAGGGGGAGGAGAGA u AG u u A u u A u A u u G u u G u u GAAA u u u G* *G u u UG u u A* *UUGGAGUUAUAG AAUAAGAUCAAAU. . . 3´ : : : : I : : I : l : I I I :l I I I : l I II : : : I I I :: I I I I : I I : I I : I I I I I : I I I I I I I I I I UUUUUUUUUUUUAUUAAUAGUAUAGUGA C AGUUUUAGA C UAAG C AAU AG C C U C AAUAU C AUAUAGG 5´

editierte mRNA

nicht editierte Prä-mRNA

UPT tpc r52=(66,(581* YW

YX

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

RMR m5+,%/L#94/0,!3-!4)3#(%2 s2!.30/24 f,( v5(1181* 921 |(//.(51 81' e<723/$60$ '85&+ (,1( m(51+@//( 5(35>6(17,(57 (,1(1 (176&+(,'(1'(1 w17(56&+,(' =:,6&+(1 d$.7(5,(1 81' (8.$5<217(1 |(//(1P f,(6( 5>80/,&+( v5(1181* 0$&+7 v5$163257925*>1*( (567$81/,&+(1 c860$M(6 ,1 %(,'( t,&+781*(1 (5)25'(5/,&+\ t(,)( tpc6 81' t,%2620(1 0@66(1 $86 '(0 |(//.(51 ,1 '$6 e<723/$60$ (;3257,(57 :(5'(1N 80 '257 )@5 ',( r527(,16<17+(6( =85 x(5)@*81* =8 67(+(1P k0 i(*(1=8* 0@66(1 $//( 18./(>5(1 r527(,1(N ',( -$ ,0 e<723/$60$ 75$16O /$7,(57 :(5'(1N ,1 '(1 |(//.(51 ,03257,(57 :(5'(1P g,1 t(Ok03257 18./(>5(5 m20O 321(17(1 ,67 (%(1)$//6 1$&+ '(5 |(//0,726( (5)25'(5/,&+N :>+5(1' '(5(5 ',( m(51O 0(0%5$1 $8)*(/?67 81' (567 1$&+ (5)2/*7(5 |(//7(,/81* :,('(5 $8)*(%$87 :,5'P p8./(2O&<723/$60$7,6&+(5 v5$163257 92//=,(+7 6,&+ '85&+ 63(=,(//( v5$163257.$O 1>/(N ',( 62*(1$117(1 m(51325(1P f,( 0(,67(1 u>8*(5=(//(1 9(5)@*(1 @%(5 (,1,*( 7$86(1' ',(6(5 ,0 x(5*/(,&+ =8 $1'(5(1 |(//%(67$1'7(,/(1 *(:$/7,*(1 u758.785(1 921 &$P SRR of$ J&$P TW 0$/ *5?M(5 $/6 t,%2620(1KP m(51325(1 6,1' 581'/,&+( u758.O 785(1N ',( $86 &$P WRASRR 817(56&+,('/,&+(1 g,1=(/%$867(,1(1 =86$00(1*(6(7=7 6,1' 81' ',( &$P SRRATRR 10 /$1*( f,67$1= '85&+ ',( m(51+@//( @%(5%5@&.(1 Jc%%P UPTYKP k1 (,1(5 u>8*(5=(//( 63,(/(1 6,&+ (7:$ S o,//,21 v5$163257925*>1*( 352 o,187( =:,O 6&+(1 m(51 81' e<723/$60$ $%N ',( 62:2+/ 68%675$763(=,76&+ $/6 $8&+ ,1 .255(.7(5 t,&+781* '85&+*()@+57 :(5'(1 0@66(1P g,1 x(5*/(,&+ 0,7 '(5 m203/(;,7>7 ,17(5O 1$7,21$/(5 h/8*+>)(1 '5>1*7 6,&+ $8)P f(5 v5$163257 ,67 (1(5*,($%+>1*,*P o2/(.@/( 0,7 (,1(0 ./(,1(5(1 f85&+0(66(5 $/6 &$P [ 10 J'$6 (17635,&+7 (,1(0 &$P XR .f$ *52M(1 */2%8/>5(1 r527(,1K .?11(1 35,1=,3,(// 3$66,9 ',581',(5(1N :(5'(1 -('2&+ ,1 '(1 0(,67(1 h>//(1 '(112&+ $.7,9 75$163257,(57P y,( :(5'(1 ',( =8 75$163257,(5(1'(1 u8%675$702/(.@/( (5.$117 81' :,( :,5' ',( .255(.7( t,&+781* ,+5(6 v5$1632576 *(:>+5/(,67(7a i581'6>7=/,&+ *,%7 (6 (,1( t(,+( 921 k03257O J,1 '(1 |(//.(51K 81' g;3257O J,1 '$6 e<723/$60$K u,*1$/(1P f,(6( v5$1632576,*1$/( 6,1' 7(,/:(,6( 5(&+7 .85=( c0,126>85(6(48(1=(1 921 u8%675$7352O 7(,1(1N ',( 921 c'$37(502/(.@/(1 (5.$117 81' *(%81'(1 :(5'(1 Jc%%P UPTZKP f(5 v5$163257 921 tpc6 (5)2/*7 (%(1)$//6 0,77(/6 d,1'81* 921 c'$37(53527(,1(1P f,(6( c'$37(53527(,1( ,17(5$*,(5(1 6(/%67 0,7 62*(1$117(1 k03257O %=:P g;32575(=(372O 5(1N ',( '$11 '(1 v5$163257 '(6 *(6$07(1 m203/(;(6 '85&+ ',( m(51325( 9(50,77(/1P

c%%P UPTY g/(.7521(10,.526.23,6&+( f$567(//81* 921 m(51325(1P f,( c%%,/'81* =(,*7 (,1( c16,&+7 $86 '(0 e<723/$60$ JcK 81' '(0 |(//.(51 JdKP f,( r+2726 :85'(1 )5(81'/,&+(5:(,6( =85 x(5)@*81* *(67(//7 921 f5P p(//< r$17(E Jd$6(/KP

UPU p8./(2O&<723/$60$7,6&+(5 v5$163257 RAN GTP

IMP · RAN GTP

IMP ‚ RAN GTP

IMP · NLSProtein

YY

NLSProtein

CAS

Exportrezeptor

IMP ‚

IMP ·

Exportsubstrat

RAN GTP

RAN GTP

IMP ‚

CAS

Nukleoplasma Cytoplasma Importrezeptor

IMP ‚

Importadapter

IMP ·

Importsubstrat mit Erkennungssignal

IMP · RAN GDP

IMP ‚ IMP · NLSProtein

RAN GDP

IMP · NLSProtein

c%%P UPTZ p8./(2O&<723/$60$7,6&+(5 v5$163257P k1 '(5 o,77( ,67 ',( m(51+@//( 0,7 ,+5(5 18O ./(>5(1 u(,7( J2%(1K 81' &<723/$60$7,6&+(5 u(,7( J817(1K '$5*(67(//7P g,1 )@5 '(1 k03257 %(O 67,007(6 u8%675$7 :,5' 0,77(/6 6(,1(5 g5.(1181*66(48(1= Jpnu 3 18./(>5( n2.$/,6,(581*6O 6(48(1=K 920 k03257$'$37(5 k03257,1 s Jkor sK (5.$117 81' *(%81'(1P f,(6(5 m203/(; :,5' $16&+/,(M(1' 920 k032575(=(3725 k03257,1 t Jkor tK *(%81'(1 81' '85&+ ',( m(51325( ,1 '(1 |(//.(51 ,03257,(57P f257 :,5' ',(6(5 m203/(; 921 t$1ivr *(%81'(1P f$6 k03257O 68%675$7 :,5' )5(,*(6(7=7N (%(162 '(5 k03257$'$37(5 kor sP f(5 kor tBt$1ivr m203/(; :,5' ',5(.7 :,('(5 ,1 '$6 e<723/$60$ (;3257,(57P f257 :,5' t$1ivr ,1 t$1ifr 80*(:$1O '(/7N 81' kor t )@5 (,1(1 :(,7(5(1 k03257=<./86 )5(,*(6(7=7P f$6 ,0 m(51 %(71'/,&+( kor s :,5' 6(/%67 =80 g;325768%675$7 81' 921 '(0 g;32575(=(3725 ecu *(%81'(1P f$)@5 ,67 (%(1)$//6 t$1ivr (5)25'(5/,&+ J2%(1 5(&+76KP p$&+ (5)2/*7(0 g;3257 ,16 e<723/$60$ :,5' :,('(580 t$1ivr ,1 t$1ifr 80*(:$1'(/7N 81' kor s )@5 '(1 1>&+67(1 k03257=<./86 )5(,*(6(7=7P

f,( o(&+$1,60(1N 0,77(/6 '(5(5 (,1 k032575(=(3725 0,7 6(,1(5 h5$&+7 ,1 ',( .25O 5(.7( .(51:>57,*( t,&+781* %=:P (,1 g;32575(=(3725.203/(; ,1 ',( (17*(*(1*(6(7=7( t,&+781* *(/(1.7 :(5'(1N 6,1' 12&+ 1,&+7 $8)*(./>57P f$*(*(1 :(,M 0$1N '$M '(5 $6<00(75,6&+(1 x(57(,/81* '(5 ivr %=:P ifrO%(/$'(1(1 h250 '(6 r527(,16 tcp *52M( d('(8781* )@5 ',( f,5(.7,21$/,7>7 '(6 v5$1632576 =8.2007\ tcp /,(*7 ,0 |(//.(51 925:,(*(1' $/6 tcpOivr 925 J:(,/ '$6 ivrO%(/$'(1'( g1=<0 18./(>5 ,67KN :>+5(1' (6 ,0 e<723/$60$ $/6 tcpOifr (;,67,(57 J:(,/ ',( u7,08/$7,21 '(5 ivrOj<'52/<6( '257 (5)2/*7KP f(0 18./(2O&<723/$60$7,6&+(1 v5$163257 .$11 $8&+ 5(*8/$725,6&+( d('(8781* =8.200(1P u2 :,5' %(,63,(/6:(,6( ',( n2.$/,6,(581* '(5 v5$16.5,37,216)$.725(1 ph|d 2'(5 gTh ,0 |(//.(51 '85&+ 5(*8/,(57(1 k03257

YZ

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

Jph|dK %=:P g;3257 JgThK *(67(8(57P k0 h2/*(1'(1 :(5'(1 '(5 k03257 81' g;3257 $1 d(,63,(/(1 (5/>87(57P

RMRMP m5+,%;2%2 h-0/24 m/$66,6&+( %$6,6&+( u,*1$/( )@5 '(1 18./(>5(1 k03257N :,( =P dP '(6 v5$16.5,37,216O )$.7256 ph|d 2'(5 '(6 21.2*(1(1 uxVR /$5*( v c17,*(16N :(5'(1 ,0 e<723/$60$ 921 '(0 c'$37(53527(,1 k03257,1 s *(%81'(1P k03257,1 s %,1'(7 '$11 @%(5 (,1( =:(,7( )81.7,21(//( f20$,1( $1 '(1 k032575(=(3725 k03257,1 tP f,(6(5 m203/(; :,5' 181 '85&+ ',( m(51325( ,1 '(1 |(//.(51 ,03257,(57N :2 tcpOivr $1 k03257,1 t %,1'(7 81' ',( f,662=,$7,21 '(6 m203/(;(6 81' '$0,7 '$6 g17/$'(1 '(5 ,0325O 7,(57(1 h5$&+7 $86/?67P f(5 k03257,1 tBtcpOivr m203/(; :,5' ',5(.7 5(O(;325O 7,(57] k03257,1 s %,1'(7 +,1*(*(1 $1 (,1(1 (,*(1(1 g;32575(=(3725 JecuK 81' *(/$1*7 $8) ',(6(0 y(*( ,16 e<723/$60$ =85@&. Jc%%P UPTZKP

RMRMQ d80/24 ).3 b94/0,!3-! q5(16,&+7/,&+( u8%675$7( )@5 '(1 g;3257 ,16 e<723/$60$ 6,1' $// ',( o2/(.@/(N ',( )@5 ',( v5$16/$7,21 %(1?7,*7 :(5'(1N 'P +P 5(,)( 0tpc6N 7tpc6 62:,( ',( ,0 p8O ./(2/86 =86$00(1*()@*7(1 t,%2620(1P f$5@%(5 +,1$86 *,%7 (6 $%(5 $8&+ 12&+ (,1( t(,+( 921 r527(,1(1N ',( 1$&+ ,+5(0 k03257 ,1 '(1 |(//.(51 :,('(5 5(O(;3257,(57 :(5'(1P f,(6( r527(,1( :(5'(1 $/6 NN6+877/,1* 3527(,16DD %(=(,&+1(7P f,( 9(56&+,('(O 1(1 m/$66(1 921 g;325768%675$7(1 9(5:(1'(1 =P vP 817(56&+,('/,&+( c'$3725(1 81' g;32575(=(3725(1P |8 (;3257,(5(1'( tpc6 %,1'(1 =80 v(,/ ',5(.7 $1 (,1(1 g;3257O 5(=(3725 J7tpc6KN 2'(5 6,( :(5'(1 921 c'$37(53527(,1(1 *(%81'(1P g,1 6(+5 ,1O 7(5(66$17(6 d(,63,(/ )@5 '(1 =:(,7(1 g;32577<3 ,67 ',( 81*(63/(,M7( jkx 0tpcN ',( (,1( 63(=,(//( d,1'81*667(//( JttgK )@5 '$6 9,5$/( c'$37(53527(,1 tgx $8):(,67 Jc%% UPT[KP tgx :,5' ,1 i(*(1:$57 921 tcpOivr .223(5$7,9 920 g;32575(=(3725 etoS *(%81'(1N 81' '(5 m203/(; :,5' (;3257,(57P k0 e<723/$60$ :,5' tcpOivr ,1 tcpOifr 80*(:$1'(/7N 81' '(5 m203/(; ',662=,,(57 817(5 h5(,6(7=81* '(6 NNg;O 3257*876DDP tgx 81' '(5 921 ',(6(0 r527(,1 9(50,77(/7( g;3257 81O %=:P 7(,/*(O 63/(,M7(5 jkx tpc ,67 )@5 '$6 x,586 921 (176&+(,'(1'(5 d('(8781*N '$ ',(6( tpc6 2+1( tgx %=:P 2+1( ,17$.7(6 ttg 1,&+7 (;3257,(57 :(5'(1 .?11(1 81' ',( 81*(O 63/(,M7( tpc =P dP %(, '(5 x(50(+581* '(6 x,586 ,0 e<723/$60$ ,1 ',( x,586+@//( 9(53$&.7 :(5'(1 08MP f,( )@5 '(1 g;3257 921 0tpc6 9(5$17:257/,&+(1 o2/(.@/( 6,1' 12&+ 1,&+7 *(1$8 ,'(17,7=,(57N :(11*/(,&+ (,1 18./(>5(5 e$3Od,1'(.203/(; 81' 9(56&+,('(1( +1tpr r527(,1( $0 g;3257 %(7(,/,*7 =8 6(,1 6&+(,1(1P h(67 67(+7 -('2&+N '$M 35>O0tpc6 :>+5(1' ,+5(6 t(,)81*6352=(66(6 =81>&+67 ,0 m(51 =8O 5@&.*(+$/7(1 :(5'(1N %(925 6,( (;3257,(5%$5 :(5'(1P d,6/$1* 6,1' 12&+ .(,1( g5.5$1.81*(1 %(6&+5,(%(1N ',( $8) u7?581*(1 '(6 18./(2O &<723/$60$7,6&+(1 v5$1632576 =85@&.=8)@+5(1 6,1'P g6 ,67 -('2&+ *87 '(1.%$5N '$M (,1 :(,7(5(6 x(567>1'1,6 '(5 =8 i581'( /,(*(1'(1 o(&+$1,60(1 ',( g17:,&./81* 7+(5$3(87,6&+(5 u75$7(*,(1 817(567@7=(1 :,5'N 925 $//(0 ,0 d(5(,&+ '(5 x,52/2*,(P y,( %(5(,76 (5:>+17N .$11 '(5 18./(2O&<723/$60$7,6&+( v5$163257 ,1 (,1,*(1 h>//(1

UPV e<723/$60$7,6&+( u&+5,77( '(5 i(1(;35(66,21

Y[

HIV RNA RRE REV CRM 1 RAN GTP

Nukleoplasma Cytoplasma CRM 1

HIV RNA RAN GDP REV

c%%P UPT[ v5$163257 81*(63/(,M7(5 jkx tpcP p,&+7 A 2'(5 1,&+7 92//67>1',* *(63/(,M7( A jkx tpc6 5(7,1,(5(1 (,1 ,17521,6&+(6 tpc g/(0(17N '$6 ttg JtgxO5(63216( (/(0(17KP f,(6(6 ttg :,5' 921 '(0 9,5$/(1 r527(,1 tgx *(%81'(1N '$6 $/6 c'$37(5 )81*,(57P k0 |(//.(51 %,1'(7 tcpOivrBetoS '(1 tgxBtpc m203/(; 81' (;3257,(57 ,+1 ,16 e<72O 3/$60$P f257 :,5' tcpOivr ,1 tcpOifr *(63$/7(1N '(5 g;3257.203/(; =(5)>//7N 81' ',( 9,5$/( tpc :,5' )5(,*(6(7=7P

$8&+ 3+<6,2/2*,6&+ 5(*8/,(57 :(5'(1P g567( o(&+$1,60(1 '$)@5 6,1' %(5(,76 %(.$117N %(, '(1(1 '85&+ r+263+251*,* 02'8/,(57 :,5'P

RMS b94/0,!3-!4)3#(% r#(2)44% $%2 f%.%802%33)/. RMSMP -qm` k/+!,)3)%25.' x,(/( |(//(1 =(,&+1(1 6,&+ '85&+ r2/$5,6,(581* %=:P c6<00(75,( $86N ',( )@5 ,+5( 817(56&+,('/,&+(1 3+<6,2/2*,6&+(1 h81.7,21(1 921 (176&+(,'(1'(5 d('(8781* 6,1'P d(,63,(/( '$)@5 6,1' p(59(1=(//(1N ',( (,1(1 |(//.?53(5N c;21( 81' f(1'5,7(1 $8)O :(,6(1N 2'(5 |(//(1 '(6 f$50O 81' p,(5(1(3,7+(/6N %(, '(1(1 ',( /80,1$/( J$3,.$/(K u(,7( $1'(5( c8)*$%(1 (5)@//7 $/6 ',( %$62/$7(5$/(P c8&+ (,1( %()58&+7(7( g,=(//( 08M ,1 '(5 h5@+(0%5<21$/(17:,&./81* ',( c86%,/'81* '2562O9(175$/(5 81' .5$1,2O &$8'$/(5 c;(1 9(5$1/$66(1P f,( '$)@5 (5)25'(5/,&+( $6<00(75,6&+( x(57(,/81* =(/O /8/>5(5 r527(,1( :,5' =80 v(,/ '85&+ r527(,16257,(581*6925*>1*( *(:>+5/(,67(7P g6 +$7 6,&+ -('2&+ ,1 /(7=7(5 |(,7 +(5$86*(67(//7N '$M $8&+ ',( )81.7,216%(=2*(1( n2O .$/,6,(581* 921 0tpc6 ,1 q2=<7(1N p(8521(1 81' g3,7+(/=(//(1 )@5 ',( c86%,/'81* 81' c8)5(&+7(5+$/781* '(5 |(//32/$5,6,(581* 9(5$17:257/,&+ ,67 Jc%%P UPURKP

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

Pr ot e in

7

mG

AU G

UA A

AA A

ZR

asymmetrische Zelle

„Transportschiene"

7mG

AUG

UAA

Adapterprotein AAA

Lokalisierungssignal Zellkern

c%%P UPUR 0tpc v5$163257 ,1 32/$5,6,(57(1 |(//(1P g,1( 32/$5,6,(57( Jp(59(1OK |(//( ,67 6&+(O 0$7,6&+ $%*(%,/'(7P k0 u20$ '(5 |(//( :,5' (,1( n2.$/,6,(581*66(48(1= ,0 UAOwvt 921 (,1(0 c'$37(53527(,1 *(%81'(1P f,(6(6 9(50,77(/7 '(1 *(5,&+7(7(1 v5$163257 '(6 0tpcBr527(,1O .203/(;(6 ,1 (,1( '(=(175$/( |(//5(*,21 J=P dP f(1'5,7(1K (17/$1* (,1(5 &<726.(/(77>5(1 NNv5$16O 32576&+,(1(DDP g567 $0 |,(/257 :,5' ',( 0tpc 75$16/$7,(57N 62 '$M $8&+ 185 '257 '$6 (17O 635(&+(1'( r527(,1 (1767(+7P f,(6(5 o(&+$1,6086 .$11 =85 $6<00(75,6&+(1 x(57(,/81* 921 r527(,1(1 81' 620,7 =85 c86%,/'81* ,175$=(//8/>5(5 r527(,1*5$',(17(1 )@+5(1P

y(/&+( x257(,/( %,(7(7 ',( 0tpc n2.$/,6,(581*a |80 (,1(1 ,67 (6 *87 92567(//%$5N '$M ',( n2.$/,6,(581* (,1(5 0tpc :(1,*(5 $8):(1',* ,67 $/6 '(5 v5$163257 9,(/(5 J921 ',(6(5 0tpc 75$16/$7,(57(5K r527(,1(P |80 $1'(5(1 %,(7(7 6,&+ ',( o?*/,&+.(,7N ',( u<17+(6( 921 r527(,1(1 /2.$/ =8 67(8(51\ g,1( 0tpc :,5' /2.$/,6,(57 81' (567 '$11 75$16/$7,(57N :(11 (,1 /2.$/(6 u,*1$/ '$=8 '(1 d()(+/ *,%7P d(,63,(/( '$)@5 6,1' :,('(580 $86 '(5 g0%5<2/2*,(N $%(5 $8&+ $86 '(5 p(8523+<6,2/2*,( %(.$117\ j,(5 1,007 0$1 ,1=:,6&+(1 $1N '$M ,0 (1*(1 p(7=:(5. 6<1$37,6&+(5 x(56&+$/781*(1 ',( c.7,9,(581* 63(=,76&+(5 u<1$36(1 ',( v5$16/$7,21 $1 ',(6(5 u<1$36( /2.$/,6,(57(5 0tpc6 $.7,9,(57P f,( )@5 ',( 0tpc n2.$/,6,(581* 9(5$17:257/,&+(1 o(&+$1,60(1 6,1' 12&+ 6(+5 8192//67>1',* $8)*(./>57P i(6,&+(57 ,67 -('2&+N '$M ',( n2.$/,6$7,216O 6,*1$/( JNNr267/(,7=$+/(1DDK 6,&+ $0 UAOg1'( '(5 (17635(&+(1'(1 0tpc6 %(71'(1P

UPV e<723/$60$7,6&+( u&+5,77( '(5 i(1(;35(66,21

ZS

}+1/,&+ :,( %(,0 m(51(;3257 *(+7 0$1 '$921 $86N '$M 63(=,(//( c'$37(53527(,1( ',( tpc6 $1 v5$1632579(+,.(/ .233(/1N :2%(, (6 (567( j,1:(,6( '$5$8) *,%7N '$M ',( &<726.(/(77>5(1 o,.5278%8/, $/6 v5$1632576&+,(1(1 )81*,(5(1 .?117(1P f$ (6 ,1 '(5 g17:,&./81*6%,2/2*,( (5:,(6(1 ,67N '$M 0tpc n2.$/,6$7,21667?581*(1 =8 6&+:(567(1 (0%5<21$/(1 h(+/%,/'81*(1 )@+5(1N '$5) 0$1 *(63$117 '$5$8) 6(,1N ,1O :,(:(,7 *(67?57( 0tpc n2.$/,6,(581* %(,63,(/6:(,6( )@5 h(+/%,/'81*66<1'520( 2'(5 1(852/2*,6&+( u7?581*(1 '(6 o(16&+(1 0,79(5$17:257/,&+ ,67P

RMSMQ -qm` s2!.3,!4)/. f,( v5$16/$7,21 ,67 '(5 |,(/381.7 '(6 y(*(6 920 i(1 =80 r527(,1P f$5@%(5 +,1$86 ,67 6,( '(5 .203/(;(67( x25*$1* $8) ',(6(0 y(*N :(,/ %,2/2*,6&+( k1)250$7,21 (;$.7 =:,6&+(1 =:(, 9(56&+,('(1(1 m/$66(1 921 d,232/<0(5(1 J921 p8./(,16>85(1 =8 r52O 7(,1(1K :(,7(5*(*(%(1 :(5'(1 08MP d(, '(5 v5$16/$7,21 (5)2/*7 ',( w06(7=81* 921 k1)250$7,21 J0tpcK ,1 h81.7,21 Jr527(,1K '85&+ c1:(1'81* '(6 *(1(7,6&+(1 e2O '(6P

RMSMQMP c%2 '%.%4)3#(% b/$% p$&+'(0 (7$%/,(57 :25'(1 :$5N '$M 0tpc6 $/6 o$75,=(1 =85 r527(,16<17+(6( ',(O 1(1N 67(//7( 6,&+ ',( h5$*(N :,( (,1 $86 9,(5 u<0%2/(1 %(67(+(1'(5 e2'( JcN wN eN iK ,1 TR %=:P TS 9(56&+,('(1( c0,126>85(1 (176&+/@66(/7 :(5'(1 .?11(P y>5( -('(0 p8./(27,' *(1$8 (,1( c0,126>85( =8*(25'1(7N %?7( '(5 *(1(7,6&+( e2'( 185 r/$7= )@5 9,(5 c0,126>85(1N %(, |825'181* 921 =:(, p8./(27,'(1 =8 (,1(5 c0,126>85( )>1'(1 SX 9(56&+,('(1( c0,126>85(1 ,0 *(1(7,6&+(1 e2'( r/$7=P g567 %(, '5(, p8O ./(27,'(1 352 c0,126>85( *(+7 ',( t(&+181* $8)\ k16*(6$07 *,%7 (6 VU 3 XV 9(5O 6&+,('(1( d$6(175,3/(776N 62 '$M $//(1 c0,126>85(1 0,1'(67(16 (,1 e2'21 $86 '5(, p8./(27,'(1 =8*(25'1(7 :(5'(1 .$11P o(+5(5( e+$5$.7(5,67,.$ '(6 ,1 v$%(//( UPV *(=(,*7(1 *(1(7,6&+(1 e2'(6 6,1' %(O $&+7(16:(57P g6 )>//7 $8)N '$M (6 )@5 ',( c0,126>85(1 u(5,1N n(8&,1 81' c5*,1,1 -(:(,/6 6(&+6 9(56&+,('(1( e2'216 *,%7N )@5 v5<3723+$1 81' o(7+,21,1 '$*(*(1 185 -(:(,/6 (,1(6P f,( v5,3/(776 wciN wcc 81' wic .2',(5(1 ,0 $//*(0(,1(1 .(,1( c0,126>85( 621'(51 67(//(1 v5$16/$7,21667236,*1$/( '$5P g,1( c861$+0( 67(//7 ',( u<17+(6( 921 u(/(123527(,1(1 :,( '(1 i/87$7+,213(52;,'$6(1 2'(5 '(5 ,0 u&+,/'O '5@6(16725:(&+6(/ :,&+7,*(1 f(,2'$6( '$5\ k1 *(1$8 '(71,(57(1 h>//(1 ',(17 (,1 wic v5,3/(77 1,&+7 $/6 u723&2'21N 621'(51 .2',(57 )@5 u(/(12&<67(,1P f257 :2 0(+O 5(5( v5,3/(776 )@5 (,1( c0,126>85( 67(+(1 .?11(1N ,67 ',( '5,77( r26,7,21 9$5,,(57P f,(6( x$5,$7,21 :,5' $8&+ $/6 NN:2%%/(DD %(=(,&+1(7P h2/*/,&+ ,67 ,0 *(1(7,6&+(1 e2'( -(:(,/6 '5(, t,%218./(27,'(1 J(,1(0 v5,3/(77K *(1$8 (,1( c0,126>85( =8*(25'1(7 J0,7 c861$+0( '(5 u723&2'216KN $1'(5(56(,76 $%(5 .$11 (,1( c0,126>85( 921 9(56&+,('(1(1 v5,3/(776 .2',(57 :(5'(1 J:2%%/(KP f(5 *(1(7,6&+( e2'( ,67 $/62 185 %(',1*7 80.(+5%$5 81' :,5' $8&+ $/6 '(*(1(5,(57 %(=(,&+1(7P

ZT

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

v$%P UPV f(5 *(1(7,6&+( e2'(P l(:(,/6 '5(, p8./(27,'( J(,1 v5,3/(77K &2',(5(1 )@5 (,1( c0,12O 6>85(P f$6 (567( p8./(27,' :,5' ,1 '(5 /,1.(1 u3$/7(N '$6 =:(,7( ,1 '(5 0,77/(5(1 |(,/(N 81' '$6 '5,77( ,1 '(5 5(&+7(1 u3$/7( $%*(/(6(1P u2 67(+7 NNecwDD %(,63,(/6:(,6( )@5 ',( c0,126>85( j,67,',1 Jj,6N jKP f,( c0,126>85(1 6,1' ,1 '(1 *(/>87*(1 f5(,O 81' g,1Od8&+67$%(1$%.@5O =81*(1 $1*(*(%(1P wccN wci 81' wic 6,1' u723&2'216N %(, %(621'(5(1 0tpc6 .$11 wic $8&+ )@5 ',( c0,126>85( u(/(12&<67(,1 &2',(5(1P SP d$6(

TP d$6(

UP d$6(

w

e

c

i

w

r+( JhK r+( JhK n(8 JnK n(8 JnK

u(5 u(5 u(5 u(5

JuK JuK JuK JuK u723

v<5 J{K v<5 J{K u723 v53 JyK

e<6 JeK e<6 JeK u723Bu(e<6 i

w e c

e

n(8 n(8 n(8 n(8

r52 r52 r52 r52

JrK JrK JrK JrK

j,6 JjK j,6 JjK i/1 JsK i,1 JsK

c5* c5* c5* c5*

JtK JtK JtK JtK

w e c i

c

k/( JkK k/( JkK k/( JkK o(7 JoK

v+5 v+5 v+5 v+5

JvK JvK JvK JvK

c61 JpK c61 JpK n<6 JmK n<6 JmK

u(5 JuK u(5 JuK c5* JtK c5* JtK

w e c i

i

x$/ x$/ x$/ x$/

c/$ c/$ c/$ c/$

JcK JcK JcK JcK

c63 JfK c63 JfK i/8 JgK i/8 JgK

i/< i/< i/< i/<

w e c i

JnK JnK JnK JnK

JxK JxK JxK JxK

JiK JiK JiK JiK

RMSMQMQ 4qm`3 $)%.%. !,3 `$!04%2-/,%+=,% f,( m(1171,6 '(6 *(1(7,6&+(1 e2'(6 :,5)7 ',( h5$*( $8)N :,( ',( |(//( (,1 d$6(1O 75,3/(77 $%=8/(6(1 9(50$* 81' '$11 ',( (17635(&+(1'( c0,126>85( ,1 (,1( :$&+6(1'( r2/<3(37,'.(77( (,1%$87P f$=8 :(5'(1 c'$37(502/(.@/( %(1?7,*7N ',( (,1 v5,3/(77 $%/(6(1 .?11(1 81' ',( =8*(+?5,*( c0,126>85( 75$*(1P g%(162 :,( ',( .203/(0(17>5( d$6(13$$581* ',( i581'/$*( )@5 (,1( $..85$7( fpcOt(3/,.$7,21 81' ',( tpcOv5$16.5,37,21 ,67N :,5' ',( +2+( u3(=,77>7 ',(6(5 k17(5$.7,21(1 $8&+ )@5 ',( c%/(681* '(6 *(1(7,6&+(1 e2'(6 $86*(187=7P f$=8 ',(1(1 ./(,1(N YWAZR p8./(27,'( /$1*( tpcOo2/(.@/(N ',( 75$16)(5 tpc6 2'(5 7tpc6 *(1$117 :(5'(1P f(1 c8)%$8 (,1(5 7tpc =(,*7 ',( c%%,/'81* UPUSP f(5 62*(1$117( c17,&2'21$50 '(5 7tpc /,(67 ',( 0tpc $% 81' 3$$57 6,&+ 0,7 '(0 =8*(+?5,*(1 0tpcOe2'21P f(5 c0,12$&*7 ,1 .29$/(17(5 d,1'81* ',( =80 e2'21Bc17,&2'21 *(+?5,*( c0,126>85(P |(//(1 9(5)@*(1 @%(5 0(+5 $/6 TS 9(56&+,('(1( 7tpc6N :(,/ (6 )@5 9,(/( c0,126>85(1 0(+5 $/6 (,1 .2O ',(5(1'(6 d$6(175,3/(77 *,%7P c1'(5(56(,76 08M 1,&+7 )@5 -('(6 '(5 XS %=:P XT $0,12O

UPV e<723/$60$7,6&+( u&+5,77( '(5 i(1(;35(66,21

G C G C m2 G

U U

Anticodon-Schleife

3´ (a)

G C

C C G 3

2 1

mRNA

5´

Akzeptor-Arm 5´ Ende

56 72

3´ Ende

7

20

12 44 26

ml Anticodon

1 2 3

64

38 32

Codon

Anticodon-Arm

A

mG U G C G

54

Anticodon

C G G

G A

A C 3´ Aminosäure C 5´ A Akzeptor-Arm G C G C G U C G G C U U U G C U UA A G G C C G U C C G G C C G C A U A G D G C G C G C G

ZU

(b)

c%%P UPUS u78.785 (,1(5 7tpcP f,( /,1.( c%%P J$K =(,*7 ',( 7<3,6&+( ./((%/$77>+1/,&+( u(O .81'>56758.785 921 7tpc6P f,( c0,126>85(%(/$'81* '85&+ 7tpc u<17+(7$6(1 (5)2/*7 $0 UA g1'( '(6 62*(1$117(1 c.=(3725$506P c0 *(*(1@%(5/,(*(1'(1 g1'( J817(1K %(71'(7 6,&+ ',( c17,&2'216(48(1=N ',( '$6 (17635(&+(1'( e2'21 '(5 0tpc 0,77(/6 d$6(13$$581* (5O .(117P f,( 5(&+7( c%%P J%K 67(//7 ',( .255(6321',(5(1'( nO)?50,*( v(57,>56758.785 '(56(/%(1 7tpc '$5P

6>85(.2',(5(1'(1 v5,3/(776 (,1( (,*(1( 7tpc (;,67,(5(1N :(,/ )@5 ',( j<%5,',6,(581* 921 e2'21 81' c17,&2'21 (,1( *(:,66( x$5,$%,/,7>7 %(=@*/,&+ '(6 '5,77(1 p8./(27,'6 %(67(+(1 '$5) J',(6 ,67 (,1 i581' )@5 '(1 :2%%/(KP h@5 -('( 7tpc *,%7 (6 (,1 =8O *(+?5,*(6 g1=<0N '$6 ',( 7tpc 0,7 '(5 .255(.7(1 c0,126>85( %(/>'7P

RMSMQMR q/,,% $%2 q)"/3/-%. "%) $%2 s2!.3,!4)/. t,%2620(1 25*$1,6,(5(1 81' .$7$/<6,(5(1 ',( v5$16/$7,21 921 0tpc6 ,1 r527(,1(P g8.$5<217( t,%2620(1 %(67(+(1 $86 9,(5 9(56&+,('(1(1 5,%2620$/(1 tpcOo2/(O .@/(1 J5tpc6K 81' @%(5 WR 5,%2620$/(1 r527(,1(1P u,( 6,1' 620,7N >+1/,&+ :,( ',( u3/(,M2620(1N $8&+ t,%218./(23527(,1Or$57,.(/ Jtpr6KP f,( t,%2620(1 %,(7(1 '$6 0(&+$1,6&+( 81' .$7$/<7,6&+( i(5@67N ,1 '(0 ',( c%/(681* '(5 0tpc 81' ',( u<17+(6( '(6 =8*(+?5,*(1 r2/<3(37,'6 '85&+ u&+$581* 921 r(37,'%,1'81*(1 92//O =2*(1 :,5'P f$6 (8.$5<217( t,%2620 %(67(+7 $86 =:(, w17(5(,1+(,7(1N '(5 VRu 81' '(5 XRu w17(5(,1+(,7 J',( g,1+(,7 NNuDD 3 u9('%(5* /(,7(7 6,&+ $86 '(0 u(',0(17$O 7,2169(5+$/7(1 %(, i5$',(17(1=(175,)8*$7,21(1 $%KN ',( 6,&+ %(, '(5 v5$16/$7,21 =80 92//67>1',*(1 ZRu t,%2620 9(5%,1'(1 J6,(+( c%%P UPUTKP o(,67(16 :,5' (,1( 0tpc */(,&+=(,7,* 921 0(+5(5(1 t,%2620(1 75$16/$7,(57] 0$1 635,&+7 '$11 921 r2/<620(1P

ZV

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( 7mG

AUG

UAA

AAA

Schritt 1: elF 4F Bindung elF 4G elF 4F

7mG

AUG

elF 4E

UAA

AAA

Schritt 2: Rekrutierung des 43S Präinitiationskomplexes elF 4G elF 3

7mG

elF 4E

40S

AUG

UAA

AAA

Schritt 3: „Scanning“

elF 2

elF 3 7mG

AUG

AAA

Schritt 4: Erkennung des AUG durch die tRNAmet > 60S Bindung

elF 2

7mG

UAA

AUG

UAA

AAA

60S

c%%P UPUT g8.$5<217( v5$16/$7,216,1,7,$7,21P g,1( 0tpc 0,7 '(5 7<3,6&+(1 e$3Ou758.785 JY0iKN '(0 3527(,1.2',(5(1'(1 25(1(1 n(6(5$67(5 JcwiP PPwccK 81' '(0 r2/<JcK u&+:$1= ,67 $%*(%,/'(7P k0 (567(1 u&+5,77 '(5 v5$16/$7,216,1,7,$7,21 %,1'(7 (,1 m203/(; J(khVhKN '(5 $86 (khVgN (/hVc 81' (/hVi %(67(+7N $1 ',( e$3Ou758.785P f,(6(0 u&+5,77 )2/*7 ',( t(.58O 7,(581* '(5 ./(,1(1 5,%2620$/(1 w17(5(,1+(,7 JVRuK ,1 h250 '(6 VUu r5>,1,7,$7,216.203/(;(6N '(5 =86>7=/,&+ ',( k1,7,$7,216)$.725(1 (khT 81' (khU 62:,( ',( k1,7,$725 7tpco(7 75>*7P f,(6(5 m203/(; %(:(*7 6,&+ ,1 UAOt,&+781* JNN6&$11,1*DDKN 80 0,77(/6 e2'21Bc17,&2'21 k17(5$.7,21 '$6 cwi k1,7,$7,216.2'21 =8 ,'(17,7=,(5(1P p$&+ (5)2/*7(5 g5.(1181* %,1'(7 6,&+ 1$&+ h5(,O 6(7=81* 921 (khT 81' (khU ,0 VP u&+5,77 ',( *52M( 5,%2620$/( w17(5(,1+(,7 JXRuKN :$6 =85 x(592//67>1',*81* '(6 =85 r527(,16<17+(6( )>+,*(1 ZRu t,%26206 )@+57P

UPV e<723/$60$7,6&+( u&+5,77( '(5 i(1(;35(66,21

ZW

f(5 m203/(;,7>7 '(5 v5$16/$7,21 75>*7 $8&+ ',( c1=$+/ %(7(,/,*7(5 o2/(.@/( t(&+O 181*\ p(%(1 '(5 =8 75$16/$7,(5(1'(1 0tpc :(5'(1 7tpcOo2/(.@/( 81' 5tpc J$/6 d(67$1'7(,/ '(5 t,%2620(1K 62:,( (,1( x,(/=$+/ 5,%2620$/(5 r527(,1( 81' v5$16O /$7,216,1,7,$7,216O %=:P O(/21*$7,216)$.725(1 %(1?7,*7P r5,1=,3,(// />M7 6,&+ ',( v5$16O /$7,21 :,( $8&+ ',( v5$16.5,37,21 ,1 '5(, r+$6(1 817(57(,/(1\ k1,7,$7,21Og/21*$7,21O v(50,1$7,21P l('( ',(6(5 r+$6(1 %(1?7,*7 *(621'(57( Jr527(,1OKh$.725(1 81' cvr %=:P ivr $/6 g1(5*,(75>*(5P

RMSMQMS s2!.3,!4)/.3).)4)!4)/. w17(5 ',(6(0 d(*5,5 )$M7 0$1 ',( x25*>1*( =86$00(1N ',( '85&+/$8)(1 :(5'(1N %(925 ',( (,*(17/,&+( r527(,16<17+(6( $0 k1,7,$7,216&2'21 cwi %(*,117P f(5 r52O =(66 '(5 v5$16/$7,216,1,7,$7,21 />8)7 %(, $//(1 (8.$5<217(1 |(//(1 921 j()(1 %,6 =80 o(16&+(1 1$&+ '(0 */(,&+(1 u&+(0$ 81' 817(5 d(7(,/,*81* 9(5*/(,&+%$5(5 m20O 321(17(1 $%] d$.7(5,(1 9(5)@*(1 '$*(*(1 @%(5 (,1(1 $1'(5(1 v5$16/$7,216,1,7,$O 7,2160(&+$1,6086P c%%,/'81* UPUT =(,*7 ',( (,1=(/1(1 u&+5,77( '(5 v5$16/$7,216,1,7,$7,21P |8(567 %,1O '(7 '(5 k1,7,$7,216)$.725 Vh J(khVhK $1 ',( e$3Ou758.785 '(5 0tpc Ju&+5,77 SKP (khVh 5(.587,(57 $16&+/,(M(1' =8(567 ',( ./(,1( 5,%2620$/( w17(5(,1+(,7 ,1 h250 '(6 VUu r5>,1,7,$7,216.203/(;(6 J%(67(+(1' 1(%(1 '(5 VRu 5,%2620$/(1 w17(5(,1+(,7 $86 '(5 o(7+,21//( $1 '(0 $0 :(,7(67(1 WA *(/(*(1(1P p(86<17+(7,6,(57( r2/<3(37,'( 75$*(1 '(6+$/% $1 ,+5(0 m23)(1'( JNNc0,127(50,186DDK ',( c0,126>85( o(7+,21,1N ',( 921 '(0 v5,O 3/(77 cwi .2',(57 :,5'P f,( k17(5$.7,21 '(6 c17,&2'216 '(5 o(7+,211',*( ZRu t,%2620P

4E-BP Insulin

4E-BP

elF 4G

P 7mG

elF 4E

c%%P UPUU k168/,1O9(50,77(/7( t(*8/$7,21 '(5 r527(,16<17+(6(P y,( ,1 c%%P UPUT *(=(,*7N ,67 (,1 m203/(; $86 (khVg 81' (khVi )@5 '(1 (567(1 u&+5,77 '(5 v5$16/$7,216,1,7,$7,21 (5)25O '(5/,&+P g,1 ./(,1(6N VgOdr JVgO%,1',1* 3527(,1K *(1$117(6 r527(,1 .$11 6,&+ $%(5 .203(7,7,9 $1 ',(6(/%( u7(//( 921 (khVg $1/$*(51N $1 ',( $8&+ (khVi $1%,1'(7P f$'85&+ :,5' ',( v5$16O /$7,21 %/2&.,(57P k168/,1 67,08/,(57 (,1(1 u,*1$/@%(575$*81*6:(*N '85&+ '(1 VgOdr 3+263+2O 5
Regulation der Translation

Regulation der mRNA Stabilität

7mG

7mG

tfr

IRE

7mG

elF

4G

elF

3 S

IRP

IRE

IRE

IRP

hohe Eisenaufnahme

RNase blockiert

IRE

IRP

geringe Eisenaufnahme

IRE

IRP

hohe TFR Synthese

tfr

IRE

IRP

Ferritin

Translation blockiert

wenig TFR Protein

AAA

4E

AUG

40

tfr mRNA stabil

RNase

IRE IRE IRE

elF

7mG

IRP-1

tfr mRNA Abbau

IRE IRE

Ferritin

Translation der Ferritin mRNA

geringe Ferritinsynthese

AAA

AAA

IRP Bindung

hohe Ferritinsynthese elF 4A

niedriger Eisenspiegel niedrige Eisenspeicherung

AAA

keine IRP Bindung

hohe Eisenspeicherung

hoher Eisenspiegel

ZX U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

UPV e<723/$60$7,6&+( u&+5,77( '(5 i(1(;35(66,21

ZY

p85 (,1 v(,/ $//(5 &<723/$60$7,6&+(1 0tpc6 :(5'(1 =8 -('(0 *(*(%(1(1 |(,7O 381.7 75$16/$7,(57P f(5 0(+56787*( r52=(M '(5 v5$16/$7,216,1,7,$7,21 .$11 921 3+581* '$)@5 *()81'(1 Jc%%P UPUUKP f(5 (khVhOm203/(; 6(7=7 6,&+ $86 '(0 e$3O%,1'(1'(1 r527(,1 (khVg 81' 6(,1(0 k1O 7(5$.7,2163$571(5 (khVi =86$00(1P f$6 5(/$7,9 ./(,1( VgO%,1'(1'( r527(,1 JVgOdrK .$11 ',(6( k17(5$.7,21 9(5+,1'(51N ,1'(0 (6 6,&+ *(1$8 $1 ',( u7(//( 921 (khVg $1/$*(57N $1 ',( 1250$/(5:(,6( (khVi %,1'(7P VgOdr ,67 $/62 (,1 v5$16/$7,216,1+,O %,725P k168/,1 6(7=7 (,1( u,*1$/75$16'8.7,216.$6.$'( ,1 i$1*N ',( =85 r+263+251*( '(6 r2/<JcKOu&+:$1=(6 9(56&+,(O '(1(5 0tpc6 :>+5(1' '(5 h(57,/,6$7,21 81' )5@+(1 g0%5<2*(1(6( 9,(/(5 q5*$1,6O 0(1 (,16&+/,(M/,&+ u>8*(51 '$5P f(5 r2/<JcKOu&+:$1= 67(,*(57 $8) 12&+ 1,&+7 (;$.7 *(./>57( y(,6( ',( c1%,1'81* '(5 ./(,1(1 5,%2620$/(1 w17(5(,1+(,7 $1 (,1( 0tpcP g6 %(67(+7 (,1( 326,7,9( m255(/$7,21 =:,6&+(1 ',(6(0 u7,08/$7,216(5(.7 81' '(5 n>1*( '(6 r2/<JcKOu&+:$1=(6P f85&+ *(=,(/7( x(5/>1*(581* %=:P x(5.@5=81* '(6 r2/<JcKOu&+:$1=(6 J'P +P '85&+ 5(*8/,(57( &<723/$60$7,6&+( r2/<$'(15(1 g,6(163(,&+(53527(,16 h(55,7,1 '$5P %(5O 6&+@66,*(6 ,175$=(//8/>5(6 g,6(1 :,5' '85&+ '$6 h(55,7,1 *(%81'(1 81' 62 (17*,)7(7P d(, +2+(0 g,6(1$1*(%27 08M h(55,7,1 '$+(5 9(50(+57 81' %(, *(5,1*(0 c1*(%27 9(50,1'(57 *(%,/'(7 :(5'(1P f$=8 9(5)@*(1 ',( h(55,7,1 0tpc6 ,1 ,+5(5 WA 1,&+7O 75$16/$7,(57(1 t(*,21 @%(5 (,1 ,521O5(63216,9( (/(0(17 JktgKN '$6 %(, 1,('5,*(1 =(/O /8/>5(1 g,6(1.21=(175$7,21(1 921 '(0 ,521 5(*8/$725< 3527(,1 JktrK *(%81'(1 :,5'P f,(6( c1%,1'81* %/2&.,(57 ',( v5$16/$7,216,1,7,$7,21 '(5 h(55,7,1 0tpc6N ,1'(0 6,( ',( t(.587,(581* '(6 VUu r5>,1,7,$7,216.203/(;(6 '85&+ (khVh 9(5+,1'(57P d(, 67(,*(1'(0 g,6(163,(*(/ /?67 6,&+ ktr 921 '(1 0tpc6 81' (5/$8%7 62 ',( v5$16/$7,21 '(6 817(5 ',(6(1 w067>1'(1 %(1?7,*7(1 g,6(163(,&+(53527(,16P c%%,/'81* UPUV =(,*7 8 c%%P UPUV r26775$16.5,37,21(//( m21752//( '(6 g,6(16725:(&+6(/6P u2:2+/ ',( g;35(66,21 '(6 g,6(163(,&+(53527(,16 h(55,7,1N $/6 $8&+ '(6 )@5 ',( g,6(1$8)1$+0( 9(5$17:257/,&+(1 v5$16O )(55,15(=(37256 :,5' '85&+ '$6 62*(1$117( ktgBktr u<67(0 *(67(8(57P f,( h(55,7,1 0tpc :(,67 $1 ,+5(0 WAOg1'( (,1 u7(8(5(/(0(17 Jktg 3 ,521O5(63216,9( (/(0(17K $8)N '$6 %(, 1,('O 5,*(1 =(//8/>5(1 g,6(163,(*(/1 921 ktrOS 2'(5 ktrOT Jktr 3 ,521 5(*8/$725< 3527(,1K *(%81'(1 :,5'P f(5 ktgBktr m203/(; $0 WAOg1'( %/2&.,(57 ',( v5$16/$7,216,1,7,$7,21N :(,/ '(5 (khVh m203/(; 1,&+7 0(+5 '(1 VUu r5>,1,7,$7,216.203/(; 5(.587,(5(1 .$11 J6,(+( c%%P UPUTKP h2/*O /,&+ ,67 ,1 (,6(1'(7=,(17(1 |(//(1 ',( u<17+(6( '(6 g,6(163(,&+(53527(,16 h(55,7,1 %/2&.,(57P f,( v5$16)(55,15(=(3725 JvhtK 0tpc 75>*7 )@1) ktg6 $1 ,+5(0 UAOg1'(P |:,6&+(1 ',(6(1 ktg6 %(71'(7 6,&+ (,1( u&+1,7767(//( )@5 (,1( g1'218./($6( Jr)(,/KP k1 (,6(1%(/$'(1(1 |(//(1 ,67 ktr 1,&+7 *(%81'(1N ',( vht 0tpc :,5' (,1*(6&+1,77(1 81' $%*(%$87P ktr d,1'81* ,1 (,6(1'(7=,(17(1 |(//(1 6&+@7=7 ',( tpc 925 ',(6(0 g,16&+1,77 81' 67$%,/,6,(57 6,( 620,7P f,( (5+?+7(1 vht 0tpc u3,(*(/ (5/$8%(1 (,1( (5+?+7( u<17+(6( ',(6(6 t(=(37256N '(5 '$11 @%(5 9(50(+57( g,6(1$8)1$+0( '(5 f(7=,(1= (17*(*(167(8(57P

ZZ

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

',( h81.7,21 '(5 ktgBktrO9(50,77(/7(1 h(55,7,15(*8/$7,21 %(, +2+(0 81' 1,('5,*(0 g,6(1$1*(%27N 62:,( '(1 =8 i581'( /,(*(1'(1 o(&+$1,6086P c/6 e+$5$.7(5,67,.80 '(5 75$16/$7,21$/(1 t(*8/$7,21 9$5,,(57 ',( r527(,16<17+(6( 7527= 819(5>1'(57(1 0tpc c1*(%276P c8&+ x,5(1 187=(1 ',( m203/(;,7>7 '(5 v5$16/$7,216,1,7,$7,21N 80 ',( =(//8/>5( r527(,16<17+(6( =8 ,+5(0 x257(,/ =8 %((,19866(1P f$6 r2/,29,586 ,1$.7,9,(57 ',( h81.7,21 '(6 (khVh ,1'(0 (6 (khVi '85&+ (,1( 9,5$/( r527($6( 63$/7(7P f,( 0(,67(1 =(//8/>5(1 0tpc6 %(1?7,*(1 ',( d(7(,/,*81* ',(6(6 h$.7256 $1 '(5 k1,7,$7,21 81' .?11(1 '(6+$/% 1,&+7 0(+5 75$16/$7,(57 :(5'(1P r2/,29,586 0tpc .$11 +,1*(*(1 6(,1( v5$16/$7,21 81$%+>1*,* 921 (khVh ,1,7,,(5(1 81' %(+(556&+7 )2/*/,&+ ',( =(/O /8/>5( v5$16/$7,216.$3$=,7>7P

RMSMQMT s2!.3,!4)/.3%,/.'!4)/. 5.$ L4%2-).!4)/. u2%$/' '$6 ZRu t,%2620 $0 k1,7,$7,216&2'21 %(5(,767(+7N .$11 ',( r527(,16<17+(6( %(*,11(1P x21 +,(5 $86 :,5' ',( 0tpc 75,3/(77:(,6( '(.2',(57N %,6 '$6 t,%2620 $8) (,1(6 '(5 '5(, u723&2'216 75,57P f,( 3527(,1.2',(5(1'( t(*,21 (,1(5 0tpc =:,6&+(1 k1,7,$7,216O 81' u723&2'21 %(=(,&+1(7 0$1 $8&+ $/6 NN25(1(6 n(6(5$67(5DDP y>+5(1' 6,&+ ,0 25(1(1 n(6(5$67(5 .(,1( u723&2'216 %(71'(1N :(,67 ',( 0tpc u(48(1= ,1 '(0 80 (,1 %=:P =:(, p8./(27,'( 9(56&+2%(1(1 t$67(5 0(,67 0(+5(5( u723&2'216 $8) J6,(+( c%%P UPUWKP offenes Leseraster

5´… AUG AUAACGAGGGCUA GCG… 3´ Me t I l e T h r A r gA l aS e r .…

+1 frameshift

+1 St op

+2 frameshift

+1 +2A s pAs nG l uG l yStop

c%%P UPUW NNh5$0(6+,)7DD o87$7,21(1 )@+5(1 2)7 =80 c%%58&+ '(5 r527(,16<17+(6(P q%(1 ,67 (,1 25(1(6 n(6(5$67(5 '$5*(67(//7P f85&+ (,1( 1S x(56&+,(%81* '(6 n(6(5$67(56 Jg,1)@*81* 921 SNVNY PP P p8./(27,'(1 2'(5 f(/(7,21 921 TNWNZ P PP p8./(27,'(1K .2',(5(1 '$6 TP %,6 WP p8O ./(27,' JwicK (,1 u723Oe2'21P g%(162 )@+57 (,1( 1T x(56&+,(%81* Jg,1)@*81* 921 TNWNZ P P P p8./(27,'(1 2'(5 f(/(7,21 921 SNVNY PP P p8./(27,'(1K 1$&+ .85=(5 |(,7 =80 u<17+(6($%%58&+ '85&+ '$6 u723&2'21 wciP p,&+7 $%*(%,/'(7\ n(',*/,&+ ',( g,1)@*81* 2'(5 f(/(7,21 921 UNXN[P P P p8./(27,'(1 9(56&+,(%7 '$6 n(6(5$67(5 1,&+7N 81' (6 :,5' (,1 9(5*5?M(57(6 %=:P 9(5O ./(,1(57(6 r527(,1 6<17+(7,6,(57P

f,( v5$16/$7,216(/21*$7,21 J*/(,&+%('(87(1' 0,7 r527(,16<17+(6(K 92//=,(+7 6,&+ ,1 :,('(5+2/7(1 |<./(1N ',( $86 -(:(,/6 '5(, g,1=(/6&+5,77(1 %(67(+(1 J6,(+( c%%P UPUXKP |8(567 %,1'(7 6,&+ ',( =80 =:(,7(1 e2'21 *(+?5,*( c0,12$&85( Ju&+5,77 TKP f$6 (1767$1'(1( f,3(37,' %(71'(7 6,&+ 12&+ $1 '(5 cOu7(//( '(6 t,%26206P u&+/,(MO

UPV e<723/$60$7,6&+( u&+5,77( '(5 i(1(;35(66,21

Z[

Met 80 S Ribosom AUG P

7mG

EF1 GTP

GGC UUA A

UAA

An

UAA

An

Gly

I. tRNA Bindung Aminoacyl-tRNA

EF1:GDP

Gly

Met AUG P

7mG

GGC UUA A

„endogene” PeptidyltransferaseAktivität der 60S Untereinheit

II. Ausbildung einer Peptidbindung

weitere Elongationsschritte Met

7mG

AUG P

III. Translokation

Gly

GGC UUA A

UAA

An

EF2 GTP EF2:GDP

Met

7mG

c%%P UPUX

AUG

Gly

GGC UUA P A

u&+(0$ '(5 v5$16/$7,216(/21*$7,21P

UAA

An

[R

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

/,&+ :,5' ',(6(6 f,3(37,' =86$00(1 0,7 '(5 0tpc ,1 ',( r(37,' JrKOu7(//( 75$16O /2=,(57 Ju&+5,77 UKN 80 ',( cOu7(//( )@5 ',( 1>&+67( c0,12$&80(1P f,(6(5 '5,77( u&+5,77 %(1?7,*7 (ghTP f,( d,1'81* '(5 '5,77(1 c0,12$&&+67(1 g/21*$7,216=<./86P u2%$/' (,1 u723&2'21 ,1 ',( cOu7(//( 5@&.7N %,1'(7 6,&+ '(5 62*(1$117( 5(/($6( )$&725 m203/(; thSBthUP f,(6( d,1'81* )@+57 '$=8N '$M '$6 )(57,*( r2/<3(37,' 921 '(5 /(7=7(1 7tpc *(/?67 :,5' 81' '$6 ZRu t,%2620 :,('(5 ,1 6(,1( VRu 81' XRu w17(5(,1+(,7(1 =(5)>//7 Jv(50,O 1$7,21KP f,( .255(.7( g176&+/@66(/81* -('(6 e2'216 81' ',( g,1+$/781* '(6 5,&+7,*(1 n(6(O 5$67(56 6,1' )@5 ',( u<17+(6( (,1(6 )81.7,2167@&+7,*(1 r527(,16 921 25(16,&+7/,&+(5 d('(8781*P f$6 t,%2620 ,67 '(6+$/% 62 .21=,3,(57N '$M (6 1,&+7 185 ',( u&+$581* 921 r(37,'%,1'81*(1 (50?*/,&+7N 621'(51 $8&+ */(,&+=(,7,* =:(, r5>=,6,216.21752/O /(1 '85&+)@+57P f,( (567( m21752//( 67(//7 6,&+(5N '$M 185 7tpc6 0,7 '(0 .255(.7(1 c17,&2'21 $8) '(5 cOu7(//( r/$7= 1(+0(1P f,( =:(,7( m21752//( ,67 '$)@5 9(5$17O :257/,&+N '$M %(,0 v5$16/2.$7,2166&+5,77 Ju&+5,77 UK ',( 0tpc 80 (;$.7 '5(, p8O ./(27,'( 925*(5@&.7 :,5'P d(,'( r5>=,6,216.21752//(1 :(5'(1 '85&+ ',( %(,'(1 g/21O *$7,216)$.725(1 9(50,77(/7P f,(6( r5>=,6,216.21752//(1 )@+5(1 '$=8N '$M %(, '(5 v5$16/$7,21 g1(5*,( ,1 h250 921 =:(, o2/(.@/(1 ivr 352 r(37,'%,1'81* 9(5O %5$8&+7 :,5'N 2%:2+/ ',( c86%,/'81* (,1(5 r(37,'%,1'81* $1 6,&+ (,1 (;(5*21,6&+(5 r52=(66 ,67P

normales Protein

M e t …………… Glu

Lys

Pro …………… St op

normale mRNA

A U G…………… GAG CUU AAG

CCU …………… U A A

5´ UTR

Leu

Offenes Leseraster

verändertes Protein

M e t …………… Va l

Leu

Lys

Pro …………… St op

missense Mutation

A U G…………… GUG CUU AAG

CCU …………… U A A

5´ UTR

3´ UTR

An 3´ UTR

verkürztes Protein

M e t …………… Glu

nonsense Mutation

A U G…………… GAG CUU UAG

Leu St op CCU …………… UAAA

5´ UTR

An 3´ UTR

verändertes Protein

M e t ……………A r g A l a St op

frameshift Mutation

A U G…………… CGA GCU U A A GCC U…………… …UA 5´ UTR

An

An 3´ UTR

c%%P UPUY g5(.7( 921 r81.7087$7,21(1 ,0 25(1(1 n(6(5$67(5 (,1(5 0tpcP g,1( 7.7,9( 1250$/( 0tpc u(48(1= :85'( *(:>+/7N 80 ',( g5(.7( 921 0,66(16(N 1216(16( 81' )5$O 0(6+,)7 o87$7,21(1 =8 9(5'(87/,&+(1P f(5 r)(,/ :(,67 $8) '$6 381.7087,(57( p8./(27,' +,1N ',( 9O)?50,*( m/$00(5 .(11=(,&+1(7 '$6 v5,3/(770867(5 '(6 -(:(,/,*(1 v5$16.5,37(6P

UPV e<723/$60$7,6&+( u&+5,77( '(5 i(1(;35(66,21

[S

f,( *(5,1*( k5578065$7( '(5 v5$16/$7,21 9(50$* (,1( .255(.7( r527(,16<17+(6( 1,&+7 6,&+(5=867(//(1N :(11 ',( 0tpc 6(/%67 9(5>1'(57 ,67P r5,1=,3,(// 817(56&+(,'(7 0$1 =:,6&+(1 '5(, 9(56&+,('(1(1 0tpc o87$7,2167<3(1N 921 '(1(1 -('(5 %(, (,1(5 x,(/=$+/ 921 g5.5$1.81*(1 '(6 o(16&+(1 *()81'(1 :(5'(1 J6,(+( c%%P UPUYKP g,1( r81.7087$7,21 9(5>1'(57 '$6 e2'21 )@5 (,1( %(67,007( c0,126>85( ,1 (,1 $1'(5(6P h2/*/,&+ :,5' $1 ',(6(5 u7(//( (,1( )$/6&+( c0,126>85( ,16 :$&+6(1'( r52O 7(,1 (,1*(%$87P o$1 635,&+7 +,(5 921 (,1(5 NN0,66(16( 087$7,21DDP g,1( 0,66(16( o87$7,21 /,(*7 %(,63,(/6:(,6( '(5 u,&+(/=(//(5.5$1.81* =8 i581'(N %(, '(5 (,1 x$/,1 JiwiK $167$77 (,1(5 i/87$0,16>85( JiciK $/6 6(&+67( c0,126>85( ,1 ',( tOi/2O %,1.(77( (,1*(%$87 :,5' 81' '(6+$/% (,1 3$7+2/2*,6&+ 9(5>1'(57(6 j>02*/2%,1 6<1O 7+(7,6,(57 :,5'P f(1 =:(,7(1 o87$7,2167<3 1(117 0$1 NN1216(16( 087$7,21DDP j,(5 :$1'(/7 (,1( r81.7087$7,21 (,1 c0,126>85(O.2',(5(1'(6 v5,3/(77 ,1 (,1 u723&2'21 80P f,( h2/*( ,67 (,1 3$7+2/2*,6&+ 9(5.@5=7(6 r527(,1N '$6 6(/%67 ,167$%,/ 6(,1 .$11P g,1 d(,63,(/ +,(5O )@5 %,(7(1 (,1,*( h250(1 '(5 tOv+$/$66>0,( J6,(+( $8&+ m$3P WPSPSKN %(, '(1(1 9(5O 6&+,('(1( '(5 ,16*(6$07 SVX e2'216 ,1 (,1 u723&2'21 JwciK 087,(57 6(,1 .?11(1P f(5 '5,77( o87$7,2167<3N NN)5$0(6+,)7 087$7,21DD *(1$117N 9(56&+,(%7 '$6 n(6(5$O 67(5 '85&+ g,1)@*81* 2'(5 f(/(7,21 921 p8./(27,'(1 J6,(+( c%%P UPUWKP f$6 9(5O 6&+2%(1( n(6(5$67(5 )@+57 =80 g,1%$8 )$/6&+(5 c0,126>85(1N %,6 '$6 t,%2620 $8) (,1 u723&2'21 ,1 ',(6(0 )$/6&+(1 n(6(5$67(5 75,57P f,( h2/*( ,67 (,1 0(,67 9(5.@5=7(6 J6(/7(1 -('2&+ $8&+ 9(5/>1*(57(6K r527(,1 0,7 (,1(0 )$/6&+(1 u&+:$1=(1'( Je$5%2;
RMSMQMU `.4)")/4)+! .54:%. t.4%23#()%$% :7)3#(%. %5+!29/.4%2 5.$ 02/+!29/.4%2 s2!.3,!4)/. q%:2+/ '$6 i581'6&+(0$ '(5 v5$16/$7,21 %(, (8.$5<217(1 81' 352.$5<217(1 |(//(1 6(+5 >+1/,&+ ,67N *,%7 (6 (,1( t(,+( 921 w17(56&+,('(1 ,1 +,(5 1,&+7 %(6&+5,(%(1(1 f(7$,/6 '(5 k1,7,$7,21N '(5 5,%2620$/(1 c5&+,7(.785 81' '(5 %(7(,/,*7(1 v5$16/$7,216O )$.725(1P f,(6( f(7$,/817(56&+,('( 0$&+7 6,&+ ',( c17,%,27,.$Ov+(5$3,( =8 p87=(P u2 %/2&.,(57 u75(3720<&,1 %(, d$.7(5,(1 '(1 %(5*$1* =:,6&+(1 v5$16/$7,216,1,O 7,$7,21 81' O(/21*$7,21P v(75$&<&/,1( %/2&.,(5(1 ',( cOu7(//( '(6 %$.7(5,(//(1 t,%2O 6206 81' '$0,7 u&+5,77 S '(5 g/21*$7,21P e+/25$03+(1,&2/ ,17(5)(5,(57 0,7 '(5 c86O %,/'81* '(5 r(37,'%,1'81*P g5<7+520<&,1 %/2&.,(57 ',( v5$16/2.$7,21 921 '(5 cOu7(//( =85 rOu7(//( Ju&+5,77 UKP o$1 +257N '$M ',( *(1$8( e+$5$.7(5,6,(581* '(6 (8.$5<217(1 81' '(6 352.$5<217(1 v5$16/$7,216925*$1*6 $8&+ ,1 |8.81)7 ',( g17O :,&./81* :(,7(5(5 +2&+:,5.6$0(5 c17,%,27,.$ (50?*/,&+(1 :,5'P

RMSMR `""!5 5.$ r4!"),)4;4 6/. -qm` u2%$/' (,1( 0tpc '$6 e<723/$60$ (55(,&+7 +$7N .$11 6,( $/6 o$75,=( =85 v5$16/$7,21 ',(1(1P c1'(5(56(,76 .$11 6,( $8&+ '85&+ t,%218./($6(1 $%*(%$87 :(5'(1P f,(6(5 c%%$8925*$1* ,67 3+<6,2/2*,6&+ 921 (%(162 *52M(5 d('(8781* :,( ',( v5$16.5,37,21

[T

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( NMD

Stabile RNA

UAA

UAA

PTC

Ter

RNA AUG 7mG

Protein

mRNA

A(n)

C-terminal verkürztes Polypeptid

Interferenz mit zellulären Funktionen

c%%P UPUZ NNp216(16(O0(',$7(' '(&$

5(5 u&+87=0(&+$1,6086P p216(16( %=:P )5$0(6+,)7 o87$7,21(1 )@+5(1 =8 9(5)5@+7(1 u723Oe2'216 J35(0$785( 7(50,1$7,21 &2'21N rveKP y>5( ',(6( 0tpc 67$%,/N :@5'( (,1 eO7(50,1$/ 9(5.@5=7(6 r527(,1 *(%,/'(7N :(/&+(6 =(//8/>5( h81.7,21(1 (5+(%/,&+ 67?5(1 .?117(P f85&+ NN1216(16(O0(',$7(' '(&$

921 0tpcP p85 '85&+ '(1 c%%$8 921 0tpc6 ,67 (6 0?*/,&+N ',( &<723/$60$7,O 6&+(1 u3,(*(/ %(67,007(5 0tpc6 '85&+ 9(50,1'(57( p(86<17+(6( =8 6(1.(1 81' (,1(0 9(50,1'(57(1 d('$5) $1=83$66(1P h(51(5 .?11(1 0,77(/6 0tpc c%%$8 $8&+ 087,(57( 0tpc6 '(*5$',(57 :(5'(1N %(925 6,( $/6 67$%,/( o$75,=(1 )@5 ',( u<17+(6( 3$7+2/2*,6&+ 9(5>1'(57(5 r527(,1( ',(1(1P f,(6( c8)*$%( (5)@//7 '(5 '85&+ 1216(16( o87$7,21(1 9(50,77(/7( c%%$8 J1216(16( 0(',$7(' '(&$0,(N :>+5(1' $1'(5( p216(16( o87$7,21(1 '(6 tOi/2%,1*(16N '(5(1 0tpc6 '(0 pof (17*(+(1N 6&+21 %(, r$7,(17(1 0,7 +(7(52O =<*27(0 i(127<3 =8 ./,1,6&+ 6,*1,7.$17(1 c8635>*81*(1 '(5 g5.5$1.81* )@+5(1P g,1 x(5*/(,&+ '(5 j$/%:(576=(,7(1 9(56&+,('(1(5 0tpc6 =(,*7N '$M *52M( w1O 7(56&+,('( ,1 ,+5(5 u7$%,/,7>7 %(67(+(1 .?11(1 Jv$%(//( UPWKP v$%P UPW u7$%,/,7>7 9(56&+,('(1(5 0tpc6 t(*8/$7253527(,1 A &2',(5(1'( 0tpc6 L=P dP o{eN hquN ioOeuhb

SW 0,1 A SZR 0,1

j$86+$/781*63527(,1 A &2',(5(1'( 0tpc6 L=P dP icrfjN h(55,7,1N c&7,1b

T + A /SR +

u(+5 67$%,/( 0tpc6 L=P dP sOi/2%,1N tOi/2%,1b

/TV +

UPV e<723/$60$7,6&+( u&+5,77( '(5 i(1(;35(66,21

[U

f,( .@5=(67(1 0tpc j$/%:(576=(,7(1 ,1 0(16&+/,&+(1 |(//(1 %(75$*(1 &$P SW o,187(1N :>+5(1' /$1*/(%,*( 0tpc6 j$/%:(576=(,7(1 921 0(+5 $/6 SRAWR u781'(1 $8):(,6(1 .?11(1P f$%(, )>//7 $8)N '$M ',( 0tpc6 (,1,*(5 q1.2*(1( 81' y$&+6O 7806)$.725(1 %(621'(56 .85=/(%,* 6,1'N 81' 62*(1$117( NN+286(.((3,1* *(1(6DD J+$8376>&+/,&+ i(1( )@5 8%,48,7>5 (;35,0,(57( u725:(&+6(/(1=<0(K /$1*( 0tpc j$/%:(576=(,7(1 +$%(1P |,(+7 0$1 ',( 3+<6,2/2*,6&+(1 h81.7,21(1 921 +286(.((O 3,1* *(1(6 81' y$&+67806)$.725(1 ,1 d(75$&+7N ,67 (6 6(+5 6,1192//N ',( r52'8.7,21 921 y$&+67806)$.725(1 (,1(5 5$6&+(1 t(*8/$7,21 =8*>1*/,&+ =8 0$&+(1] '(5 67>1O ',*( d('$5) $1 '(1 r52'8.7(1 '(5 NN+286(.((3,1* *(1(6DD 35277,(57 '$*(*(1 ,0 u,11( =(//8/>5(5 ~.2120,( 921 /$1*/(%,*(1 0tpc v5$16.5,37(1P f85&+ :(/&+( o(5.0$/( 817(56&+(,'(1 6,&+ /$1*/(%,*( 921 .85=/(%,*(1 0tpc6a f$6 u(48(1=027,9 cwwwc 71'(7 6,&+ 0(+5)$&+ :,('(5+2/7 ,1 '(5 UA 1,&+7O75$16O /$7,(57(1 t(*,21 '(5 0tpc6 (,1,*(5 q1.2*(1( 81' =(//8/>5(5 y$&+67806)$.725(1P f,(6( cwwwcO5(,&+(1 u(48(1=(1 9(50,77(/1 ',( 3+<6,2/2*,6&+ .85=( j$/%:(576=(,7 ',(6(5 v5$16.5,37(N :(11*/(,&+ '(5 y(* $8) '(0 ',(6( u(48(1=027,9( ',( 0tpc6 9(50(+57(0 c%%$8 =8)@+5(1 12&+ 81%(.$117 ,67P q%:2+/ ',( j$/%:(576=(,7(1 81O 7(56&+,('/,&+(5 0tpc6 67$5. 9$5,,(5(1N 6&+(,17 (,1( *(*(%(1( 0tpc *(:?+1/,&+ (,1( 5(/$7,9 .2167$17( j$/%:(576=(,7 =8 %(6,7=(1P g6 *,%7 $%(5 $8&+ d(,63,(/(N %(, '(1(1 ',( j$/%:(576=(,7 %(67,007(5 0tpc6 ,1 c%+>1*,*.(,7 921 (,1(0 %,2/2*,O 6&+(1 u,*1$/ 5(*8/,(57 :,5'P g,1 62/&+(6 d(,63,(/ ,67 ',( v5$16)(55,15(=(3725 JvhtK 0tpcP f(5 vht ,67 )@5 ',( c8)1$+0( v5$16)(55,1O*(%81'(1(1 g,6(16 ,1 ',( |(//( 9(5$17:257/,&+P y,( %(5(,76 %(6&+5,(%(1N (5)2/*7 ',( )(,1( c%67,0081* '(5 ,175$=(//8/>5(1 g,6(1+20?267$6( (,1(56(,76 '85&+ '$6 d,1'(1 @%(56&+@66,*(1 ,175$=(//8/>5(1 g,6(16 $1 h(55,7,1P c1O '(5(56(,76 :,5' ',( g,6(1$8)1$+0( @%(5 ',( t(*8/$7,21 '(5 |$+/ 921 v5$16)(55,1O 5(=(3725(1 $8) '(5 |(//0(0%5$1 .21752//,(57P k0 UA 1,&+7O75$16/$7,(57(1 g1'( '(5 7)5 0tpc %(71'(1 6,&+N (%(162 :,( $0 WAOg1'( '(5 h(55,7,1 0tpc6N ,521O5(6321O 6,9( (/(0(176 JktgKN ',( 921 ktr *(%81'(1 :(5'(1 .?11(1 81' '$0,7 ',( 7)5 0tpc 67$%,/,6,(5(1P f,( ktr d,1'81* $1 ',( ktg6 '(5 7)5 0tpc ,67 $%+>1*,* 920 =(/O /8/>5(1 g,6(163,(*(/ 81' ,67 %(, g,6(10$1*(/ (5+?+7 Jc%%P UPUVKP w0*(.(+57 )@+57 +2+(6 =(//8/>5(6 g,6(1$1*(%27 =8 9(50,1'(57(5 c5,1,7>7 '(6 ktr )@5 ',( ktg6 81' '$0,7 =8 5$6&+(5(0 c%%$8 '(5 81*(6&+@7=7(1 v5$16)(55,15(=(3725 0tpcP f,(6( t(*8/$7,21 ,67 ,0 u,11( '(5 g,6(1+20?267$6( 6,1192//N '$ 921 '(5 u2//.21=(175$7,21 $%:(,&+(1'( g,6(163,(*(/ =8 *(*(1/>87*(1 x(5>1'(581*(1 '(5 g,6(1$8)1$+0( )@+O 5(1P y,( ',(6(6 m$3,7(/ *(=(,*7 +$7N ,67 '(5 y(* 920 i(1 =80 r527(,1 /$1* 81' (5)25'(57 (,1( =(,7/,&+ 81' ?57/,&+ :2+/$%*(67,007( k17(5$.7,21 9,(/(5 =(//8/>5(5 m20321(1O 7(1P f,( n>1*( ',(6(6 y(*(6 %,(7(7 '(5 |(//( (,1(56(,76 c16$7=381.7( )@5 9,(/( t(O *8/$7,2166&+5,77(] $1'(5(56(,76 (;,67,(5(1 (%(1629,(/( o?*/,&+.(,7(1 )@5 3$7+2/2*,O 6&+( u7?581*(1P f,( =81(+0(1'( m(1171,6 02/(.8/$5(5 g,1=(/+(,7(1 '(5 i(1(;O 35(66,21 81' 02/(.8/$5(5 w56$&+(1 921 g5.5$1.81*(1 ,67 '(5 c86*$1*6381.7 )@5 ',( g17:,&./81* 1(8(5 5$7,21$/(5 81' .$86$/(5 f,$*126(O 81' v+(5$3,(Ou75$7(*,(1P

[V

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

RMT f%.2%+/-").!4)/. !,3 f25.$,!'% %).%2 30%:)&)3#(%. h--5.!.47/24 d,6+(5 +$%(1 :,5 i(1/2&, $/6 6758.785(// 7;,(57( fpcOc%6&+1,77( %(6&+5,(%(1N '(5(1 k1)250$7,21(1 '(1 d('@5)1,66(1 (,1(5 |(//( (17635(&+(1' $%*(58)(1 :(5'(1 .?11(1P f$6 k00816<67(0 67(+7 925 '(5 %(621'(5(1 c8)*$%(N $8) (,1( 1$+(=8 81%(*5(1=7( |$+/ )5(0'(5 o2/(.@/( Jc17,*(1(K *$1= 63(=,76&+ =8 5($*,(5(1P j,(5=8 ,67 ',( u<1O 7+(6( (,1(5 x,(/=$+/ 48$/,7$7,9 817(56&+,('/,&+(5 i(1352'8.7( Jc17,.?53(5K 1?7,*P f$6 k00816<67(0 :,5' ',(6(5 63(=,76&+(1 c1)25'(581* '85&+ (,1( %(,0 o(16&+(1 (,10$/,*( 620$7,6&+( t(.20%,1$7,21 '(5 *(1(7,6&+(1 k1)250$7,21 6(/%67 ,1 '(1 n<03+2&<7(1 *(5(&+7P f$%(, :(5'(1 =81>&+67 817(56&+,('/,&+( x(56$7=67@&.( '(6 %(75(5(1'(1 i(1/2&86 =8 (,1(5 ,1',9,'8(//(1 k1)250$7,21 =86$00(1*(6(7=7P g567 ',(6( 1(8 5(.20%,1,(57(1 fpcOu(48(1=(1 :(5'(1 '$11 75$16.5,%,(57 81' (17635(O &+(1' '(1 2%(1 %(6&+5,(%(1(1 r5,1=,3,(1 ,1 (,1 r527(,1 @%(56(7=7P o$1 817(56&+(,'(7 dO|(//(1N ',( $/6 $86',5(5(1=,(57( r/$60$=(//(1 k0081*/2%8O /,1( ,16 d/87 6(=(51,(5(1 J+8025$/( c%:(+5K 921 vOn<03+2&<7(1N ',( 0(0%5$1O 67>1',*( t(=(3725(1 (;35,0,(5(1 81' '85&+ k17(5$.7,21 0,7 o2/(.@/(1 '(6 ojeO m203/(;(6 J0$-25 +,672&203$7,%,/,7< &203/(;K ',( =(//8/>5( c%:(+5 9(50,77(/1P k0O 081*/2%8/,1( Jk*K 6(7=(1 6,&+ (%(162 :,( vO|(//Ot(=(3725(1 JvetK $86 =:(, 9(5O 6&+,('(1(1 m(77(17<3(1 =86$00(1] %(, '(1 k0081*/2%8/,1(1 :(5'(1 6&+:(5( J+($9+O 5(1' vO|(//Ot(=(3725(1 (17:('(5 $86 sO 81' tOm(77(1 2'(5 $86 uO 81' vOm(77(1 %(67(+(1P r5,1=,3,(// */(,&+7 6,&+ '(5 6758.785(//( c8)%$8 921 k*O 81' vetOo2/(O H

H VH

VH

S

S

S

S

L

S

CH1

CH1 S S

S

S

S

S

VL

S

S

S S S S

S

CL

CH2 S S

CH3

S C S H2

S S

S S

H

H IgG

CH3

L

‚

·

S

S

S

S

S

S

S

S

S

VL

V‚

S

V·

CL

C‚

C·

Zellmembran

TCR ·/‚

c%%P UPU[ r5,1=,3,(//( u758.785 921 k0081*/2%8/,1(1 81' vO|(//Ot(=(3725(1P d(,63,(/6:(,6( %(67(+(1 k*iOo2/(.@/( $86 =:(, /(,&+7(1 JnK 81' =:(, 6&+:(5(1 JjK m(77(1N :>+5(1' vO|(//O t(=(3725(1 920 vetsBtOv<3 $86 (,1(5 sO 81' (,1(5 tOm(77( =86$00(1*(6(7=7 6,1'P h81.O 7,21(// 5(/(9$17( f20>1(1 Jm(77(16&+/$8)(1K '(5 .2167$17(1 JeK %=:P 9$5,$%/(1 JxK m(77(1O 5(*,21(1 6,1' @%(5 f,68/7'%5@&.(1 9(5%81'(1P

UPW i(15(.20%,1$7,21

[W

.@/(1 Jc%%P UPU[K\ f(5 )@5 ',( g5(.725)81.7,21 9(5$17:257/,&+( .2167$17( JeK c%O 6&+1,77 :,5' $0,127(50,1$/ '85&+ '(1 9$5,$%/(1 JxK d(5(,&+ (5*>1=7N :(/&+(5 '(5 g5.(1181* 921 h5(0'02/(.@/(1 ',(17 81' ',( u3(=,77>7 '(5 -(:(,/,*(1 k*O 2'(5 vetOm(77( $860$&+7P f,( i(1( '(5 9(56&+,('(1(1 k*O 81' vetOm(77(1 6,1' $8) V e+5202620(1 9(57(,/7 81' (5675(&.(1 6,&+ -(:(,/6 @%(5 (,1( f,67$1= 921 TRR %,6 URRR m% Jc%%P UPVRKP f,( d(621'(5+(,7 ',(6(5 i(1/2&, %(67(+7 '$5,1N '$M ',( 9$5,$%/(1 m(77(1$17(,/( '85&+ =$+/5(,&+( i(16(*0(17( 5(35>6(17,(57 :(5'(1N ',( =81>&+67 '85&+ (,1( fpcOt(O .20%,1$7,21 =8 )81.7,2167@&+7,*(1 g,1+(,7(1 9(5.1@3)7 :(5'(1 0@66(1P f,(6(6 r5,1=,3 '(6 620$7,6&+(1 t($55$1*(0(176 921 fpcOu(48(1=(1 (50?*/,&+7 '(0 k00816<67(0N $8) (,1( 1$+(=8 81%(*5(1=7( |$+/ 921 .?53(5)5(0'(1 o2/(O .@/(1 63(=,76&+ =8 5($*,(5(1P f5(, v<3(1 921 fpcOu(*0(17(1 63,(/(1 %(, '(5 62O 0$7,6&+(1 t(.20%,1$7,21 9$5,$%/(5 m(77(16(48(1=(1 (,1( t2//(\ xOg/(0(17( J9$5,O $%,/,71.81*N '$M 1,&+7 $//( i(1$%6&+1,77( '(5 9$5,$%/(1 t(*,21(1 */(,&+%(5(&+7,*7 )@5 t($55$1*(0(176 +(5O $1*(=2*(1 :(5'(1P

Gen

Chromosom

IgH

14q32

Ig∫

2p12

IgÏ

22q11

TCR·

14q11

TCR‚

7q34

TCRÁ

7p15

TCR‰

14q11

RSS 23 Nukleotide Spacer

V

D

J

RSS 12 Nukleotide Spacer

c%%P UPVR e+5202620$/( n2.$/,6$7,21 '(5 k* 81' vet i(1( 62:,( ',( c125'181* '(5 u,*1$/(5.(1181*66(48(1=(1 JtuuK 9$5,$%/(5 m(77(16(*0(17(P f,( u,*1$/(,1+(,7(1 0,7 ST %3 %=:P TU %3 *52M(0 u3$&(5 :(5'(1 '85&+ '81./( %=:P +(//( f5(,(&.( '$5*(67(//7P

[X

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

k1 c%%,/'81* UPVS 6,1' (;(03/$5,6&+ ',( :(6(17/,&+(1 u&+5,77( $8) '(0 y(* =85 u<17+(6( (,1(5 )81.7,2167@&+7,*(1 k*jOm(77( '$5*(67(//7P |81>&+67 .2007 (6 =8 t($55$1*(0(176 $8) fpcOg%(1(N ,1 '(5(1 x(5/$8) (,1 fO 0,7 (,1(0 lOg/(0(17 81' $16&+/,(M(1' (,1 xOg/(0(17 0,7 '(1 %(5(,76 5(.20%,1,(57(1 flOu(48(1=(1 9(5.1@3)7 :,5'P g567 ',(6(6 5($55$1*,(57( k*jOc//(/ :,5' '$11 ,1 tpc 80*(6&+5,(%(1N '85&+ u3/(,M925*>1*( =8 (,1(5 5(,)(1 0tpc :(,7(59(5$5%(,7(7 81' 6&+/,(M/,&+ ,1 (,1 r52O 7(,1 75$16/$7,(57P f,( WAOg;216 '(5 xOg/(0(17( .2',(5(1 ',( 62*(1$117(1 /($'(5JnKO u(48(1=(1P f$%(, +$1'(/7 (6 6,&+ 80 '(1 +<'523+2%(1N $0,127(50,1$/(1 c17(,/ '(6 r527(,16N '(5 '(1 75$160(0%5$1?6(1 v5$163257 '(5 k*Om(77(1 (5/(,&+7(57 81' 925 '(5 k*Ou(.5(7,21 $86 r/$60$=(//(1 $%*(63$/7(1 :,5'P f,( t(.20%,1$7,21 '(5 k*O 81' vetOg/(0(17( (5)2/*7 ,1 n<03+2=<7(1 1$&+ (,1(0 u78)(13/$1P x25/>8)(5=(//(1 '(5 dOt(,+( )@+5(1 =81>&+67 flO 81' $16&+/,(O M(1' xOflOt($55$1*(0(176 ,0 d(5(,&+ '(5 i(1( )@5 ',( 6&+:(5(1 k*Om(77(1 $8) e+5202620 SV '85&+P f$%(, :(5'(1 =81>&+67 :(,7(5 UA *(/(*(1( xOg/(0(17( %(O 5@&.6,&+7,*7P m2007 (6 1,&+7 =85 t(.20%,1$7,21 (,1(5 u(48(1=N ',( (,1(1 )81.O 7,2167@&+7,*(1 9$5,$%/(1 m(77(17(,/ .2',(57N :,5' (,1 :(,7(5(5 x(568&+ $8) '(0 =:(,O 7(1 c//(/ *(67$57(7P f(5 (5)2/*5(,&+( c%6&+/8M (,1(6 k*jOt($55$1*(0(176 /(,7(7 '$11 =85 xOlOt(.20%,1$7,21 ,0 k*|On2&86 $8) e+5202620 T @%(5P u2//7( (6 $8) %(,'(1 c//(/(1 =8 $%(55$17(1 t($55$1*(0(176 .200(1N :,5' (,1 :(,7(5(5 x(568&+N )81.O L1 V1

L2 V2

Ln Vn

D1 D2 Dn

J1 J2 J3 J4 J5 J6

CH

DNA 5´

3´ D-J Rekombination L1 V1

L2 V2

D1 D2 J1 J2 J3 J4 J5 J6

Ln Vn

CH 3´

DNA 5´

V-DJ Rekombination L2V2 D2J1 J2 J3 J4 J5 J6

L1 V1 DNA

CH 3´

5´

Transkription L2V2 D2J1 J2 J3 J4 J5 J6 RNA

CH 3´

5´

Spleißen L2V2 D2 J1 mRNA

CH 3´

5´

Translation Protein

Ig schwere Kette

c%%P UPVS i(1(7,6&+( o(,/(167(,1( '(5 k*jOm(77(1 u<17+(6(P k0 u&+(0$ 6,1' 185 :(1,*( '(5 =$+/5(,&+(1 xON fO %=:P lOu(*0(17( :,('(5*(*(%(1P f,( .2167$17( t(*,21 JeK ,67 9(5(,1O )$&+(1' '85&+ (,1 u(*0(17 5(35>6(17,(57P

UPW i(15(.20%,1$7,21 V

CACAGTG 12 Nukleotide

ACAAAAACC

Nonamer

Spacer (23)

5´ 3´

Heptamer

[Y J

3´ V

RSS

RSS

J

5´

RAG1+RAG2 V

J

signal joint

Ligase KU70/KU80 DNA-PKcs V

CCT G GGAC

Endonuklease, Polymerase Exonuklease, TdT V

CC GGACGT P

T GTC ACAG

J Deletion

+++ CCA TC GG T AG N

J

XRC4 Ligase4 V

CCTGCA CCA T C GGACGT GGT A G P N

J

coding joint

c%%P UPVT u&+(0$ '(5 xJfKl t(.20%,1$7,21P xO 81' lOg/(0(17( :(5'(1 921 u,*1$/6(48(1O =(1 JtuuK 9$1.,(57 Jf5(,(&.(KN ',( 817(56&+,('/,&+( *52M( 63$&(5 JSTBTU %3K (17+$/7(1P r81.7( .(11=(,&+1(1 ',( )@5 '(1 t(.20%,1$7,216352=(M 81$%',1*%$5(1 p8./(27,'( '(5 tuuP f,( *(120,6&+( f,67$1= %(,'(5 .2',(5(1'(5 u(*0(17( .$11 0(+5(5( SRR .% $860$&+(1P tciS 81' tciT 6&+1(,'(1 *(1$8 =:,6&+(1 tuu 81' .2',(5(1'(0 g/(0(17 (,1N :2%(, ',( .2',(O 5(1'(1 g1'(1 (,1( j$$51$'(/6758.785 %,/'(1P mwOj(7(52',0(5( %,1'(1 $1 ',( )5(,(1 fpcO g1'(1P d(,'( tuu :(5'(1 =80 5,1*)?50,*(1 NN6,*1$/ -2,17DD 9(5.1@3)7 81' '(/(7,(57P p$&+ j,1=875(7(1 '(5 .$7$/<67,6&+(1 w17(5(,1+(,7 Jrm&6K %(*,117 '(5 fpcOrm m203/(; u8%675$7( =8 5(.587,(5(1N ',( (,1( o2',7.$7,21 '(5 .2',(5(1'(1 u(*0(17( .$7$/<6,(5(1P f,( j$$51$'(/O 6758.785(1 :(5'(1 '85&+ (,1( g1'218./($6( =(175$/ JlOg/(0(17K 2'(5 $6<00(75,6&+ JxOg/(O 0(17K *(?51(7N :2%(, '$11 (,1 @%(5+>1*(1'(5 u75$1* 0,7 r p8./(27,'(1 (1767(+7] (,1( fpcO r2/<0(5$6( (5*>1=7 '(1 .203/(0(17>5(1 g,1=(/675$1*P k0 lOg/(0(17 ,67 (,1 x(5/867 JOK 921 =:(, p8./(27,'(1 $8)*(75(7(1N *()2/*7 921 (,1(5 '( 1292 k16(57,21 J1K 921 '5(, )5(,(1 p8O ./(27,'(1 JpK '85&+ '$6 g1=<0 v'vP c%6&+/,(M(1' :,5' '$6 xO 81' lOg/(0(17 '85&+ '(1 zteVOfpc n,*$6( V m203/(; 9(5%81'(1 J&2',1* -2,17KP f,( x(5.1@3)81*65(*,21 :85'( '85&+ ',( f(/(7,21 921 l u(48(1=(1 62:,( ',( k16(57,21 921 r 81' p u(48(1=(1 02',7=,(57P

[Z

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

7,2167@&+7,*( /(,&+7( m(77(1 =8 352'8=,(5(1N '85&+ xlOt(.20%,1$7,21 '(6 k*}On2&86 $8) e+5202620 TT ,1,7,,(57P |8925 -('2&+ :,5' '(5 *(6$07( k*|On2&86 '85&+ x(5O 0,77/81* (,1(6 |O'(J'(/(7,1*KOg/(0(176 $86 %(,'(1 e+5202620(1 T (/,0,1,(57N 80 .21.855,(5(1'( x(568&+( (,1(6 k*|O 81' k*}Ot($55$1*(0(176 ,1 (,1(5 |(//( =8 81O 7(5%,1'(1P f,(6( 6&+5,77:(,6( c%)2/*( '(5 k*Ot(.20%,1$7,21(1 9(5+,1'(57 ,1 5(,)(1 dO|(//(1 ',( */(,&+=(,7,*( r52'8.7,21 921 |O 81' }Ok627<3(1 Jk627<3Og;./86,21K %=:P ',( g;35(66,21 %(,'(5 c//(/( (,1(6 k*On2&86 Jc//(/Og;./86,21KP k1 vO|(//(1 817(5/,(*7 ',( m20%,1$7,21 921 vetOu(48(1=(1 (,1(5 >+1/,&+(1 q5'O 181*N :2%(, (,1( t(,+(1)2/*( vetv 925 vetu 925 vets 925 vets %(67(+7P k0 d(5(,&+ 921 e+5202620 SV4SS /,(*7 ,162)(51 (,1( %(621'(5( u,78$7,21 925 $/6 +,(5 '(5 vetvOn2&86 ,11(5+$/% '(6 vets m203/(;(6 $1*(6,('(/7 ,67P d(925 vets t(O .20%,1$7,21(1 *(67$57(7 :(5'(1N .2007 (6 =8 (,1(5 g17)(5181* '(6 vetv c17(,/6N ,16%(621'(5( '(5 )@5 ',( g5(.725)81.7,21 0$M*(%/,&+(1 eOt(*,21N @%(5 (,1 925*(O 6&+$/7(7(6 t($55$1*(0(17 817(5 p87=81* '(6 v5(& Jv 5(&20%,1,1* %=:P '(/(7,1*K g/(0(176P f,( t(.20%,1$7,21 '(5 k* 81' vet u(*0(17( :,5' '85&+ (,1( 62*(1$117( xJfKl t(.20%,1$6( *(67(8(57P f(5=(,7 6,1' ',( h$.725(1 81' o(&+$1,60(1N ',( :>+5(1' '(5 n<03+232(6( ',( -(:(,/,*(1 i(1/2&, '(5 t(.20%,1$6(0$6&+,1(5,( =8*>1*/,&+ 0$&+(1N 12&+ 81=85(,&+(1' 9(567$1'(1P u(+5 9,(/ 0(+5 m(1171,6 +$7 0$1 $%(5 921 '(1 v(,/6&+5,77(1 '(6 t(.20%,1$7,216352=(66(6 6(/%(5P x21 (66(17,(//(5 d('(8781* ,67 ',( m(11=(,&+181* '(5 (,1=(/1(1 .2',(5(1'(1 u(*0(17( '85&+ t(.20%,1$7,21O u,*1$/6(48(1=(1 JtuuKN ',( ,1 &+$5$.7(5,67,6&+(5 y(,6( 80 ',( xON fO 81' lOg/(0(17( $1*(25'1(7 6,1' Jc%%P UPVRN c%%P UPVTKP f$%(, +$1'(/7 (6 6,&+ 80 h2/*(1 921 Y %=:P [ p8./(27,'(1N :(/&+( '85&+ r/$7=+$/7(5 Ju3$&(5K 921 ST 2'(5 TU p8./(27,'(1 *(75(117 :(5'(1 Jj(37$0(5Ou3$&(5Op21$0(5KP t($55$1*(0(176 (5)2/*(1 -(:(,/6 185 =:,6&+(1 u(*0(17(1N '(5(1 u,*1$/6(48(1=(1 817(56&+,('/,&+ /$1*( u3$&(5 JST %3 %=:P TU %3K $8):(,6(1] 0$1 635,&+7 921 '(5 STBTU t(*(/P u2 .$11 (6 (7:$ ,0 k*jO n2&86 =85 t(.20%,1$7,21 921 fO =8 l %=:P xO =8 flOg/(0(17(1 .200(1N 1,&+7 -('2&+ 921 xO =8 lO 2'(5 xO=8 xOc%6&+1,77(1P p,&+7 $//( p8./(27,'( '(5 u,*1$/6(O 48(1=(1 6,1' )@5 '(1 t(.20%,1$7,216352=(M 921 */(,&+(5 d('(8781*P f(5 r52=(M '(5 xJfKl t(.20%,1$7,21 :,5' '85&+ ',( %(,'(1 r527(,1( tciS Jt(.20%,1$7,21 $.7,9,(5(1'(6 i(1K 81' tciT (,1*(/(,7(7 Jc%%P UPVTKP tciS (5O .(117 ',( u,*1$/6(48(1=(1 JtuuKN :2%(, '$6 p21$0(5 '$6 )@5 ',( fpcOd,1'81* .5,7,6&+( o27,9 67(//7] $16&+/,(M(1' :,5' tciT *(%81'(1P f(5 tciSBtciT m20O 3/(; )81*,(57 $/6 g1'218./($6( 81' 6&+1(,'(7 35>=,6( =:,6&+(1 '(0 /(7=7(1 p8./(27,' '(6 i(16(*0(17(6 81' '(0 (567(1 p8./(27,' '(6 tuu j(37$0(56 (,1P f$%(, :(5'(1 ',( 6(16( 81' $17,6(16( u75>1*( '(6 -(:(,/,*(1 xON fO 2'(5 lOu(*0(17(6 .29$/(17 0,7(,1$1'(5 9(5%81'(1N :$6 =85 c86%,/'81* (,1(5 j$$51$'(/6758.785 J+$,53,1K )@+57P f,( %(,'(1 tuu g1'(1 :(5'(1 ,0 :(,7(5(1 x(5/$8) 0,77(/6 (,1(5 fpc n,*$6( 2+1( =86>7=/,&+( o2',7.$7,21 =8 (,1(5 5,1*)?50,*(1 u758.785 9(5%81'(1 J6,*1$/ -2,17KN ',( .(,1( h81.7,21 %(6,7=7 81' $/6 (;75$&+5202620$/( fpc %$/' (/,0,1,(57 :,5'P u(+5 9,(/ .203/(;(5 9(5/>8)7 ',( x(5.1@3)81* '(5 .2',(5(1'(1 g/(0(17( J&2'O ,1* -2,17KP |81>&+67 )$//(1 tciS 81' tciT 921 '(5 j$$51$'(/6758.785 $%P g6 .2007 =85 d,1'81* '(6 mwOm203/(;(6N (,1(0 $86 '(1 r527(,1(1 mwYR 81' mwZR %(67(+(1'(1 j(7(52',0(5N '$6 $1 '(1 )5(,(1 g1'(1 '(6 f233(/675$1*%58&+(6 %,1'(7N $1 '(5 fpc (17/$1**/(,7(7 81' (,1 :(,7(5(6 r527(,1 0,7 '(5 .$7$/<7,6&+(1 g,*(16&+$)7 (,1(5 u(5,1Bv+5(21,1.,1$6( JfpcOrm&6K 5(.587,(57P f,(6( '5(, m20321(17(1 %,/'(1

UPW i(15(.20%,1$7,21

[[

v$%P UPX i581'/$*(1 '(5 k*O 81' vetOx,(/)$/7 m20%,1$7,21 9(56&+,('(1(5 m(77(17<3(1 Jk*jBnN vetsBtN vetuBvK m(,0%$+15(3(572,5( 921 xON fO 81' lOg/(0(17(1 t(.20%,1$7,21(1 =:,6&+(1 xON fO 81' lOu(*0(17(1 x$5,$%,/,7>7 '(5 (;$.7(1 t(.20%,1$7,21667(//( =:(,(5 g/(0(17( x(5/867 921 p8./(27,'(1 '(5 t(.20%,1$7,2165(*,21 k16(57,21 921 p8./(27,'(1 JpBrOg/(0(17(K :>+5(1' '(5 t(.20%,1$7,21 u20$7,6&+( o87$7,21(1 ,1 5(.20%,1,(57(1 i(1(1

',( fpcO$%+>1*,*( r527(,1.,1$6( JfpcOrmKN :(/&+( ,+5(56(,76 )@5 '(1 t(.20O %,1$7,216352=(M :,&+7,*( u8%675$7( $.7,9,(57P j,(5=8 *(+?57 (,1( g1'218./($6(N ',( ',( j$$51$'(/6758.785(1 $1 '(1 fpcOg1'(1 ?51(7P f$%(, .$11 '(5 g,16&+1,77 (17:('(5 =(175$/N $1 '(5 u3,7=( '(5 j$$51$'(/ JlOg/(0(17N c%%P UPVTK 2'(5 $6<0O 0(75,6&+ JxOg/(0(17N c%%P UPVTK (5)2/*(1N 62 '$M %,6 '$+,1 .203/(0(17>5 *(*(1O @%(567(+(1'( p8./(27,'( 1(%(1(,1$1'(5 =8 /,(*(1 .200(1 81' 62*(1$117( r$/,1O '520( JrOg/(0(17(K %,/'(1N ',( '85&+ (,1( fpcOr2/<0(5$6( .203/(0(17>5 (5*>1=7 :(5'(1P g,1 /<03+2&<7(163(=,76&+(6 g1=<0N ',( v(50,1$/(Of(62;<18./(27,'+5(1' '(5 o2',7.$7,21 $8&+ p8./(27,'( $86 '(1 .2',(5(1'(1 d(5(,&+(1 (17)(517 :(5'(1P f(1 $%6&+/,(M(1'(1 u&+5,77 '(5 x(5.1@3)81* %(,'(5 02',7=,(57(5 i(16(*0(17( 92//O =,(+7 (,1 m203/(; $86 '(1 r527(,1(1 zteeV 81' fpcOn,*$6( VP u20,7 80)$M7 '$6 xJfKl t($55$1*(0(17 (,1(56(,76 m20321(17(1N ',( *(1(5(// (,1( d('(8781* )@5 ',( t(3$5$785 921 fpc f233(/675$1*%5@&+(1 %(6,7=(1 J=P dP fpcOrmN g1'218O ./($6(N n,*$1'(1KN :>+5(1' tciSN tciT 81' v'v )@5 ',(6(1 t(.20%,1$7,216O 352=(M 63(=,76&+( h81.7,21(1 %(,67(8(51P f,( x,(/)$/7 '(5 k* 81' vet o2/(.@/( %(58+7 '(01$&+ 1,&+7 185 $8) '(0 m(,0O %$+15(3(572,5( '(5 9$5,$%/(1 m(77(16(*0(17( Jv$%P UPXKP x,(/0(+5 .$11 ',( (;$.7( x(5.1@3)81*667(//( =:,6&+(1 =:(, g/(0(17(1 80 0(+5(5( p8./(27,'( 9$5,,(5(1P p8./(27,'( '(5 .2',(5(1'(1 d(5(,&+( .?11(1 '(/(7,(57 :(5'(1N 80*(.(+57 .?11(1 $%(5 $8&+ =86>7=/,&+( p8./(27,'( ,17(*5,(57 :(5'(1N 6(, (6 817(5 p87=81* (,1(5 m(,0O %$+10$75,=( JrOg/(0(17(K 2'(5 81$%+>1*,* +,(5921 JpOg/(0(17(KP u&+/,(M/,&+ :(5O '(1 )81.7,2167@&+7,* 5(.20%,1,(57( 9$5,$%/( m(77(16(*0(17( 12&+ 1$&+75>*/,&+ '85&+ 620$7,6&+( o87$7,21(1 02',7=,(57N :2%(, ',( o87$7,2165$7( +,(5 (,1( 0,//,O 210$/ +?+(5 /,(*7 $/6 ,1 $1'(5(1 m?53(5=(//(1 '(6 o(16&+(1P f,(6( o(&+$1,60(1 %(6,7=(1 )@5 ',( (,1=(/1(1 m(77(17<3(1 (,1( 817(56&+,('/,&+( d('(8781*P u2 :,5' '$6 63>5/,&+( m(,0%$+15(3(572,5( '(5 vetuO 81' vetvOn2&, '85&+ g,1)@*(1 921 pOg/(0(17(1 :(6(17/,&+ (5*>1=7N :>+5(1' 620$7,6&+( o87$7,21(1 %(, k*N 1,&+7 -(O '2&+ %(, vetOo2/(.@/(1 ',( x,(/)$/7 9(5*5?M(51P h@5 ',( k0081*/2%8/,16<17+(6( ,67 12&+ (,1 $1'(5(5 v<3 *(120,6&+(5 t(.20O %,1$7,21 921 d('(8781*N $8) '(0 '(5 y(&+6(/ J6:,7&+K '(5 k*Om/$66(1 %(58+7 Jc%%P UPVUKP j,(5%(, :,5' 817(5 d(,%(+$/781* (,1(5 63(=,76&+ 5($55$1*,(57(1 9$5,$%/(1 k*jO u(48(1= '(5 )81.7,21(// 5(/(9$17( .2167$17( d(5(,&+ 02',7=,(57P f,( .2167$17( t(O *,21 '(6 k*jOi(1/2&86 80)$M7 ~?> u?> w?>sOu(48(1=(1N :(/&+( ',( k*oON k*fON k*iON

SRR

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( L2 V2 D2 J1

CÁ

CÛ

DNA 5´

L2 V2 D2 J1

CÁ 3 s

s

CÂ

C· 2 s

DNA 5´

CÁ 1 s

„Â

C· 1

„Á

s

CÁ 2 s

CÁ 4 s

CÂ s

C· 2 s

3´

Switch Rekombination 3´

Transkription, Spleißen L2 V2 D2 J1 CÂ RNA 5´

3´ Translation IgE

c%%P UPVU k* m/$66(1:(&+6(/ 9(50,77(/7 '85&+ 6:,7&+ JuK u(48(1=(1 1$&+ (5)2/*5(,&+(5 t(O .20%,1$7,21 '(5 9$5,$%/(1 m(77(16(*0(17(P f$5*(67(//7 ,67 '(5 y(&+6(/ 921 (,1(5 ~O %=:P vOm(77(1 (;35,0,(5(1'(1 |(//( =8 (,1(5 wOm(77(1 352'8=,(5(1'(1 r/$60$=(//(P

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UPW i(15(.20%,1$7,21

SRS

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SRT

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

n2&, &+$5$.7(5,6,(57P f,(6( v$76$&+( (5?51(7 '(5 q1.2/2*,( (,1( ',$*1267,6&+( r)257( 921 *52M(5 ./,1,6&+(5 t(/(9$1=P f$ 6,&+ n<03+20( 81' n(8.>0,(1 921 (,1=(/1(1 n<03+2&<7(1925/>8)(51 $%/(,7(1N 6,1' ',(6( o$/,*120( '85&+ (,1 -(:(,/6 ,1',9,'8O (//(6 i(15($55$1*(0(17 *(.(11=(,&+1(7P j,(5$8) %$6,(5(1 ',( 62*(1$117( k0081O *(127<3,6,(581* +>0$7232(7,6&+(5 p(23/$6,(1 62:,( x(5)$+5(1 =80 p$&+:(,6 (,1(5 0,1,0$/(1 5(6,'8(//(1 t(67(5.5$1.81* J6,(+( m$3P XPSRKP

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UPX |(//=<./86

SRU

G0

G2 ~4h

M ~1h

G1 ~12h S ~7h

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RMUMP cm` q%0,)+!4)/. 5.$ y%,,4%),5.' p$&+ '(0 g1'( (,1(5 o,726( +$7 ',( |(//( ,1 c%+>1*,*.(,7 921 r52/,)(5$7,2166,*1$O /(1 $86 '(5 w0*(%81* ',( o?*/,&+.(,7N 62*/(,&+ :,('(5 ,1 '(1 1>&+67(1 |(//=<./86 (,1=875(7(1 2'(5 6,&+ ,1 ',( iROr+$6( =85@&.=8=,(+(1P x21 '257 .$11 6,( 1$&+ 81O %(67,007(5 |(,7 **)P :,('(5 ,1 '(1 |(//=<./86 (,175(7(1P w1$%+>1*,* '$921N 2% (,1( |(//( $86 o 2'(5 iR .2007N :,5' '(5 1(8( |(//=<./86 ,00(5 0,7 (,1(5 iSOr+$6( %(*211(1N '(11 ,1 ',(6(5 r+$6( 67(//7 ',( |(//( '$6 %,2&+(0,6&+( o,/,(8 )@5 ',( t(O 3/,.$7,21 '(5 fpc =86$00(1P k16%(621'(5( %('(87(7 ',(6 ',( g;35(66,21 921 i(O 1(1N '(5(1 r52'8.7( (66(17,(//( h81.7,21(1 %(, '(5 fpcOt(3/,.$7,21 J=P dP r527(,1( '(6 p8./(27,'6725:(&+6(/6 :,( v+<0,',1.,1$6( 2'(5 f(+<'52)2/$75('8.7$6(K 81' '(5 |(//=<./86352*5(66,21 921 iS ,1 t,&+781* uOr+$6( @%(51(+0(1P f$5@%(5 +,1$86 %(67(+7 ,1 iS ',( o?*/,&+.(,7N (9(178(// (,1*(75(7(1( u&+>'(1 $1 '(5 fpc 925 '(5 t(3/,.$7,21 =8 5(3$5,(5(1 J6,(+( m$3P UPYPVKN 80 62 185 ,17$.7(6 g5%0$7(5,$/ =8 '83/,=,(5(1P f(5 fpcOi(+$/7 (,1(5 iSO|(//( (17635,&+7 (,1(0 .203/(77(1 ',3/2,'(1 e+5202620(16$7=P p$&+ x(5'233/81* '(6 e+5202620(16$7=(6 ,1 u .$11 ',( |(//( ,1 '(5 iTOr+$6( :(,7(5 $1 x2/80(1 =81(+0(1 81' ,16%(621'(5( ',( r527(,1O 81' tpcOu<17+(6( 925 d(*,11 '(5 o,726( =80 c%6&+/8M %5,1*(1P f$5@%(5 +,1$86 (5O /$8%7 ',( iTOr+$6( O>+1/,&+ :,( ,1 iSO m21752//)81.7,21(1N ',( $1 ',(6(5 u7(//( 35,0>5 ',( %(535@)81* '(5 x2//67>1',*.(,7 '(5 fpcOt(3/,.$7,21 =80 |,(/ +$%(1P c0 g1'( '(5 iTOr+$6( (5)@//7 ',( |(//( ',( x25$866(7=81*(1 )@5 ',( |(//7(,/81*P

SRV

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

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3´

führender Strang

5´

RNA-Primer

DNA-Polymerase ·

Replikationsgabel 5´ 3´

3´ Helicase

5´ 3´ 5´

Okazaki-Fragmente

3´ 5´ DNA-Polymerase · 3´

(a)

nachfolgender Strang

UPX |(//=<./86 ORC

SRW

Ende der Mitose CDC 6

CDC 6 ORC

frühe G1-Phase MCM 2 – 7

CDC 6 ORC CDC 7 ASK

späte G1-Phase CDC 6

P

CDC 7 ASK ORC

P

G1/S-Übergang P

DNA-Polymerase ORC

S-Phase

(b)

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SRX

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UPX |(//=<./86

SRY

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3´

5´

3´

5´

3´

5´

(a)

3´ 5´

3´

5´ verkürztes Ende

5´ RNA-Primer

3´

3´

3´

+

führender

nachfolgender

5´

5´

3´ Telomer 5´

5´ 3´

centromerwärts

DNA-Polymerase

5´

3´

3´

5´

(b)

3´

3´ 5´

5´

3´ 5´

5´

TTAGGG

+

3´

5´

Telomerase

3´ Telomer 5´

3´

3´

5´

5´ 3´

5´

centromerwärts

3´

5´

3´

SRZ U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

UPX |(//=<./86

5´ 3´

3´ 5´ CAAUCCC A A U TTAGGG 3´

Telomerase

C

(a)

centromerwärts 5´ 3´

SR[

5´ (b)

3´

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SSR

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( Prophase Prometaphase

Metaphase Cytokinese

Anaphase

Telophase

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.21'(16,(57 ',( fpc J0?*/,&+(5:(,6( $/6 h2/*( '(5 r+263+25M7 ',( e+5202620(1 0,7 '(1 u&+:(67(5&+520$7,'(1 (5.(11(1P k1 '(5 o(7$3+$6( 25'1(1 6,&+ ',( e+5202620(1 ,1 '(5 }48$725,$/(%(1( '(5 |(//( $1P i/(,&+=(,7,* /?67 6,&+ ',( m(510(0%5$1 $8)N 81' (6 .2007 =85 c86%,/'81* '(6 u3,1'(/$33$5$7(6N '(66(1 h$6(51 ',( %(,'(1 e(1752620(1 $1 '(1 r2/(1 '(5 |(//( 0,7 '(1 e(17520(5(1 '(5 u&+:(67(5&+520$7,'(1 9(5%,1'(1P k1 ',(6(5 r+$6( '(6 |(//O =<./86 /,(*(1 ',( e+5202620(1 ,1 ,+5(5 .203$.7(67(1 h250 925 J(7:$ SRPRRR ; .21'(16,(57KP f,(6( v$76$&+( 0$&+7 0$1 6,&+ ,1 '(5 e<72*(1(7,. =8 p87=(N 80 0,7

UPX |(//=<./86

SSS

9(56&+,('(1(1 p$&+:(,6O 81' h>5%(0(7+2'(1 &+5202620$/( c%(55$7,21(1 0,.52O 6.23,6&+ '$567(//(1 =8 .?11(1P |8 d(*,11 '(5 c1$3+$6( 75(11(1 6,&+ ',( u&+:(67(5&+520$7,'(1 81' :$1'(51 -(:(,/6 ,1 ',( t,&+781* (17*(*(1*(6(7=7(5 r2/(P f,( d(:(*81* .2007 '$%(, '85&+ '$6 x(5.@5=(1 '(5 o,.5278%8/, ,1 '(1 u3,1'(/)$6(51 =867$1'(P k1 '(5 v(/23+$6( (55(,&+(1 ',( e+5202620(1 6&+/,(M/,&+ ',( e(1752620(1 81' 80 '$6 :,('(5 '(O .21'(16,(5(1'( e+520$7,1 )250(1 6,&+ 1(8( m(516758.785(1P |85 */(,&+(1 |(,7 9(5O -@1*7 6,&+ '(5 t$80 =:,6&+(1 '(1 %(,'(1 1(8(1 p8./(,N %,6 6,&+ ,1 '(0 r52=(66 '(5 e<72.,1(6( =:(, .203/(77( v2&+7(5=(//(1 921(,1$1'(5 $%6&+1@5(1P f,(6( |(//(1 %(6,7=(1 (,1(1 (,1)$&+(1 ',3/2,'(1 e+5202620(16$7= 81' 67(//(1 7<3,6&+( iSOr+$6( |(//(1 '$5N '(5(1 :(,7(5(6 u&+,&.6$/ 921 '(0 f,5(5(1=,(581*6O %=:P r52/,)(5$7,216O 352*5$00 '(6 80*(%(1'(1 o,/,(86 $%+>1*,* ,67P

RMUMQ q%'5,!4)/. $%2 y%,,:9+,5302/'2%33)/. i581'/(*(1'( g5.(1171,66( '(5 t(*8/$7,21 %,2/2*,6&+(5 h81.7,216$%/>8)( %(,0 o(16&+(1 :(5'(1 9,(/)$&+ =8(567 ,1 (,1)$&+(1 g8.$5<217(1 *(:211(1P u2 +$%(1 w17(568&+81*(1 =85 t(*8/$7,21 '(5 |(//=<./86352*5(66,21 ,1 '(1 %(,'(1 3+&.(5+()(1 JuP 320%( 81' uP &(5(9,6,$(K =85 k'(17,7=,(581* 921 =:(, +2&+.216(59,(57(1 i(1(1 *()@+57N '(5(1 x(5/867 ',( |(//=<./86352*5(66,21 '(5 j()(1 $0 iTBoO 81' J:,( 63>7(5 *(=(,*7 :(5O '(1 .2117(K $8&+ $0 iSBuO%(5*$1* 817(5%5,&+7P f,(6( i(1( :85'(1 $/6 o87$17(1 '(6 &(// ',9,6,21 &<&/( 0,7 &'&T JuP 320%(K 81' &'&TZ JuP &(5(9,6,$(K %(=(,&+1(7P f,( efeTO 81' efeTZOr527(,1( :,('(580 6,1' j202/2*( '(6 h$.7256 rUV $86 '(0 h526&+ z(12386 /$(9,6P rUV ,67 v(,/ (,1(6 m203/(;(6N '(5 ,1 zP /$(9,6 )@5 '(1 %(5*$1* 921 iT =85 o,726( %(1?7,*7 :,5' 81' '(6:(*(1 $/6 oO3+$6( 352027,1* )$&725 JorhK %(=(,&+1(7 :,5'P orh ,67 (,1 r527(,1.203/(; '(5 63(=,76&+( |,(/352O 7(,1( 3+263+251*,*( m,1$6( 2'(5 efm J&<&/,1 '(3(1'(17 .,1$6(K %(=(,&+1(7 Jc%%P UPV[KP y(,7(5( c1$/<6(1 +$%(1 *(=(,*7N '$M efeT ,1 9(56&+,('(1(1 |(//=<./863+$6(1 '85&+ 817(56&+,('/,&+( e<&/,1( $.7,9,(57 :,5'P u20,7 6&+(,17 ',( r+263+257=/,&+( c86O 6$*( :,5)7 '5(, :,&+7,*( h5$*(1 $8)\ JSK k67 '$6 e{eBefmOu<67(0 $8) o(16&+(1 @%(575$*%$5a JTK y,( :,5' ',( c.7,9,7>7 '(5 e{eBefmOm203/(;( 5(*8/,(57a JUK y(/&+(6 6,1' ',( |,(/3527(,1( '(5 &<&/,1$%+>1*,*(1 m,1$6(1a

SST

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( katalytische Untereinheit

aktiver KinaseKomplex

MPF

mitotisches Cyclin regulatorische Untereinheit

(a)

I

M

I

M

I

M

Expression

M

I

M

P34 P45 t MPF

MPF

MPF

MPF

Aktivitätsfenster des MPF in mehreren Zyklen

(b)

c%%P UPV[ f(5 NNoO3+$6( 352027,1* )$&725DD $/6 d(,63,(/ (,1(6 e<&/,1OefmOm203/(;(6P J$K f(5 NNoO3+$6(O352027,1*O)$&725DD ,67 (,1 f,0(5 (,1(5 e<&/,1O$%+>1*,*(1 m,1$6( $/6 .$7$/8)( '(5 rUV 81' rVW w17(5(,1+(,7(1 '(6 NNoO3+$6(O352027,1*O )$&7256DD $1*(*(%(1P f$5$86 5(68/7,(57 '$6 c.7,9,7>76)(167(5 '(6 $.7,9(1 m,1$6(.203/(;(6 ,1 '(5 o,726(P

RMUMQMP b9#,).!"(;.')'% j).!3%. !,3 l/4/2 $%2 y%,,:9+,5302/'2%33)/. y,( 62 2)7 6,1' =:$5 ',( %,2/2*,6&+(1 h81.7,216$%/>8)( %(,0 o(16&+(1 >+1/,&+ =8 '(1(1 ,1 (,1)$&+(1 g8.$5<217(1N -('2&+ ,67 ',( m203/(;,7>7 '(5 t(*8/$7,21 ',(6(5 h81.7,216$%/>8)( %(,0 o(16&+(1 :(6(17/,&+ *5?M(5 A ',(6(6 75,57 $8&+ $8) ',( |(//O =<./865(*8/$7,21 =8P u2 %(6,7=(1 0(16&+/,&+( |(//(1 1,&+7 185 (,1 &'.Oi(1 621'(51 0,1'(67(16 $&+7 j202/2*(N 921 '(1(1 ',( 0(,67(1 %(5(,76 %(.$117( h81.7,21(1 ,1 '(5 |(//=<./865(*8/$7,21 %(6,7=(1 Jc%%P UPWR$KP f$6 0(16&+/,&+( i(1 &'.OS %(6,7=7 ',( *5?M7( j202/2*,( =8 &'&TB&'&TZ 81' :,5' ,1 c1/(+181* $1 '$6 u3$/7+()(Oi(1 $/6 &'&T 81' $//( $1'(5(1 0(16&+/,&+(1 &<&/,1$%+>1*,*(1 m,1$6( $/6 &'.Oi(1( %(O =(,&+1(7P

UPX |(//=<./86

SSU

CYC B M G2

G1 CYC D S

(a)

CDK 4 CDK 6 CDK 2 CDC 2

CYC D

CDK 7

CYC H

CYC E CYC A CYC B

CYC A CYC E (b)

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f$5@%(5 +,1$86 71'(1 6,&+ ,1 0(16&+/,&+(1 |(//(1 =$+/5(,&+( e<&/,1(N ',( 185 0,7 %(67,007(1 efm6 ,1 m203/(;(1 *()81'(1 :(5'(1 .?11(1P c%%,/'81* UPWRd =(,*7N :$11 ',( e<&/,1Om,1$6(Om203/(;( ,0 |(//=<./86 $8)75(7(1P u2 $662=,,(5(1 v<3 fOe<&/,1( 0,7 efmV %=:P OX 81' 75(7(1 )5@+ ,1 iS $8)] 63>7(5 ,1 iS .2007 (6 '$11 =85 d,/'81* '(5 e{eOgBefmTOm203/(;(P c0 iSBuO%(5*$1* )250,(57 6,&+ (,1 m203/(; $86 efmT 81' e{eOcN :(/&+(6 (%(162 :,( e{eOd ,1 '(5 63>7(1 uOr+$6( 62:,( ,1 iT 81' o $8&+ 0,7 efeOT $662=,,(57 ,67P f,(6( x(57(,/81* 921 e{eBefmOm203/(;(1 67(//7 '$6 i581'*(5@67 '(5 |(//=<./865(*8/$7,21 %(,0 o(1O 6&+(1 '$5P c%(5 (6 ,67 1,&+7 '$6 c8)75(7(1 ',(6(5 m203/(;( 3(5 6(N :(/&+(6 ',( r52O *5(66,21 ,0 |(//=<./86 *$5$17,(57N 621'(51 9,(/0(+5 ,+5( m,1$6($.7,9,7>7N ',( J>+1/,&+ :,( ,1 j()(1K '85&+ =86>7=/,&+( h$.725(1 5(*8/,(57 :,5'P u2 ,67 ',( k1'8.7,21 '(5 9(56&+,('(1(1 |(//=<./863+$6(1 $%+>1*,* 921 '(0 =(,7/,&+ '(71,(57(1 c8)75(7(1 $.O 7,9(5 e{eBefmOm203/(;(P

RMUMQMQ o/3)4)6% 5.$ .%'!4)6% q%'5,!4/2%. 6/. bxb?bcjLj/-0,%8%. e<&/,1O$%+>1*,*( m,1$6(Ok1+,%,725(1 e<&/,1O$%+>1*,*(1 m,1$6(Ok1+,%,725(1 JemkK 6,1' r527(,1(N ',( ,1 '(5 n$*( 6,1'N ',( c.7,9,7>7 921 e{eBefmOm203/(;(1 1(*$7,9 =8 5(*8/,(5(1 Jc%%P UPWSKP k+5( %(5(;35(66,21 $55(7,(57 |(//(1 ,1 iSN :(,/ .(,1( $.7,9(1 efmOm203/(;( 0(+5

SSV

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( P21 ähnliche CKIs CDK +

+

P21

P21

CYC nicht aktiv

aktiv

nicht aktiv

(a) P16 ähnliche CKIs CDK4/6 + P16 CYC D nicht aktiv

aktiv

nicht aktiv

(b)

c%%P UPWS e<&/,1O$%+>1*,*( m,1$6(Ok1+,%,725(1 $/6 t(35(6625(1 '(5 e<&/,1.,1$6($.7,9,7>7P J$K f,( e<&/,1.,1$6(Ok1+,%,725(1 '(5 rTSOh$0,/,( JrTSN rTY 81' rWYK .?11(1 $//( e<&/,1O $%+>1*,*(1 m,1$6(1 ,1+,%,(5(1P k0 i(*(16$7= '$=8 6,1' ',( rSXO>+1/,&+(1 e<&/,1.,1$6(1O k1+,%,725(1 JrSWN rSXN rSZN rS[K 63(=,76&+ )@5 ',( e<&/,1O$%+>1*,*(1 m,1$6(1 V 81' X Jefm VBXKP

925/,(*(1P rTSN rTY 81' rWY %,/'(1 (,1( i5833( 6758.785(// 9(5:$1'7(5 h$.725(1N ',( efm6 ,1+,%,(5(1 .?11(1P f$6 3TS i(1 ,67 (,1 ',5(.7(6 |,(/*(1 '(6 v8025683O 35(66253527(,16 rWU 81' rTS ,67 620,7 (,1 :,&+7,*(6 g5(.7253527(,1 '(5 |(//=<./86O 5(*8/$7,21 '85&+ rWU J6P 8PKP rTY ,67 7<3,6&+(5:(,6( ,1 iRO|(//(1 =8 71'(1 81' :,5' %(, g,175,77 ,1 ',( iS r+$6( 326775$16.5,37,21$/ .217,18,(5/,&+ 5('8=,(57P rSWN rSXN rSZ 81' rS[ %,/'(1 ',( =:(,7( u8%*5833( 921 emk6P k0 i(*(16$7= =8 '(5 2P *P i5833( ,1+,%,(5(1 ',(6( r527(,1( $//(5',1*6 63(=,76&+ efmV 81' efmX '85&+ .203(7,7,9( x(5'5>1*81* '(5 v<3fOe<&/,1(P f,( rSWOi(1(;35(66,21 :,5' ,0 t$+0(1 '(5 c.7,9,(581* $17,0,72*(1(5 u,*1$/:(*( '85&+ '(1 75$16)250,1* *52:7+O)$&725Ot JvihOtK +2&+5(*8/,(57P f,( 3SX i(15(*,21 .2',(57 ,1 (,1(0 $/7(5O 1$7,9(1 n(6(5$67(5 12&+ )@5 (,1 :(,7(5(6 r527(,1N rSVcth JrSV $/7(51$7,9( 5($',1* )5$0(KP rSVcth )81*,(57 1,&+7 $/6 emkN ,67 $%(5 :,&+7,*(6 d,1'(*/,(' '(5 rWUOc.O 7,9,(581* %(, %(67,007(1 h250(1 '(6 NN*(120,6&+(1 u75(66(6DD J6,(+( m$3P UPXPVKP %(5 ',( 3+<6,2/2*,6&+( k1'8.7,21 ',(6(5 i5833( 921 emk6 ,67 $162167(1 :(1,* %(.$117P t(9(56,%/( t(*8/$7,21 '(5 efm6 '85&+ r+263+25
UPX |(//=<./86 WEE1-Kinase CDC2

CDC25 Phosphatase

CAK P

CDC2

SSW

P

CDC2

P

CDC2

CYC B

CYC B

CYC B

CYC B

inaktiv

inaktiv

inaktiv

aktiv

P

c%%P UPWT f,( c.7,9,7>7 921 e<&/,1OefmOm203/(;(1 .$11 '85&+ r+263+251*,*( m,1$6( $0 v<526,15(67 SW '85&+ ',( yggSOm,1$6( 3+263+257 '(5 y((SO m,1$6( %=:P '(5 efeTW r+263+$7$6( 6(/%67 ,67 '$%(, '(5$57 |(//=<./86O$%+>1*,* 5(*8/,(57N '$M ',( c.7,9,(581* '(6 e<&/,1 dBefeTOm203/(;(6 (567 1$&+ m203/(77,(581* '(5 uOr+$6( (5)2/*7P

0@66(1P g6 *,%7 j,1:(,6( '$5$8)N '$M %(67,007( h$.725(1 81' u,*1$/:(*( J:,( =P dP '$6 r527221.2*(1352'8.7 eOo<& 2'(5 '$6 c17,0,72*(1 vihOtK ',( efeTWO g;35(66,21 .21752//,(5(1 81' '$'85&+ ',5(.7(1 g,198M $8) '(1 c.7,9,7>76=867$1' 921 e{eBefmOm203/(;(1 $86@%(1P f,( c.7,9,(581* 921 e{eBefmOm203/(;(1 (5)25'(57 1(%(1 '(5 2P *P v<526,1O '(3+263+251*,*(1 v5$16.5,37,216.21752//( 63,(/(1 J6,(+( m$3P UPSPTKP f,( t(*8/$7,21 '(5 ecmOc.7,9,7>7 ,67 %,6+(5 $//(5',1*6 185 :(1,* 9(5O 67$1'(1P k55(9(56,%/( t(*8/$7,21 '(5 efmOc.7,9,7>7 '85&+ r527(2/<6( 921 |<./,1(1 f$6 d(,63,(/ '(5 efmOt(*8/$7,21 '85&+ ',( $17$*21,67,6&+(1 c.7,9,7>7(1 '(5 y((SB efeTW r527(,1( =(,*7 ',( o?*/,&+.(,7(1 (,1(6 5(9(56,%/(1 t(*8/$7,21635,1=,36 $8)P l( 1$&+ u,*1$//$*( .$11 ',( c.7,9,7>7 '(5 r527(,1( $1*(3$M7 :(5'(1P k0 i(*(16$7= '$=8 ,67 ',( r527(,1'(*5$'$7,21 (,1( ,55(9(56,%/( k1$.7,9,(581* (,1(6 r527(,16P f,(6( h250 '(5 1(*$7,9(1 t(*8/$7,21 %,(7(7 925 $//(0 ,1 62/&+(1 u,78$7,21(1 x257(,/(N :2 %,2&+(0,6&+( u,*1$/:(*( $1 (,1(0 r81.7 $1*(/$1*7 6,1' 1$&+ '(0 925+(5 127:(1O ',*( h$.725(1 185 12&+ 67?5(1 :@5'(1P g,1( 62/&+( u,78$7,21 /,(*7 :>+5(1' '(5 o,726( 925 Jc%%P UPWUKP f,( m,1$6($.7,O 9,7>7 '(5 e{eOdBefeTOm203/(;( ,67 127:(1',*N 80 |(//(1 ,1 ',( o,726( =8 )@+5(1P u2 75>*7 ',( e{eOdBefeTOc.7,9,7>7 @%(5 ',( r+263+255(0 n$0,1 =85 c89?681* '(5 m(516758.785 925 '(5 u3,1'(/)25O 0$7,21 J6,(+( r523+$6(Bo(7$3+$6(K %(,P k1 '(5 v(/23+$6( -('2&+ 08M (6 :,('(5 =85 f(.21'(16,(581* '(5 e+5202620(1 81' p(8$86%,/'81* 921 m(516758.785(1 .200(1P c1+$/7(1'( e{eOdBefeTOc.7,9,7>7 +>77( =8 ',(6(0 |(,7381.7 .$7$6752O

SSX

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( G2 CDC2

P

CYC B

CDC2

Prophase Metaphase

P

Anaphase Telophase

G1

G1

c%%P UPWU |,(/*(5,&+7(7( r527(2/<6( 921 e<&/,1 d ,1 '(5 63>7(1 o,726(P k1 '(5 5(&+7(1 d,/'O +>/)7( ,67 (,1 v(,/ '(6 |(//=<./86 6.,==,(57N '(5 ',( 63>7( iTOr+$6( 0,7 '(0 %(5*$1* ,1 ',( o,726( 62:,( '(1 d(*,11 '(5 iSOr+$6( '(5 (1767(+(1'(1 v2&+7(5=(//(1 $%'(&.7P f(5 '85&+ r+263+257 $0 g1'( '(5 c1$3+$6( ,1+,%,7,(57 :,5'P f,(6 *(6&+,(+7N :,( '85&+ ',( h5$*0(17,(581* '(6 e<&/,1 dOr527(,16 $1*('(87(7N '85&+ *(=,(/7(1 3527(2/<7,6&+(1 c%%$8 '(6 e<&/,13$571(56P

3+$/( h2/*(1 81' :@5'( '(1 v2' )@5 ',( |(//( %('(87(1P f,(6( i()$+5 :,5' '85&+ ',( r527(2/<6( 921 e{eOd 81' 620,7 '(5 92//67>1',*(1 k1$.7,9,(581* '(6 e{eOdB efeTOm203/(;(6 1$&+ '(5 c1$3+$6( *(%$117P f,( r527(2/<6( 08M '$%(, $8) ',( o,187( *(1$8 (,16(7=(1N '(11 $8&+ -('( 9(5)5@+7( |(567?581* 921 e{eOd :@5'( '(1 v2' '(5 |(//( %('(87(1P f(0(17635(&+(1' (;,67,(57 (,1 .203/(;(6 m21752//685(1 *52M( r2/<3(37,' w%,48,7,1 Jw%K $1 6(,1(0 eO7(50,1$/(1 g1'( '85&+ (,1 w%O$.7,9,(5(1'(6 g1=<0 JgSK $.7,9,(57P f,(6( c.7,9,(581* (50?*/,&+7 ',( %(5*$%( 921 w%,48,7,102/(.@/(1 $1 w%,48,7,1O .21-8*,(5(1'( JgTK g1=<0(P g,1 gTOh$.725 .$11 $16&+/,(M(1' ,1 m223(5$7,21 0,7 (,1(0 w%O/,*,(5(1'(1 g1=<0 JgUK '(1 w%,48,7,15(67 $8) (,1 |,(/3527(,1 @%(575$*(1P g,1 '(5$57,* 0$5.,(57(6 u8%675$7 :,5' '85&+ '$6 TXu r527($620 (5.$117 81' 63(O

UPX |(//=<./86 U ATP AMP E1

U E1

U CYC B CDC 2

E2 E3 E2 U

U

U

SSY

U U

U CYC B CDC 2 ATP

CYC B CDC 2

26 S Proteasom ADP

U

U

U

CDC 2

U

c%%P UPWV f$567(//81* '(6 3527(2/<7,6&+(1 w%,48,7,1Or527($620(16<67(06P w17(5 x(5%5$8&+ 921 cvr :,5' w%,48,7,1 J8K '85&+ (,1 w%,48,7,1O$.7,9,(5(1'(6 g1=<0 $.7,9,(57 81' $1 (,1 w%,48,7,1O.21-8*,(5(1'(6 g1=<0 JgTK :(,7(5*(*(%(1P k1 m223(5$7,21 0,7 (,1(0 w%,48,7,1O /(*,(5(1'(1 g1=<0 JgUK (5)2/*7 ',( u8%675$7O63(=,76&+( o$5.,(581* '(6 $%=8%$8(1'(1 e<&/,1O r527(,16 0,7 '(0 w%,48,7,102/(.@/P f,( u8%675$763(=,77>7 ',(6(6 x25*$1*(6 :,5' *(:>+5/(,67(7 '85&+ ',( 62*(1$117( rguvOf20>1( ,0 pOv(50,186 921 e<&/,1 d 62:,( '85&+ '(1 o8/7,O r527(,1.203/(; gUN '(5 ',( rguvOu(48(1= ,1 e<&/,1 d 63(=,76&+ (5.(117P p$&+ '(5 c1+()781* '(6 (567(1 w%,48,7,15(67(6 (5)2/*7 (,1( r2/<8%,48,7,1,(581* 0,7 '(0 $16&+/,(M(1'(1 3527(2O /<7,6&+(1 c%%$8 ',(6(6 m203/(;(6 ,0 TXu r527($620P

=,76&+ 3527(2/<7,6&+ $%*(%$87P k16%(621'(5( '(1 gUOh$.725(1 )>//7 %(, ',(6(0 r52O =(M ',( t2//( '(5 u3(=,7.$7,216)$.725(1 =8P gUOh$.725(1 6,1' =P vP *52M( o8/7,352O 7(,1.203/(;(P g,1 d(,63,(/ )@5 (,1( 62/&+( gUOc.7,9,7>7 ,67 '(5 NN$1$3+$6( 352027,1* &203/(;DD JcreKN '(5 8P $P '85&+ '(1 c%%$8 921 e<&/,1Od '(1 %(5*$1* 921 '(5 c1$3+$6( ,1 ',( v(/23+$6( (50?*/,&+7 J6P 2PKP

RMUMR c)% r4)-5,!4)/. $%3 y%,,:9+,53 $52#( v!#(345-3&!+4/2%. |(//(1 6,1' ,1 ,+5(0 y$&+678069(5+$/7(1 921 '(0 80*(%(1'(1 o,/,(8 $%+>1*,*P y$&+67806)$.725(1 5(35>6(17,(5(1 (,1(1 u7,08/86N 2+1( '(1 .(,1( $.7,9,(57(1 e{eB efmOm203/(;( (1767(+(1P f,( |(//( 9(5+$557 62 ,0 u7$',80 iRP g567 ',( i$%( 921 y$&+67806)$.725(1 J:,( =P dP '(6 (3,'(50$/O*52:7+ )$&725K )@+57 %(, (,1(5 .8/O 7,9,(57(1 h,%52%/$67(1=(//( :,( ,1 c%%,/'81* UPWW 6&+(0$7,6&+ '$5*(67(//7 &$P ST u781O '(1 63>7(5 =85 fpcOu<17+(6(P f$%(, ,67 ',( c1:(6(1+(,7 '(5 y$&+67806)$.725(1 %,6 =80 f85&+/$8)(1 921 &$P TBU '(5 iSOr+$6( $%62/87 127:(1',*N 80 ',( uOr+$6( (,1=8/(,7(1P f(5 g17=8* 921 y$&+67806)$.725(1 %,6 =8 ',(6(0 |(,7381.7 )@+57 =8 (,1(0 t@&.)$// '(5 |(//( ,1 ',( iROr+$6(P %(56&+5(,7(1 ',(6(6 ,0$*,1>5(1 |(,7381.7(6 ,1 '(5 i(*(1:$57 921

SSZ

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( G0

G2 ~4h

Mitogene

mitogenabhängige Progression

M ~1h

G1 ~12h ZellzyklusAutonomie

G ~7h

Restriktionspunkt

c%%P UPWW o,72*(1O$%+>1*,*( c.7,9,(581* '(6 |(//=<./86P o,72*(1( u7,08/,N :,( y$&+6O 7806)$.725(1N )?5'(51 '(1 g,175,77 921 |(//(1 ,1 '(1 |(//=<./86P f$0,7 (6 =85 fpcOt(3/,O .$7,21 (,1(5 67,08/,(57(1 |(//( .200(1 .$11N 08M '(5 0,72*(1( u7,08/86 %,6 63>7 ,1 '(5 iSOr+$6( $1+$/7(1P d(,0 %(56&+5(,7(1 '(6 62*(1$117(1 t(675,.7,216381.7(6 %(*,117 '(5 o,72*(1O81$%+>1*,*(N $872120( c%6&+1,77 '(6 |(//=<./86P f$6 +(,M7N '$M '$6 :(,7(5( h257O 6&+5(,7(1 ,0 |(//=<./86 $8&+ ,1 '(5 c%:(6(1+(,7 921 y$&+67806)$.725(1 (5)2/*7P

y$&+67806)$.725(1 )@+57 +,1*(*(1 =8 (,1(0 '$11 $872120(1 h2576&+5(,7(1 '(6 |(//=<./86 Jc%%P UPWWKP u(/%67 :(11 =8 (,1(0 63>7(5(1 |(,7381.7 ',( y$&+67806O )$.725(1 (17=2*(1 :(5'(1N .203/(77,(57 ',( |(//( '(1 %(*211(1(1 v(,/81*6=<./86P g17635(&+(1' :,5' ',(6(5 |(,7381.7 ,1 iS $/6 t(675,.7,216381.7 %(=(,&+1(7P f,(6( d(2%$&+781*(1 :(5)(1 =:(, (176&+(,'(1'( h5$*(1 $8)\ SP y(/&+( x25*>1*( 67$57(1 '(1 |(//=<./86 1$&+ '(5 i$%( 921 y$&+67806)$.725(1 81' TP :(/&+( g5O (,*1,66( )@+5(1 =85 c872120,( '(6 |(//=<./86 $0 t(675,.7,216381.7P p$&+ '(0 +(87,*(1 x(567>1'1,6 '(5 r52/,)(5$7,216.21752//( 805(,M(1 ',(6( %(,'(1 h5$*(1 ',( (66(17,(//(1 x25*>1*( '(5 y$&+67806.21752//( 0(16&+/,&+(5 |(//(1N 81' +,17(5 ,+5(5 d($17:25781* 9(5%,5*7 6,&+ ',( k'(17,7=,(581* 921 i(1(1N '(5(1 r52'8.7( '$6 y$&+6780 816(5(5 |(//(1 5(*8/,(5(1 81' '(5(1 k1$.7,9,(581* i581'/$*( )@5 |(//O 75$16)250$7,21 81' v8025:$&+6780 ,67P u2 ,67 ',( *52M( o(+5=$+/ $//(5 %,6 +(87( ,'(17,7=,(57(1 r5272Oq1.2*(1( 81' v802568335(6625*(1( $1 '(5 m21752//( =80,1O '(67 (,1(5 ',(6(5 %(,'(1 u&+5,77( %(7(,/,*7P

RMUMRMP c%2 r4!24 $%3 y%,,:9+,53Y `+4)6)%25.' $%2 cLs90 b9#,).% y$&+67806)$.725(1 J2'(5 o,72*(1(K 6,1' ,1 '(5 t(*(/ ./(,1( o2/(.@/(N ',( $/6 n,O *$1'(1 0(0%5$167>1',*( t(=(3725(1 %,1'(1P f,(6( d,1'81* $.7,9,(57 '(1 t(=(3O 725N '(5 @%(5 (,1( m$6.$'( 921 r527(,13+263+255(5 NN,00(',$7( ($5/< 5(63216(DD i(1( JkgOi(1(KN %(, '(1(1

UPX |(//=<./86

SS[

(6 6,&+ ,1 '(5 t(*(/ 6(/%67 80 v5$16.5,37,216)$.725(1 +$1'(/7P d(,63,(/( '$)@5 6,1' ',( h$.725(1 hqu 81' lwp J6,(+( m$3P UPSPTKP v<3,6&+(5:(,6( (5)2/*7 ',( c.7,9,(O 581* '(5 kgOi(1( ,11(5+$/% :(1,*(5 o,187(1 1$&+ i$%( '(5 y$&+67806)$.725(1 Jc%%P UPWXKP f2&+ :,( %,1'(1 6,&+ kgOr527(,1( '$1$&+ ,1 '(1 |(//=<./86 (,1a f,( fOv<3 e<&/,1( 6,1' ',( (567(1 e<&/,1(N ',( ,0 |(//=<./86 (;35,0,(57 :(5'(1P f(5 |(,7381.7 ,+5(6 c8)75(7(16 J&$P TAV u781'(1 1$&+ 0,72*(1(5 u7,08/$7,21K 62:,( ',( c%+>1*,*.(,7 ,+5(5 g;35(66,21 921 0,72*(1(1 u7,08/$17,(1 J,0 i(*(6$7= =8 $//(1 $1'(5(1 e<&/,1(1K 48$/,7=,(57 fOv<3 e<&/,1( $/6 r52'8.7( '(5 NN'(/$<(' ($5/< 5(63216(DD i(1( JfgOi(1(KP u2 )@+57 '(5 g17=8* 921 o,72*(1(1 =80 x(5/867 '(5 e{e fOg;35(66,21P f,(6( d()81'( (17635(&+(1 '(1 g5:$5781*(1 1$&+ '(0 2P *P c.7,9,(581*60867(5 '(6 |(//=<./86 %,6 =80 t(675,.7,216381.7P q%:2+/ (6 .@5=/,&+ *(/81*(1 ,67N ',( g;35(66,21 921 e{e fS .$86$/ 0,7 '(5 c.7,9,(581* '(6 tcuO u,*1$/:(*(6 ,1 |86$00(1+$1* =8 %5,1*(1 J6,(+( m$3P UP[PTKN ,67 ',( 75$16.5,37,21(//( c.7,9,(581* '(6 .203/,=,(57 $8)*(%$87(1 &<& 'SOr52027256 '85&+ kgOi(1352'8.7( :(1,* 9(567$1'(1P v527='(0 :,5' ',( 0(',=,1,6&+( d('(8781* '(5 c1%,1'81* 921 y$&+678066,*O 1$/:(*(1 @%(5 e<&/,1 f $1 '(1 |(//=<./86 '85&+ ',( 21.2*(1( c.7,9,(581* =$+/O 5(,&+(5 o,7*/,('(5 ',(6(5 u,*1$/:(*( 1$&++$/7,* %(/(*7P c8) 35$.7,6&+ -('(5 u78)( 0,72*(1(5 u,*1$/:(*( .?11(1 $.7,9,(5(1'( o87$7,21(1 J*$,1 2) )81&7,21 087$176K 21.2*(1( r27(1= (17)$/7(1 J6,(+( m$3P UP[PTKP f85&+ ',( .2167,787,9( c.7,9,(581* 921 r272Oq1.2*(1(1 :,5' 6(/%67 ,1 '(5 c%:(6(1+(,7 921 o,72*(1(1 (,1 y$&+6O

Mitogen Rezeptor

+ ++ + wenige Minuten

Zellmembran

Signalkaskade Kernmembran IE-Gene

wenige Stunden DE-Gene (CYC D)

c%%P UPWX f,( i$%( 921 y$&+67806)$.725(1 )@+57 =85 g;35(66,21 '(5 e<&/,1 f i(1(P c/6 g5*(%1,6 '(5 d(+$1'/81* 1,&+7O352/,)(5,(5(1'(5 |(//(1 0,7 o,72*(1(1 .?11(1 ,11(5+$/% :(O 1,*(5 o,187(1 62*(1$117( NN,00(',$7( ($5/

8)7 @%(5 0(0%5$167>1',*( t(=(3725(1 81' (,1( u,*1$/.$6.$'( ,1 '(1 |(//.(51 J6,(+( m$3P UP[PTKP NNk00(',$7( ($5/

)250,(57(1 u,*1$/.$6.$'(1 )81*,(5(1P |(//8/>5( NN,0O 0(',$7( ($5/

STR

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

78066,*1$/ 925*(7>86&+7 81' NN'2:1675($0DD '(5 o87$7,21 J'P +P 817(5+$/% '(6 08O 7,(57(1 h$.7256 ,1 '(5 u,*1$/.$6.$'(K .2007 (6 =85 3(50$1(17(1 c.7,9,(581* '(6 u,*1$/:(*(6 %,6 +,1 =85 g;35(66,21 '(5 kgOi(1(N ',( 6&+/,(M/,&+ 0,7 '(5 J,1K',5(.7(1 v5$16$.7,9,(581* '(5 &<& 'Oi(1( '(1 |(//=<./86 $16&+$/7(1P u2 6,1' kgOi(1( :,( )26 81' -81 6(,7 /$1*(5 |(,7 $/6 r527221.2*(1( %(.$117 81' $8&+ e{e fS .2117( $/6 327(17(6 q1.2*(1 ,'(17,7=,(57 :(5'(1 J6P 8PKP

RMUMRMQ c)% q%'5,!4)/. $%3 q%342)+4)/.305.+4%3 f(5 t(675,.7,216381.7 ,67 (,1 62*(1$117(5 e+(&.32,17 ,0 |(//=<./86P e+(&.32,176 6,1' ,0$*,1>5( |(,7381.7(N $1 '(1(1 (,1 .203/(;(6 02/(.8/$5(6 m21752//6<67(0 :,5.7N 80 6,&+(5=867(//(1N '$M (,1( |(//=<./863+$6( .255(.7 $%*(6&+/266(1 ,67N %(925 ',( )2/*(1'( r+$6( %(*,117P u2 .$11 (,1 e+(&.32,17Om21752//6<67(0 '85&+ 9(56&+,(O '(1( u,*1$/(N :,( =P dP (,1( fpcOu&+>',*81*N $.7,9,(57 :(5'(1P c/6 h2/*( :,5' '(5 |(//=<./86 $1 ',(6(0 m21752//381.7 62/$1*( $55(7,(57 %,6 '$6 u,*1$/ :,('(5 (17)>//7P c8) ',(6( y(,6( .$11 $0 t(675,.7,216381.7 6,&+(5*(67(//7 :(5'(1N '$M 185 81%(O 6&+>',*7( fpc ,1 '(5 uOr+$6( 5(3/,=,(57 :,5' 81' '(5 iTBo e+(&.32,17 62// 6,O &+(567(//(1N '$M 185 .255(.7 5(3/,=,(57( fpc $8) ',( v2&+7(5=(//(1 9(57(,/7 :,5'P f(5 )81.7,21(// ,1 0(16&+/,&+(1 |(//(1 :,&+7,*67( e+(&.32,17 ,67 '(5 t(675,.7,216O 381.7 ,1 iSP f,( ./,1,6&+( d('(8781* '(5 t%Oe{e fOrSXOd(=,(+81* $0 t(675,.7,216381.7 f$6 &<& 'S i(1 :85'( 85635@1*/,&+ $/6 $03/,7=,(57(6 q1.2*(1 ,1 v8025=(//(1 (17O '(&.7P g17635(&+(1' '(5 &<& 'S h81.7,21 $/6 /,0,7,(5(1'(5N 326,7,9(5 t(*8/$725 921 efm VBX *(:,11(1 |(//(1 '$'85&+ (,1( *5?M(5( y$&+67806327(1=P f(5 efmOk1O +,%,725 rSXN (,1 63(=,76&+(5 c17$*21,67 '(5 e{e fOefm VBX m,1$6(N 5(*8/,(57 '(1 r+263+2587* ,1 v8025(1 ,1$.7,9,(57 :,5'P f$6 :,&+7,*67( %,6+(5 (17'(&.7( u8%675$7 '(5 e{e fBefmVBX m,1$6(.203/(;( ,67 '$6 r52'8.7 '(6 t(7,12%/$6720*(16 J5%KP 5% :85'( $/6 (,1 v802568335(6625*(1 ,'(17,7=,(57N :(/&+(6 %(, $//(1 m,1'(51 0,7 (,1(0 t(7,12%/$6720 ,1$.7,9,(57 925/,(*7P k0 n$8)( '(5 /(7=7(1 l$+5( .2117(1 5%Oo87$7,21(1 ,1 9,(/(1 $1'(5(1 v8025(1 *(O )81'(1 :(5'(1 J6,(+( m$3P XPYPTKP c86 ',(6(1 d()81'(1 )2/*7(N '$M ',( f(/(7,21 '(6 5% i(16 2'(5 ',( j<3(53+263+255( o(/$120( $/6 )(67 '(7(50,1,(57( m216(48(1=(1 (,1(6 (5%/,&+(1 x(5/867(6 921 td %=:P rSX $1*(6(+(1 :(5'(1P h@5 e<&/,1 f ,67 %,6 +(87( .(,1 v8025 ,'(17,7=,(57 :25'(1N '(5 =:$1*6/>87* $86 (,1(5 c03/,7=,(581* ',(6(6 e<&/,16 +(5925*(+(1 :@5'(P f,( k1$.7,9,(581* 921 5% 2'(5 3SX 62:,( ',( c03/,7=,(581* 921 &<& 'S 67(//7 -('2&+ (,1( :,&+7,*( m20321(17( '(5 08/7,)$.72O

UPX |(//=<./86

STS

5,(//(1 i(1(6( 921 v8025(1 '$5P m20%,1$7,21(1 $86 '(5 c03/,7.$7,21 921 e<&/,1 f 81' '(0 x(5/867 921 5% %=:P 3SX 2'(5 $%(5 $86 '(0 '233(/7(1 x(5/867 921 3SX 81' 5% :(5'(1 ,1 v8025=(//(1 1,&+7 %(2%$&+7(7P u20,7 6&+(,1(1 tdN e{e fBefmVBX 81' rSX ,0 i(:(%( (,1 81' ',(6(/%( u&+$/767(//( =8 5(*8/,(5(1] (,1(6 ',(6(5 '5(, r527(,1( ,67 ,1 '(5 *52M(1 o(+5=$+/ $//(5 v8025( '()(.7 Jc%%P UPWYKP

P16 RB

Zellzyklusarrest

CYC D CDK 4/6 P -RB - P

Zellzyklusprogression

c%%P UPWY m21752//( '(6 |(//=<./86 $0 t(675,.7,216381.7P e<&/,1 fN rSX 81' '$6 t(7,12%O /$67203527(,1 JtdK 67(+(1 817(5(,1$1'(5 ,1 d(=,(+81*P e<&/,1 f ,1'8=,(57 ',( efmVBXO9(5O 0,77(/7( r+263+257,*7N '$M %(, '(5 :(,7$86 *5?M7(1 |$+/ 0(16&+/,&+(5 v8025( 0,1'(67(16 (,1 o,7*/,(' ',(6(5 '5(, h$.725(1 '(5(*8/,(57 ,67P u2 )@+57 -(:(,/6 ',( %(5(;35(66,21 921 e<&/,1 f J'85&+ c03/,7=,(581* '(6 e<&/,1 f i(16K 62:,( '(5 x(5/867 921 rSX 2'(5 td J'85&+ i(1'(/(7,21(1 2'(5 ,1$.7,9,(5(1'( o87$7,21(1K =8 (,1(5 k1$.7,9,(581* '(6 t(675,.7,216381.7(6 81' )2/*/,&+ (,1(5 (5+?+7(1 |(//=<./86352*5(66,21P

RMUMRMR c%2 %&&%2%.4% r#(%.+%, $%3 qaLr)'.!,7%'%3 td /,(*7 ,1 6(,1(5 1,&+7 3+263+25+5(1' '(5 iSOr+$6( '85&+ ',( c.7,9,(581* '(5 efmVBXOr527(,1( =85 r+263+2O 5//7 (,1 v(,/ '(5 tdBgThOm203/(;(P c/6 t(68/7$7 :(5'(1 i(1(N ',( ,1 '(5 )5@+(1 iSOr+$6( '85&+ ',(6(1 m203/(; 5(35,0,(57 :85'(1 -(7=7 (;35,0,(57P |,(/*(1( '(5 gThOh$.725(1 .2',(5(1 )@5 r527(,1( 0,7 (,1(5 h81.7,21 ,1 '(5 r52O *5(66,21 '(6 |(//=<./86 921 iS 1$&+ uN '(5 t(3/,.$7,21 '(5 fpc 81' '(5 k1'8.7,21 921 c323726( Jc%%P UPWZ%KP k16%(621'(5( ',( t(*8/,(581* '(6 e<&/,1 g i(16 J&<& (K '85&+ tdBgTh 6&+(,17 (,1( :,&+7,*( t2//( ,1 '(5 t(*8/$7,21 '(6 t(675,.7,216381.7(6 =8 63,(/(1P u2 .2007

STT

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

RB E2F

--

frühe G1

TTTCGCGC

RB

späte G1

P P P E2F TTTCGCGC

+

E2F-Targetgene (Auswahl) Target • cyc e

Funktion Zellzyklusregulation

• p14 arf

Apoptose

• tk • dhfr • ·-pol

DNA-Replikation

R

S (a)

(b)

c%%P UPWZ td ,67 (,1 75$16.5,37,21$/(5 t(35(6625 921 gTh |,(/*(1(1P J$K k1 6(,1(5 817(5O 3+263+257 921 td =80 |(,7381.7 '(6 t(675,.7,216381.7(6 JtKP c/6 m216(48(1= :,5' gThO$%+>1*,*( i(1(;35(6,621 $.7,9,(57 J1KP J%K r52'8.7( 921 gThO|,(/*(1(1 @%(51(+0(1 h81.7,21(1 ,1 '(5 t(*8/$7,21 '(5 |(//=<./86352*5(66,21N '(5 c323726( 62:,( '(5 fpcOt(3O /,.$7,21 J7.N v+<0,',1.,1$6(] '+)5N f(+<'52)2/$75('8.7$6(] sO32/N fpc r2/<0(5$6( sKP

(6 ,0 u,11( '(5 2P *P t(*8/$7,21 921 gThO|,(/*(1(1 %(5(,76 $% '(5 (567(1 j>/)7( '(5 iSOr+$6( =85 67(,*(1'(1 g;35(66,21 '(6 &<& (Oi(16P f85&+ ',( ,1 ',(6(5 |(,7 3(50$1(17 )$//(1'( m21=(175$7,21 '(6 emk rTY J6P 2PK .2007 (6 '$11 =85 d,/'81* $.7,9(5 e{e gBefmT m203/(;(N )@5 ',( '$6 tdOr527(,1 (,1 :,&+7,*(6 u8%675$7 ,67P f$'85&+ :,('(580 :(5'(1 .217,18,(5/,&+ tdBgThOt(35(6625.203/(;( =(567?57N :$6 ,1 (,1(1 63581*+$)7(1 c167,(* '(5 e{e gBefmTOm,1$6( 0@1'(7P f,(6( 326,7,9( t@&..233/81* 0$5.,(57 (,1(1 :,&+7,*(1 r81.7 ,1 iSN 1>0/,&+ '$6 w06&+$/7(1 '(5 0,72*(1$%+>1*,*(1 k1$.7,9,(581* 921 td '85&+ e{e fBefmVBX $8) (,1( 0,72O *(181$%+>1*,*( k1$.7,9,(581* 921 td '85&+ e{e gBefmT Jc%%P UPW[KP f(5 u&+(,O 7(/381.7 ,1 ',(6(5 g1:,&./81* :,5' $/6 0?*/,&+( f(0$5.$7,21 '(6 t(675,.7,216381.O 7(6 $1*(6(+(1 81' $/6 (,1 d$867(,1 '(5 |(//=<./86$872120,( 9(567$1'(1P g6 62// $%(5 $8&+ %(7217 :(5'(1N '$M ',(6(6 o2'(/ 1,&+7 $8) $//( |(//(1 */(,&+(50$M(1 =875,57 81' ',( e{e gBefmTOm,1$6( $8&+ $1'(5( J12&+ 1,&+7 ,'(17,7=,(57(K u8%O 675$7( %(6,7=(1 08MP k1 -('(0 h$//( ,67 '(5 t(675,.7,216381.7 $%(5 '(5 %(, :(,7(0 :,&+7,*67( y$&+6O 7806.21752//381.7 ,0 v(,/81*6=<./86 0(16&+/,&+(5 |(//(1P f85&+ '$6 c8)75(7(1 '(5 |(//=<./86$872120,( 6,1' ',( ,0 |(//=<./86 )2/*(1'(1 r+$6(1 )@5 ',( y$&+67806O .21752//( '(5 |(//(1 921 817(5*(25'1(7(5 d('(8781*P f,(6( g5.(1171,6 %(58+7 ,16O %(621'(5( $8&+ $8) ,1 '(5 o(',=,1 *(6$00(/7( g5)$+581*(1N 1$&+ '(1(1 =(//=<.O /865(*8/,(5(1'( r527(,1( 0,7 75$16)250,(5(1'(5 m$3$=,>7 (,1'(87,* $8) ',( |(,7 %,6 =80 t(675,.7,216381.7 (17)$//(1P

UPX |(//=<./86

STU

CYC D/CDK 4,6 RB

RB/E2F

G1-Phase

mitogenabhängig

Mitogene

E2F R

autonom

CYC E (Zellzyklusprogression) S-Phase

c%%P UPW[ o2'(// )@5 ',( g1767(+81* '(5 $872120(1 |(//=<./86352*5(66,21P f,( o,72*(1O $%+>1*,*( k1'8.7,21 921 e<&/,1 f ,1$.7,9,(57 '(1 tdBgTh t(35(6625.203/(;P c0 t(675,.O 7,216381.7 .2007 (6 1$&+ h5(,6(7=81* 921 gTh =85 75$16.5,37,21$/(1 c.7,9,(581* '(6 e<&/,1 gOi(16P e<&/,1 g 75>*7 '85&+ :(,7(5( r+263+25581* '(5 $872120(1N o,72*(1O 81$%+>1*,*(1 |(//=<./86352*5(66,21 1$&+ f85&+6&+5(,7(1 '(6 t(675,.7,216381.7(6P

RMUMS oTRL!"(;.')'% y%,,:9+,53+/.42/,,% f$6 rWU r527(,1 75>*7 '(1 d(,1$0(1 NNi8$5',$1 2) 7+( i(120(DD Jy>&+7(5 '(6 i(1206KP f,(6 9(5:(,67 $8) ',( h>+,*.(,7 921 rWU $0 u&+1,77381.7 =:(,(5 u,*1$/O :(*( 326,7,21,(57 =8 6(,1N ',( -(:(,/6 k1)250$7,21(1 @%(5 *(120,6&+(1 u75(M $1 ',(6(6 r527(,1 9(50,77(/1 Jc%%P UPXRKP c/6 *(120,6&+(5 u75(M 62// ,1 ',(6(0 u,11( (,10$/ ',( ',5(.7( u&+>',*81* 921 fpc '85&+ wxO 2'(5 uOu75$+/81* 62:,( '85&+ *(12O 72;,6&+( u8%67$1=(1 :,( =P dP ',( e+(027+(5$3(87,.$ o(7+275(;$7 2'(5 g72326,' 9(567$1'(1 :(5'(1P |80 $1'(5(1 ,67 '$0,7 ',( 3$7+2/2*,6&+( c.7,9,(581* (,1=(/1(5 q1.2*(1( *(0(,17N ',( (,1(1 ,62/,(57(1 t(,= =85 |(//=<./86$.7,9,(581* J81' '$0,7 '(5 t(3/,.$7,21 '(6 i(1206K '$567(//(1N 2+1( '$%(, ,1 '$6 .203/(77( 3+<6,2/2*,6&+( r52*5$00 '(5 0,72*(1(1 c.7,9,(581* ,17(*5,(57 =8 6(,1P c/6 NNy>&+7(5 '(6 i(1206DD ,67 (6 ',( 3+<6,2/2*,6&+( h81.7,21 921 rWU ',( |(//( %=:P '(1 q5*$1,6086 925 '(1 0?*/,&+(1 m216(48(1=(1 '(6 *(120,6&+(0 u75(66(6 =8 6&+@7=(1P u2 .?117(1 fpcOu&+>'(1 =85 c15(,&+(581* 327(17,(// *()>+5/,&+(5 o87$7,21(1 ,1 '(1 817(56&+,('/,&+67(1 i(1(1 )@+5(1 81' $8) ',(6( y(,6( =8 '(5 v5$16)250$7,21 921 |(//(1 %(,75$*(1P f,( c.7,9,(581* 921 q1.2*(1(1 J2'(5 k1$.7,9,(581* 921 v8O 02568335(6625*(1(1K :@5'( 352/,)(5$7,9( u,*1$/( ',5(.7 $1 '(1 |(//=<./86 :(,7(5O /(,7(1 81' 620,7 (%(1)$//6 ',( v5$16)250$7,21 921 |(//(1 %(*@167,*(1P w0 ',(6 =8 9(5+,1'(51N :,5' rWU 1$&+ *(120,6&+(0 u75(M +2&+5(*8/,(57 81' '85&+ rWU (,1 (17635(&+(1'(6 u&+87=352*5$00 ,1'8=,(57P f,( v$76$&+(N '$M rWU ,1 @%(5 WR @

STV

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( „Genomischer Streß” DNA Schäden

Onkogenaktivierung

MYC, RAS E2F

ATM

CDC25

P14 ARF

14-3-3

P53

MDM2

P21

CYC/CDK 4/6

RB

P16

G2-Arrest

DNA-Reparatur

Apoptose

Seneszenz

G1-Arrest

c%%P UPXR rWUO$%+>1*,*( |(//=<./86.21752//(P h@5 ',( c1%,1'81* 921 rWU $1 ',( t(*8/$7,21 '(5 fpcOt(3$5$785 81' c323726( 6,(+( m$3,7(/ UPYPW 81' UPZPWP

$//(5 0(16&+/,&+(1 v8025( ,1$.7,9,(57 ,67 81' '$0,7 '$6 $0 +>87*67(1 %(7525(1( i(1 ,1 '(5 q1.2/2*,( @%(5+$837 '$567(//7N 6&+(,17 ',( d('(8781* '(5 rWU h81.7,21 )@5 ',( |(//( ,1 ',(6(0 u,11( =8 %(67>7,*(1P f,( 9(56&+,('(1(1 u,*1$/:(*( =85 g5)$6681* '(6 *(120,6&+(1 u75(66(6 %=:P ',( rWUO9(50,77(/7(1 i(*(10$M1$+0(1 %(5@+5(1 (,1( x,(/=$+/ :,&+7,*(5 %,2/2*,6&+(5 t(*(/.5(,6/>8)( 81' 6,1' ,1 c%%,/'81* UPXR =86$00(1)$66(1' '$5*(67(//7P rWU /,(*7 ,1 '(5 |(//( ,1 *(5,1*67(1 m21=(175$7,21(1 925N :$6 +$8376>&+/,&+ '$5$1 /,(*7N '$M (6 ,1 6(,1(5 h81.7,21 $/6 v5$16.5,37,216)$.725 ',( c.7,9,(581* '(6 i(16 0'0T 9(5O 856$&+7N '(66(1 r52'8.7 :,('(580 '$6 rWU r527(,1 ,1$.7,9,(57P f,(6( ofoTO9(5O 0,77(/7( k1$.7,9,(581* (5)2/*7 @%(5 ',( k1'8.7,21 '(6 3527(2/<7,6&+(1 c%%$86 921 rWU @%(5 '(1 w%,48,7,1Or527($620(1Oy(*P c86 ',(6(0 1(*$7,9(1 t@&..233/81*6O :(* 5(68/7,(57 (,1( 817(5 3+<6,2/2*,6&+(1 w067>1'(1 >8M(567 6(16,7,9( t(*8/$7,21 '(5 o(1*( $1 rWU ,1 '(5 |(//(P p$+(=8 $//( h81.7,21(1 81' f<6)81.7,21(1 921 rWU 6,1' $8) (,1 *(>1'(57(6 i/(,&+*(:,&+7 ',(6(5 rWUBofoTOk17(5$.7,21 =85@&.=8)@+5(1P u2 ,67 0'0T ,1 9(5O 6&+,('(1(1 v8025(1 $/6 J$03/,7=,(57(6K q1.2*(1 ,'(17,7=,(57 :25'(1N :(/&+(6 (,1(1 x(5/867 '(5 (5(.7,9(1 c15(,&+(581* 921 rWU 1$&+ *(120,6&+(0 u75(M %('(87(7P g%(162 )@+5(1 ,1$.7,9,(5(1'( r81.7087$7,21(1 ,1 rWU ,1 '(5 t(*(/ =8 (,1(0 x(5/867 '(5 c.7,9,(581* 921 rWU |,(/*(1(1P f$5$86 :,('(580 5(68/7,(57 ',( ,1 9,(/(1 v8O 025(1 *()81'(1( *52M( o(1*( $1 )81.7,216817@&+7,*(0 rWUN '$6 0$1*(/6 '(5 0'0TOv5$16$.7,9,(581* 1,&+7 '(*5$',(57 :,5'P

UPX |(//=<./86

STW

RMUMSMP j/.42/,,&5.+4)/.%. 6/. oTR "%) cm`Lr#(;$%. g,1 :,&+7,*(5 u&+5,77 %(, '(5 k'(17,7=,(581* 921 *(6&+>',*7(5 fpc ,1 '(5 |(//( ,67 ',( c.7,9,(581* (,1(5 h$0,/,( 921 m,1$6(1 =8 '(1(1 $8&+ '$6 v802568335(6625O 3527(,1 cvo *(+?57 J6,(+( m$3P UPYPVKP o,7*/,('(5 ',(6(5 h$0,/,( +$%(1 8P $P =:(, :,&+7,*( u8%675$7(\ rWU J',5(.7K 81' efeTW J,1',5(.7KP f85&+ ',( r+263+255 =:(, rWU |,(/*(1(1P g,1(56(,76 ,67 ',(6 '$6 emkOi(1 3TSN :(/&+(6 '85&+ ',( k1$.O 7,9,(581* '(5 e{e fBg k17(5$.7,21 0,7 efm6 =8 (,1(5 c55(7,(581* '(6 |(//=<./86 ,1 iS )@+57P f$6 =:(,7( rWU |,(/*(1 ,67 SVOUOUN :(/&+(6 63(=,76&+ ',( '85&+ ',( cvoO h$0,/,( 3+263+25',*81* '(5 |(//=<./86 ,1 iS 81' iT 81O 7(5%52&+(1P f,(6( w17(5%5(&+81* (5/$8%7 '(5 |(//(N ',( fpcOu&+>'(1 =8 5(3$5,(5(1 J6,(+( m$3P UPYPWK 81' $8) ',(6( y(,6( 6,&+(5=867(//(1N '$M 185 ,17$.7( fpc 5(3/,=,(57 81' $8) ',( v2&+7(5=(//(1 9(57(,/7 :,5'P

RMUMSMQ c%2 oTRL).$5:)%24% fPLj/.42/,,05.+4 .!#( n.+/'%.!+4)6)%25.' f,( ,62/,(57( q1.2*(1$.7,9,(581* )@+57 1,&+7 185 =8 (,1(5 k1'8.7,21 '(6 |(//=<./86N 621'(51 $8&+ =85 J81*(:2//7(1K c.7,9,(581* (,1(5 y$&+678066,&+(581*P f,(6( u,O &+(581* :,5' '85&+ ',( c.7,9,(581* '(6 i(16 3SV$5) '85&+ ',(6(/%(1 q1.2*(13O 52'8.7( $86*(/?67P f$6 rSVcth r527(,1 ,67 (,1 ',5(.7(5 k1+,%,725 921 ofoTN :$6 :,('(580 =8 (,1(5 u7(,*(581* '(6 rWU r527(,16 )@+57P }+1/,&+ :,( ,0 fpcOu&+$'(1O u,*1$/:(* )@+57 ',(6 @%(5 ',( c.7,9,(581* 921 rTS =8 (,1(5 k1+,%,7,21 '(5 e{eOfBg $.7,9,(57(1 efm6 81' (,1(0 iSOc55(67P y,( '(5 rWUO9(50,77(/7( iSOc55(67 %(, 3+0/,&+ 3WU 81' 5%N 5(*8/,(5(1 .?11(1 Jc%%P UPXSKP

RMUMSMR oTRL6%2-)44%,4% `0/04/3% 5.$ 6/2:%)4)'% y%,,!,4%25.' p(%(1 '(5 |(//=<./86$55(7,(581* ,1 iS 81' iT .$11 rWU 1$&+ *(120,6&+(0 u75(M $8&+ =:(, :(,7(5( u&+87=)81.7,21(1 $.7,9,(5(1\ ',( k1'8.7,21 '(5 c323726( J352O *5$00,(57(5 |(//72'N 6,(+( m$3P UPZPWK 81' '(5 u(1(6=(1= J925=(,7,*( |(//$/7(581*K Jc%%P UPXRKP o?*/,&+(5:(,6( 6,1' ',(6 o$M1$+0(1 1$&+ ,55(3$5$%/(1 fpcOu&+>'(1 2'(5 0$66,9(5 q1.2*(1$.7,9,(581*P f,( u(1(6=(1= ,67 (,1 $8) 02/(.8/$5(5 g%(1( :(1,* 9(567$1'(1(5 x25*$1* '(6 1$7@5/,&+(1 c/7(581*6352=(66(6 921 |(//(1P g17635(&+(1' :,5' ',( rWUO9(50,77(/7( u(1(6=(1= $8&+ $/6 NN925=(,7,*DD J35(0$785( 6(1(6&(1&(K $1*(6(+(1P u2 :(5'(1 125O

STX

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( P53

P14

p14 mRNA

1‚

1·

2

3

p16 mRNA

P16 RB-P CYCD CDK4/6 E2F

c%%P UPXS f,( r52'8.7( '(6 rSX kpmVcBrSVcth i(1/2&86P k1 (,1(0 )@5 '$6 0(16&+/,&+( i(120 %,6/$1* (,1=,*$57,*(1 d(,63,(/ .2',(57 '(5 n2&86 [3TS ,1 =80 v(,/ @%(5/$33(1'(1 n(O 6(5$67(51 )@5 rSVcth 81' rSXkpmVcP rSXkpmVc ,1$.7,9,(57 $/6 e<&/,1.,1$6(Ok1+,%,725 efmVBXN :$6 =8 (,1(0 |(//=<./86$55(67 ,1 iS )@+57P rSVcth +,1*(*(1 $.7,9,(57 '$6 v8025O 68335(66253527(,1 rWUN :(/&+(6 '$11 @%(5 ',( c.7,9,(581* '(6 e<&/,1.,1$6(Ok1+,%,7256 rTS (%(1)$//6 =80 iSOc55(67 $0 t(675,.7,216381.7 )@+57P

0$/( |(//(1 '85&+ ',( %(5(;35(66,21 '(6 5$6Oq1.2*(16 1,&+7 (7:$ 75$16)250,(57N 621'(51 5($*,(5(1 ,1 c1:(6(1+(,7 921 )81.7,21(//(0 rWU $8) ',( i()$+5 '(5 v5$16O )250$7,21 0,7 (,1(0 ,55(9(56,%/(1 v(,/81*66723P u(1(6=(1= =(,&+1(7 6,&+ $8) '(5 |(//O =<./86(%(1( '85&+ ',( +2+( g;35(66,21 921 rWUN rTS 81' rSX $86N $/62 921 h$.O 725(1N ',( ,1 ',(6(5 m20%,1$7,21 '(1 |(//=<./86 ,1 $//(1 r+$6(1 $55(7,(5(1 .?11(1P g567 ',( =86>7=/,&+( g;35(66,21 (,1(6 :(,7(5(1 q1.2*(16 J:,( =P dP 921 0<&K ,1 '(1 6(/%(1 |(//(1 )@+57 =80 x(5/867 '(5 rWUO$%+>1*,*(1 u(1(6=(1= 81' 6&+/,(M/,&+ =8 ,+5(5 v5$16)250$7,21P

RMUMSMS oTRY KKo!..%.(),&%AA &=2 $%. qaLr)'.!,7%' f,(6( x(568&+( 9(5'(87/,&+(1 (,1( :,&+7,*( g5.(1171,6 '(5 v8025%,2/2*,(\ p250$/( |(//(1 .?11(1 0,7 *(1(7,6&+ '(7(50,1,(57(1 u&+87=352*5$00(1 $8) 327(17,(// 75$16O )250,(5(1'( g5(,*1,66( 5($*,(5(1 81' ',(6( '$0,7 $%:(+5(1P g567 :(11 (6 =8 0(+O

UPX |(//=<./86

STY

RB und P53 aktiv P53

physiologische Stimulation

Apoptose

P14 ARF ?

RB/E2F

E2F

MDM2 Zellzyklusprogression DNA-Synthese

kontrollierte Zellteilung

RB- P

(a)

RB inaktiv - P53 aktiv P53

nicht physiologische Stimulation

Apoptose

P14 ARF MDM2

(b)

RB

E2F

Zellzyklusprogression

RB und P53 inaktiv P53

nicht physiologische Stimulation

Apoptose

P14 ARF MDM2

(c)

RB

E2F

Zellzyklusprogression

? unkontrollierte Zellteilung

Tumor

c%%P UPXT rWUONNr$11(1+,/)(DD )@5 '(1 tdOu,*1$/:(*P J$K y>+5(1' (,1(5 3+<6,2/2*,6&+(1 y$&+6780667,08/$7,21 .2007 (6 =85 r+263+25
STZ

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U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

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RMVMQMP q%0!2!452 6/. a!3%.&%(,0!!25.'%.Y c)#+$!2-+!2:)./- /(.% o/,90/3)3 g,1 i52M7(,/ '(5 :>+5(1' '(5 fpcOt(3/,.$7,21 (,1*(%$87(1 d$6(1)(+/3$$581*(1 :,5' 62*/(,&+ '85&+ ',( m255(.785$.7,9,7>7 '(5 fpcOr2/<0(5$6( $86*(*/,&+(1 J6,(+( m$3P UPXPSPSKP h(+/3$$581*(1N ',( 921 ',(6(0 u<67(0 1,&+7 (5)$M7 :(5'(1N .?11(1 921 (,1(0 63(=,76&+(1N $/6 r267Ot(3/,.$7,216Od$6(1)(+/3$$581*6Ot(3$5$7856<67(0 %(=(,&+1(7(1 m203/(; .255,*,(57 :(5'(1 Jc%%P UPXWKP f,(6(6 u<67(0 (50?*/,&+7 ',( t(3$5$785 921 (,1)$&+(1 d$6(1)(+/3$$581*(1 62:,( g,1=(/675$1*,16(57,21(1 921 %,6 =8 9,(5 =86>7=/,&+(1 d$6(1P q%:2+/ 1,&+7 %(.$117 ,67N :,( '(5 t(3$5$785.203/(; '(1 087,(57(1 920 1,&+7 087,(57(1 u75$1* =8 817(56&+(,'(1 9(50$*N *(/$1* ',( k'(17,7=,(581* 81' m/21,(O 581* '(5 i(1352'8.7(N ',( ',5(.7 ,1 '(1 g5.(1181*6352=(66 '(5 h(+/3$$581*(1 ,192/9,(57 6,1'P f,( 810,77(/%$5( c167(8(581* '(6 f()(.7(6 *(6&+,(+7 '85&+ '$6 r527(,1 oujT Jc%.P )@5 o87u j202/2*N :2%(, o87u (,1 h(+/3$$581*65(3$5$785O 3527(,1 $86 gP&2/, ,67KN :(/&+(6 (,1)$&+( d$6(1)(+/3$$581*(1 81' k16(57,21(1 921 (,1 2'(5 =:(, d$6(1 $/6 j(7(52',0(5 0,7 oujX 81' *5?M(5( k16(57,21(1 $/6 j(7(52O ',0(5 0,7 oujU (5.(117P f,(6( m203/(;( :(5'(1 ,1 (,1(0 1>&+67(1 u&+5,77 921 c1.(53527(,1(1 JrouT 81' onjSK *(%81'(1N ',( '(1 (,*(17/,&+(1 t(3$5$785Og1O =<0.203/(; 5(.587,(5(1N '(5 ',( g;=,6,21 '(5 d$6( J81' **)P ,+5(1 g56$7=K 9251,007P f,(6(5 m203/(; ,67 %,6+(5 1,&+7 (,1'(87,* ,'(17,7=,(57 :25'(1N :,5' $%(5 $1$/2* .216(59,(57(5 t(3$5$7856<67(0( ,1 j()(1 81' gP&2/, g;218./($6(1N fpcOr2/<0(O 5$6(1 81' n,*$6(1 %(,1+$/7(1N ',( '(1 f()(.7 ,0 1(86<17+(7,6,(57(1 u75$1* .255,O *,(5(1P f,( 0(',=,1,6&+( d('(8781* '(6 ootOu<67(06 :,5' ,16%(621'(5( '$'85&+ %(O /(*7N '$M (7:$ XR @ '(5 d(7525(1(1 0,7 (5%/,&+(0 f,&.'$50.5(%6 2+1( r2/<326,6 Jc%.P jpree )@5 (1*/P\ +(5(',7$5< 121O32/<326,6 &2/21 &$1&(5K (,1( o87$7,21 ,0 oujTOi(1 81' UR @ (,1( o87$7,21 ,0 onjSOi(1 $8):(,6(1 J6,(+( m$3P XPZPUKP jpree r$7,(17(1 :(,6(1 $8M(5'(0 ,1 0(+5 $/6 (,1(0 f5,77(/ '(5 h>//( |:(,778O 025(1 $8)N :$6 ',( d('(8781* '(6 x(5/867(6 921 oot )@5 ',( $//*(0(,1( i(120O ,17(*5,7>7 817(5675(,&+7P u2 ,67 $8&+ (,1 %(621'(56 +(592567(&+(1'(6 o(5.0$/ $// ',(6(5 g5.5$1.81*(1 ',( $//*(0(,1( k167$%,/,7>7 921 o,.526$7(//,7(1 J6,(+( m$3P VKN ',( :$+56&+(,1/,&+ $8) '(1 t(3$5$7,2169(5/867 921 t(3/,.$7,216)(+/(51 ,1 f,18.O /(27,'Ot(3($7(/(0(17(1 J%(621'(56 ecOf,18./(27,'(K =85@&.=8)@+5(1 ,67P g,1 $1O '(5(6 +>87* *()81'(1(6 r52%/(0N :(/&+(6 '85&+ '(1 x(5/867 921 oot %(',1*7 ,67N ,67 ',( v+(5$3,(5(6,67(1= 921 v8025(1 %(, d(+$1'/81* 0,7 $/.5 '$5,1 %(*5@1'(7 =8 /,(*(1N '$M ',( 0$1*(/1'( g5.(1O 181* '(5 7+(5$3(87,6&+(1 fpcOu&+>'(1 1,&+7 =8 (,1(5 g/,0,1,(581* '(5 v8025O =(//(1 )@+57P

UPY fpcOt(3$5$785

SUY

CH3 MSH2

CH3

MLH1

PMS2

CH3 Exonuklease

CH3 SSB

CH3 DNA Polymerase

DNA Ligase

c%%P UPXW x25*$1* '(5 t(3$5$785 921 d$6(1)(+/3$$581*(1P f,( 6&+5,77:(,6( g5.(1181* 81' g17)(5181* 921 d$6(1)(+/3$$581*(1 1$&+ '(5 fpc t(3/,.$7,21 ,67 '$5*(67(//7P g176&+(,'(1' )@5 ',( g17)(5181* '(5 1(8,1.25325,(57(1N )$/6&+(1 d$6( ,67 ',( v$76$&+(N '$M '(5 1(86<17+(O 7,6,(57( u75$1* 12&+ 1,&+7 '85&+ fpcOo(7+
SUZ

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

RMVMQMQ c)% a!3%.Ld8:)3)/.32%0!2!452 v>*/,&+ .2007 (6 ,1 -('(5 |(//( 816(5(6 q5*$1,6086 =8 +81'(57(1 921 &+(0,6&+(1 d$6(16&+>',*81*(1 :,( (7:$ '(5 63217$1(1 f(6$0,1,(581* 921 e<726,1 =8 w5$&,/P f$ 6,&+ w5$&,/ 0,7 c'(1,1 81' i8$1,1 3$$57N .$11 (6 %(, '(5 1>&+67(1 t(3/,.$7,21 =8 i B c v5$16,7,21(1 .200(1N ,1'(0 ,0 1(86<17+(7,6,(57(1 u75$1* $167(//( (,1(6 i8$1,16 (,1 c'(1,1 *(*(1@%(5 '(0 w5$&,/ (,1*(%$87 :,5'P f(6+$/% 0@66(1 %(6&+>O ',*7( d$6(1 (17)(517 81' (56(7=7 :(5'(1P f,(6(5 x25*$1* :,5' '85&+ ',( d$6(1O g;=,6,2165(3$5$785 $86*()@+57 Jc%%P UPXXKP g1=<0$7,6&+ %(58+7 ',( dgt $8) fpcO i/<.261'(57(1 d$6(1 :,( (7:$ o(7+',*7( d$6( )5(,*(6(7=7 :,5'P k1 (,1(0 1>&+67(1 u&+5,77 (5=(8*7 (,1( 63(=,76&+( g1'218./($6( (,1( n@&.( 921 (,1(0 p8./(27,' ,0 g,1=(/675$1*N ',( 921 g;218./($6(1 ,1 %(,'( t,&+781*(1 (5:(,7(57 :(5'(1 .$11P y,( 6&+21 %(, '(5 p8O ./(27,'Og;=,6,2165(3$5$785 *(6(+(1N .$11 $16&+/,(M(1' (,1 $86 fpcOr2/<0(5$6(1 81' n,*$6(1 %(67(+(1'(5 m203/(; ',( n@&.( :,('(5 9(56&+/,(M(1N :2%(, $8&+ +,(5 '(5 1,&+7 %(6&+>',*7( fpcOu75$1* $/6 o$75,=( ',(17N 62 '$M .(,1 k1)250$7,2169(5O /867 (1767(+7P

RMVMR cm` k;3)/.%.K $)% "%)$% cm` r42;.'% "%42%&&%. d,6+(5 :85'(1 n>6,21(1 925*(67(//7N ',( 185 (,1(1 u75$1* '(5 fpcOf233(/+(/,; %(75(5(1P k1 ',(6(1 h>//(1 ',(17 '(5 1,&+7 %(6&+>',*7( u75$1* $/6 x25/$*( )@5 ',( p(86<17+(6( '(6 %(6&+>',*7(1 u75$1*6P c1'(56 9(5+>/7 (6 6,&+ %(, n>6,21(1N ',( %(,'( u75>1*( %(75(5(1 :,( f233(/675$1*%5@&+( 81' k17(5675$1*9(51(7=81*(1 J62O *(1$117( &5266/,1.6KP k1 ',(6(1 h>//(1 *,%7 (6 .(,1( 810,77(/%$5( o$75,=(N $1+$1' '(5(5 (,1 (;=,6,(57(6 fpc h5$*0(17 :,('(5$8)*(%$87 :(5'(1 .$11P f233(/675$1*%5@&+( JfudK :(5'(1 +$8376>&+/,&+ '85&+ ,21,6,(5(1'( u75$+/(1 9(5856$&+7 81' .?11(1 @%(5 =:(, 35,1=,3,(//( y(*( 5(3$5,(57 :(5'(1P f(5 (567( y(* (17)(517 fud '85&+ n,*$7,21 '(5 fpcOg1'(1N '$6 62*(1$117( 121O+202/2*286 (1' -2,1,1* JpjglKP d(, ',(6(0 x25*$1* :(5'(1 -('2&+ ',( '85&+ '(1 d58&+ 9(585O 6$&+7(1 fpc g1'(1 (,1=(/675>1*,* $%*(%$87N %,6 (,1( *(:,66( m203/(0(17$5,7>7 '(5 @%(567(+(1'(1 g1'(1 *()81'(1 :,5'P f$'85&+ (1767(+(1 ./(,1(5( f(/(7,21(1N ',( 327(17,(//( o87$7,21(1 '$567(//(1P u20,7 ,67 ',(6( c57 '(5 t(3$5$785 )(+/(5+$)7P f(5 =:(,7( y(* (17)(517 fud @%(5 +202/2*( t(.20%,1$7,21N %(187=7 $/62 ,0 r5,1O =,3 ',( u(48(1=,1)250$7,21 '(6 +202/2*(1 e+52026206 80 fud 0,7 *(5,1*)@O *,*67(0 k1)250$7,2169(5/867 =8 5(3$5,(5(1P f,( %(,'(1 fudOt(3$5$785:(*( =(,*(1 -(:(,/6 (,1 '(87/,&+(6 c.7,9,7>763527/ ,0 |(//=<./86P y>+5(1' pjgl 925:,(*(1' ,1 iS 81' $0 d(*,11 '(5 uOr+$6( '(5 $.7,9(5( fud t(3$5$785:(* ,67N *5(,)(1 ',( o(&+$1,60(1 '(5 +202/2*(1 t(.20%,1$7,21 925:,(*(1' :>+5(1' 81' 1$&+ '(5 fpc t(3/,.$7,21 ,1 '(5 uOr+$6(P q5(16,&+7/,&+ :,5' ',( 810,77(/%$5( c1:(6(1+(,7 (,1(6 u&+:(67(5&+520$7,'6 $86*(187=7N 80 fudN ',( 1$&+ '(5 t(3/,.$7,21 (1767(+(1N @%(5 '(1 *(1$8(5(1 t(3$5$785:(* '(5 +202/2*(1 t(.20%,1$7,21 =8 .255,*,(5(1P

UPY fpcOt(3$5$785

SU[

Glykosylase

Endonuklease OH

Exonuklease OH

DNA Polymerase

DNA Ligase

c%%P UPXX d$6(1Og;=,6,2165(3$5$785P f,( c%%,/'81* =(,*7 '$6 i581'0867(5 '(5 fpcOt(O 3$5$785 :,( 6,( ,1 6>07/,&+(1 352O 81' (8.$5<217,6&+(1 q5*$1,60(1 '85&+*()@+57 :,5'P |8O 1>&+67 :,5' (,1( n>6,21N =P dP (,1( 02',7=,(57( d$6(N '85&+ (,1 r527(,1N +,(5 (,1 i/<.265(1 u75$1*6 1(8 6<17+(7,6,(57P fpcOn,*$6( 6&+/,(M7 '$11 ',( 1(86<17+(7,6,(57( fpc .29$/(17 $1 '(1 $/7(1 u75$1* $1P

SVR

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

RMVMRMP q%0!2!452 6/. c/00%,342!.'"2=#(%. j202/2*( t(.20%,1$7,21 k1 (,1(0 (567(1 u&+5,77 :,5' '(5 fud =8 (,1(0 g,1=(/675$1* 0,7 UAO%(5+$1* 352O =(66,(57P f,(6(5 x25*$1* %(1?7,*7 (,1( j(/,.$6(O %=:P p8./($6($.7,9,7>7N ',( 12&+ 1,&+7 6,&+(5 ,'(17,7=,(57 ,67P c//( :(,7(5(1 u&+5,77( :(5'(1 921 '(0 62*(1$117(1 tcfWTOm203/(; '85&+*()@+57N '(5 $86 0,1'(67(16 1(81 g,1=(/)$.725(1 =86$0O 0(1*(6(7=7 ,67P tcfWS ,67 (,1 =(175$/(6 r527(,1 ,1 ',(6(0 m203/(;P g6 32/<0(5,6,(57 $1 '(1 352=(66,(57(1 g,1=(/675>1*(1N 80 '257 (,1 5(*(/5(&+7(6 p8./(23527(,17/$0(17 $86=8%,/'(1N :(/&+(6 817(5 g,1%(=,(+81* :(,7(5(5 h$.725(1 '(6 tcfWTOm203/(;(6 ',( +202/2*( f233(/+(/,; J%=:P '$6 u&+:(67(5&+520$7,'K ,'(17,7=,(5(1 .$11P p$&+ (5)2/*5(,&+(5 c1/$*(581* '(5 +202/2*(1 fpcOc%6&+1,77( .2007 (6 =80 u75$1*O $867$86&+ =:,6&+(1 '(1 UAO%(5+>1*(1 '(6 *(6&+>',*7(1 o2/(.@/6 81' '(0 +202O /2*(1 c%6&+1,77 '(5 ,17$.7(1 f233(/+(/,; Jc%%P UPXY$KP o,7 j,/)( 921 fpc r2/
KU

RAD50

Nucleasen

MRE11 NBS1

DNA-PK

RAD51, RAD52 vermittelt XRCC4

DNA Ligase IV

Auflösung

(a)

(b)

c%%P UPXY f233(/675$1*%58&+Ot(3$5$785P f,( t(3$5$785 921 n>6,21(1N ',( %(,'( u75>1*( '(5 fpc %(75(5(1N :,( f233(/675$1*%5@&+(N %('$5) %(621'(5(5 o(&+$1,60(1N =P dP '(5 j2O 02/2*(1 t(.20%,1$7,21 J$KN :2%(, (,1 1,&+7%(6&+>',*7(6 +202/2*(6 fpc o2/(.@/ %(1?7,*7 :,5'P c/7(51$7,9 +,(5=8 .?11(1N ,0 h$//( '(6 f233(/675$1*%58&+(6 817(5 x(5:(1'81* 921 :(1,*67(16 =:(, =P vP 81$%+>1*,*(1 g1=<0.203/(;(1N ',( fpcOg1'(1 :,('(5 0,7(,1$1'(5 9(5.1@3)7 :(5'(1N 62*P g1'Ol2,1,1* J%KP g,1=(/+(,7(1 6,1' '(0 v(;7 =8 (171(+0(1P

UPY fpcOt(3$5$785

SVS

*()@*7 :(5'(1P u&+/,(M/,&+ :,5' '(5 t(3$5$785OfpcOm203/(; @%(5 (,1( t(62/9$6( $8)*(/?67P c8&+ :>+5(1' '(5 o(,26( ,67 '(5 tcfWT m203/(; $.7,9N %(1?7,*7 '$11 $%(5 :(,7(5( h$.725(1 JtcfWRN otgSS 81' (,1 ztuTrOj202/2*KP k1 0,727,6&+(1 |(/O /(1 (5)@//7 ',(6(5 u8%.203/(; '$5@%(5 +,1$86 (,1( h81.7,21 ,1 '(5 t(3$5$785 921 fud @%(5 121O+202/2*286 (1' -2,1,1*P f,(6(5 u$&+9(5+$/7 ,67 ,162)(51 921 d('(8O 781*N $/6 '$6 '$6 0(16&+/,&+( ztuTrOj202/2* .@5=/,&+ $/6 '$6 p,-0(*(1Od5($.$*( r527(,1 ,'(17,7=,(57 :25'(1 ,67 J6P 8PKP p21O+202/2*286 (1' -2,1,1* g6 ,67 1,&+7 %(.$117 :$580 fud 817(5 *(:,66(1 w067>1'(1 35>)(5(17,(// '85&+ '$6 )(+/(5+$)7( u<67(0 '(6 pjgl 5(3$5,(57 :(5'(1P x25 '(0 j,17(5*581'N '$M '$6 0(16&+/,&+( i(120 $%(5 185 =8 (,1(0 ./(,1(1 r52=(176$7= $86 .2',(5(1'(1 %=:P *(15(*8/$725,6&+(1 u(48(1=(1 %(67(+7N %(, '(1(1 (6 '85&+ '(1 327(17,(//(1 k1)25O 0$7,2169(5/867 '(6 pjgl =8 0$1,)(67(1 o87$7,21(1 .200(1 .?117(N 6&+(,17 )@5 *52M( d(5(,&+( '(6 i(1206 pjgl (,1 +,15(,&+(1'(6 t(3$5$7856<67(0 =8 6(,1P k1O 7(5(66$17(5:(,6( *(+(1 %(67,007( f()(.7( '(6 pjgl $8&+ 0,7 f()(.7(1 '(5 xJfKl Ot(.20%,1$7,21 921 k0081*/2%8/,1(1 81' vO|(// t(=(3725(1 J6,(+( m$3P UPWK (,1O +(5N :$6 '$5$8) =85@&.=8)@+5(1 ,67N '$M %(,'( x25*>1*( (,1(1 @%(5/$33(1'(1 m20O 3/(; $1 h$.725(1 %(1?7,*(1P k1 ',(6(0 h$//( .?117( '$6 )(+/(5+$)7( pjgl $8&+ =80 x$5,$17(15(,&+780 %(, '(5 c17,.?53(5*(1(5,(581* %(,75$*(1 J6P 8PKP k1 (,1(0 )5@+(1 u&+5,77 '(6 pjgl :(5'(1 ',( )5(,(1 fpcOg1'(1 1$&+ (,1(0 f233(/675$1*%58&+ 921 (,1(0 j(7(52',0(5 $86 mwYR 81' mwZR *(%81'(1N :2%(, 1,&+7 *(./>57 ,67N 2% mwOr527(,1( ',( 7$76>&+/,&+(1 u(1625(1 '(6 fpcOu&+$'(16 6,1' 2'(5 (567 1$&+ c.7,9,(581* 921 J%,6+(5 1,&+7 %(.$117(1K r5,0>56(1625(1 $1 ',( %(6&+>',*7( fpc %,1'(1 Jc%%P UPXY %KP d(,'( h$.725(1 6,1' 5(*8/$725,6&+( w1O 7(5(,1+(,7(1 '(5 fpcO$%+>1*,*(1 r527(,1.,1$6(N '(5(1 .$7$/<7,6&+( w17(5(,1+(,7N fpcOrm&6N '85&+ '$6 mwOj(7(52',0(5 ,1 '(1 m203/(; (,1*(%81'(1 :,5'P g6 :,5' 9(5087(7N '$M ',(6(5 m203/(; ',( fpcOg1'(1 =86$00(1)@+57 81' $16&+/,(O M(1' '(1 g,175,77 '(6 2%(1 %(5(,76 (5:>+17(1 tcfWTOu8%.203/(;(6 $86 tcfWRN otgSS 81' '(0 p,-0(*(1 d5($.$*( u<1'520 r527(,1N pduSN (5/$8%7P f,(6(5 u8%O .203/(; %(6,7=7 (,1( g;218./($6($.7,9,7>7N ',( )@5 ',( r52=(66,(581* '(5 fpcOg1O '(1 %(1?7,*7 :,5'P c16&+/,(M(1' :(5'(1 ',( fpcOg1'(1 '85&+ (,1(1 n,*$6(Om20O 3/(; =86$00(1*()@*7P y,( 2%(1 %(5(,76 (5:>+17 %(6,7=7 ',( fpcO$%+>1*,*( r527(,1.,1$6( 1(%(1 '(5 h81.7,21 ,1 pjgl $8&+ (66(17,(//( c8)*$%(1 %(, '(5 xJfKlOt(.20%,1$7,21 J6,(+( m$3P UPWKP u2 %(58+7 '(5 02/(.8/$5( f()(.7 '(5 62*(1$117(1 uekfOo$86N ',( ,1 '(5 o(',=,1 (,1 9,(/%(187=(6 o2'(//6<67(0 (,1(6 6&+:(5(1 k0081'()(.7(6 '$567(//7N $8) '(0 x(5/867 '(5 fpcO$%+>1*,*(1 r527(,1.,1$6(P f$5@%(5 +,1$86 6&+(,1(1 ',( mwOr527(,1( $8&+ :,&+7,*( h81.7,21(1 %(, '(5 g5+$/781* '(5 v(/20(5/>1*( =8 63,(O /(1 81' 80*(.(+57 ',( uktOr527(,1(N ',( 75$16.5,37,21(//( t(35(66,21 $1 v(/20(5(1 9(50,77(/1N $8&+ :(6(17/,&+( J$%(5 12&+ 1,&+7 1>+(5 817(568&+7(K h81.7,21(1 %(, pjgl =8 @%(51(+0(1P

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pro- und anti-apoptotische Stimuli

C. elegans

CED-9

CED-4

CED-3

menschliche Homologe

BCL2

APAF1

Caspasen

Apoptose

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externe und interne pro-apoptotische Stimuli

Aktivierung der zellulären Signalwege

Exekution der Apoptose

wichtigste regulatorische Ebene der Apoptose

Zelltod

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SWR

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

RMWMS b!30!3%. 5.$ )(2% y)%,-/,%+=,% f,( p27:(1',*.(,7 0(+5(5(5 e$63$6(1 %(,0 o(16&+(1 (5*,%7 6,&+ $86 '(1 1,&+7 @%(5/$33(1'(1N =P vP =(//7<363(=,76&+(1 r52=(66(1N $1 '(5(1 g1'( ',( c323726( 67(+7P u2 ,67 =P dP ',( e$63$6( Z (,1 ,17(*5$/(5 d(67$1'7(,/ '(5 c323726( ,0 t$+0(1 '(5 vO|(// k0081$17:257N :2+,1*(*(1 ',( e$63$6( [ 127:(1',* )@5 ',( '85&+ uO u75$+/(1N i/8.2.257,.2,'( 2'(5 &<7272;,6&+( r+$50$.$ ,1'8=,(57( c323726( ,67 J6P 8PKP f(5 p$0( NNe$63$6(DD /(,7(7 6,&+ 921 '5(, %,2&+(0,6&+(1 e+$5$.7(5,67,.$ ',(6(5 r527(,1( $%P u2 6,1' e$63$6(1 J:,( $8&+ egfOUK r527($6(1N ',( ,1 ,+5(0 $.7,9(1N (1=<0$7,6&+(1 |(17580 (,1(1 e<67(,15(67 Je<6K $8):(,6(1 81' ,+5( u8%675$7( ,00(5 +,17(5 (,1(0 v(75$3(37,' 6&+1(,'(1N '$6 0,7 (,1(0 c63$57$75(67 Jc63K (1'(7P f$6 u85,; NN$6(DD 6&+/,(M/,&+ :(,67 $8) ',( (1=<0$7,6&+( c.7,9,7>7 '(6 r527(,16 +,1P e$63$6(1 /,(*(1 ,1 |(//(1 $/6 ,1$.7,9( r52(1=<0( 925N ',( '85&+ 3527(2/<7,6&+(1 x(5'$8 $.7,9,(57 :(5'(1 0@66(1 Jc%%P UPYSKP o,7 '(5 g5.(1171,6N '$M (6 6,&+ %(, '(1 e$63$6(O$.7,9,(5(1'(1 g1=<0(1 2)70$/6 6(/%67 80 e$63$6(1 +$1'(/7N =(,&+1(1 6,&+ =:(, w17(5*5833(1 921 e$63$6(1 $%P f,( egfOU >+1/,&+(1 e$63$6(1 6,1' ',( (,*(17/,&+(1 g5(.725&$63$6(1N ',( '85&+ '(1 x(5'$8 $323727,6&+(5 u8%675$7( J6P 8PK ',( %(6&+5,(%(1(1 0253+2/2*,6&+(1 x(5>1'(581*(1 '(5 |(//( %(',1*(1P c'O Procaspase Untereinheiten Prodomäne

A

B cys

aktivierender proteolytischer Verdau Prozessierung aktivierte Caspase

A

B

DE X D

cys

Substrat

c%%P UPYS r52=(66,(581* 921 r52&$63$6(1P r52&$63$6(1 :(5'(1 '85&+ =:(, 3527(2/<7,6&+( u3$/781*(1 ,1 (,1( r52'20>1( 81' ',( %(,'(1 w17(5(,1+(,7(1 c 81' d 352=(66,(57P f,( w17(5O (,1+(,7(1 )250,(5(1 6,&+ =8 '(5 $.7,9(1 e$63$6(N '(5(1 3527(2/<7,6&+(6 |(17580 '85&+ (,1(1 e<67(,15(67 Je<6K &+$5$.7(5,6,(57 ,67P k1 '(5 817(5(1 d,/'+>/)7( ,67 ,1 (,1(0 u8%675$7O 3527(,1 '$6 v(75$3(37,' fgzf J:2%(, NNzDD )@5 -('( 0?*/,&+( c0,126>85( 67(+7K $/6 g5.(1O 181*66(48(1= )@5 ',( $.7,9( e$63$6( '$5*(67(//7P f(5 3527(2/<7,6&+( x(5'$8 '85&+ ',( e$63$6( (5)2/*7 +,17(5 '(0 =:(,7(1 c63$57$75(67P

UPZ c323726(

SWS

v$%P UPZ e$63$6(1 81' ,+5( h81.7,21 ,1 '(5 c323726( e$63$6(1 g5(.725&$63$6(1 Jegf U >+1/,&+K e$63$6( U e$63$6( Y e$63$6( T c'$37(5&$63$6(1 e$63$6( X e$63$6( Z e$63$6( [

g5.(1181*6O 6(48(1=

u8%675$7

h81.7,21

fgzf

n$0,1 c&7,1 td kecf +1tpr fpc rm 8P9P$P0P

g;(.87,21 '(5 c323726(

JkBxBnK gzf

g5(.725&$63$6(1

c.7,9,(581* '(5 c323726(

$37(5&$63$6(1 6,1' d,1'(*/,('(5 =:,6&+(1 '(1 ',( c323726( $86/?6(1'(1 =(//8/>5(1 g5(,*1,66(1 JNNu,*1$/(DDK 81' '(1 g5(.725&$63$6(1 Jv$%P UPZKP f,( i5833( '(5 kegO >+1/,&+(1 e$63$6(1 Jkeg 3 ,17(5/(8.,1OStO&219(57,1* (1=<0(K 62// +,(5 $8) i581' ,+5(5 )@5 ',( c323726( (+(5 817(5*(25'1(7(1 t2//( 1,&+7 1>+(5 %(75$&+7(7 :(5'(1P u&+21 '(5 6758.785,(57( y$1'(/ '(5 |(//0253+2/2*,( '(87(7 $1N '$M $3237,(5(1'( |(//(1 .(,1(0 NN&+$27,6&+(1DD r527(2/<6(352=(66 =80 q3)(5 )$//(1N 621'(51 '$M ',( e$63$6(1 *(=,(/7 925*(+(1'( r527($6(1 0,7 '(71,(57(1 u8%675$7(1 6,1'P v<3,6&+( x(5O 75(7(5 '(5 u8%675$7( J2'(5 |,(/3527(,1(K 921 g5(.725&$63$6(1 6,1' ,1 v$%(//( UPZ $8)O *()@+57P d(, '(5 d(75$&+781* ',(6(5 u8%675$7( )>//7 $8)N '$M 6,( ,0 u,11( '(5 |(//=(5O 67?581* *87 1$&+92//=,(+%$5( |,(/( :>+5(1' '(5 c323726( '$567(//(1P |86$00(1*(O )$M7 6&+(,17 ',( k1$.7,9,(581* %,6+(5 ,'(17,7=,(57(5 u8%675$7( 0,7 )2/*(1'(1 m216(O 48(1=(1 )@5 ',( 67(5%(1'( |(//( (,1+(5=8*(+(1\ JSK w17(5%5(&+81* 921 u,*1$/O @%(575$*81*(1 ,1 '(5 |(//(N JTK k1+,%,7,21 '(5 i(1(;35(66,21N JUK c55(7,(581* '(6 |(//O =<./86N JVK x(5/867 921 fpcOt(3$5$785)81.7,21(1N JWK h5$*0(17,(581* &+520262O 0$/(5 fpc 81' JXK c%%$8 921 18./(>5(1 81' &<723/$60$7,6&+(1 u758.7853527(,1(1P y,( .$11 0$1 6,&+ -('2&+ ',( w06(7=81* '(5 c.7,9,(581* (,1(5 e$63$6( %,6 +,1 =85 9(5>1'(57(1 |(//0253+2/2*,( 92567(//(1a c0 d(,63,(/ '(5 fpcOh5$*0(17,(581* 62// ',( c&+6( e$63$6( A u8%675$7 A 0253+2/2*,6&+(6 m255(/$7 *(1$8(5 %(75$&+7(7 :(5'(1 Jc%%P UPYTKP g6 .2117( (,1 g1=<0 ,'(17,7=,(57 :(5'(1N :(/&+(6 1$&+ c.7,9,(581* '85&+ e$6O 3$6( U fpc 9(5'$8(1 .$11 J&$63$6(O$&7,9$7(' '(62;<5,%218&/($6(N ecfKP ecf .$11 =:$5 ,1 9,(/(1 |(//(1 *()81'(1 :(5'(1N ,67 (567$81/,&+(5:(,6( $%(5 ,0 e<723O /$60$ 921 |(//(1 /2.$/,6,(57N 2%:2+/ (6 (,1 18./(>5(6 n2.$/,6$7,2166,*1$/ %(6,7=7P g6 +$7 6,&+ $%(5 +(5$86*(67(//7N '$M ecf '85&+ (,1 $1'(5(6 r527(,1N NN,1+,%,725 2) ecfDD JkecfKN $.7,9 ,0 e<723/$60$ =85@&.*(+$/7(1 81' 62 ,1 1250$/(1 |(//(1 ,1 NNu,&+(5+(,76*(:$+56$0DD *(1200(1 :,5'P f,( c0,126>85(6(48(1= 921 kecf %(,1+$/7(7 =:(, 7<3,6&+( g5.(1181*6(/(0(17( )@5 ',( e$63$6( UP m2007 (6 $/62 =85

SWT

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,( Aktivierung

Caspase 3

N L S

N L S

CAD

CAD

ICA

D

ICAD

Kernmembran genomische DNA

c%%P UPYT c%%$8 *(120,6&+(5 fpc 1$&+ e$63$6( U c.7,9,(581*P g,1( '85&+ e$63$6( U $.7,9,(57( f(62;<5,%218./($6( JecfK :,5' '85&+ 3527(2/<7,6&+( u3$/781* (,1(6 k1+,%,725O 3527(,16JkecfK ,1 '(1 |(//.(51 75$163257,(57 81' .$11'257*(120,6&+( fpc ,17(518./(2620$/ 9(5'$8(1P

c.7,9,(581* 921 e$63$6( UN :,5' kecf 3527(2/<7,6&+ 9(5'$87N 81' '(5 m203/(; $86 kecf 81' ecf =(5)>//7P c/6 m216(48(1= '$5$86 75$16/2=,(57 ecf ,1 '(1 |(//O .(51 81' .$11 '257 ',( &+5202620$/( fpc $%%$8(1P

RMWMT r)'.!,7%'% $%2 `0/04/3% p$&+'(0 (6 =85 c.7,9,(581* '(5 g5(.725&$63$6(1 *(.200(1 ,67N ,67 '$6 $32372O 7,6&+( u&+,&.6$/ '(5 |(//(1 %(6,(*(/7P g6 ,67 '(6+$/% 921 *5?M7(5 d('(8781* )@5 -('( |(//(N ',( c.7,9,(581* '(5 c323726( J'P +P ',( c.7,9,(581* '(5 g5(.725&$63$6(1K 35>=,6( =8 67(8(51P f,(6 (5)2/*7 @%(5 $323727,6&+( u,*1$/:(*(N ',( '85&+ 817(56&+,('O /,&+( u7,08/, $.7,9,(57 :(5'(1P x(56&+,('(1( 352O$323727,6&+( u7,08/, 6,1' ,1 v$%(//( UP[ =86$00(1*()$M7P

UPZ c323726(

SWU

v$%P UP[ r52O$323727,6&+( u7,08/, r52O$3237,6&+( u7,08/, R R R R R R

wxOu75$+/81* uOu75$+/81* i/8.2.257,.2,'( g17=8* 921 y$&+67806)$.725(1 e<72.,1( evnOc1*5,5

f(5 hcuBhcu nOu,*1$/:(* f(5 hcuOn,*$1' Jhcu nK ,67 (,1 o,7*/,(' '(5 NN78025 1(&526,6 )$&725DDOh$0,/,( JvphK 921 e<72.,1(1P hcu n (;,67,(57 925 $//(0 $/6 0(0%5$167>1',*(5 h$.725N :$6 (,1( u,*1$/)81.7,21 ,1 '(5 ',5(.7(1 |(//Ok17(5$.7,21 (50?*/,&+7P f(5 =8 hcu n *(+?5,*( t(=(3725 ,67 hcu J$8&+ crqOS 2'(5 ef[W *(1$117KN '(5 o,7*/,(' '(5 vphOt(=(3725)$0,/,( ,67N ',( 8P $P $8&+ '(1 vphOt(=(3725OS JvphtOSK (17+>/7P f,( c.7,9,(581* 921 hcu 2'(5 vphtOS '85&+ n,*$1'(1%,1'81* .$11 =8 (,1(5 327(17(1 k1'8.7,21 921 c323726( )@+5(1N 2+1( '$M '$)@5 1(8( r527(,1( ,1 '(5 |(//( 6<17+(7,6,(57 :(5'(1 0@66(1P f(5 u,*1$/:(* =:,6&+(1 t(=(3725 81' e$63$6( U ,67 ,1 |(//(1 620,7 %(5(,76 35>)250,(57P y$6 3$66,(57 1$&+ '(5 d,1'81* 921 n,*$1' 81' t(=(3725a f(5 &<723/$60$7,6&+( c17(,/ 921 hcu 81' vphtOS (17+>/7 (,1( .216(59,(57( r527(,1'20>1(N ',( )@5 ',( y(,7(5/(,781* '(6 u,*1$/6 127:(1',* ,67 81' '(6+$/% $/6 NN'($7+ '20$,1DD %(=(,&+1(7 :,5'P p$&+ n,*$1'(1%,1'81* )2507 '(5 t(=(3725 (,1 j20275,0(5P g6 ,67 ',(6( v5,0(5,6,(581* '(5 NN'($7+ '20$,1DDN ',( '$5$8)+,1 ',( c1.233/81* (,1(6 c'$37(53527(,16 (5/$8%7 81' 62 '$6 |(//72'6,*1$/ :(,7(5/(,7(7 Jc%%P UPYUKP f$6 c'$37(502/(.@/ 921 hcuN hcff Jhcu $662&,$7(' 3527(,1 :,7+ '($7+ '20$,1KN %,1'(7 '(1 t(=(3725 (%(1)$//6 @%(5 6(,1( NN'($7+ '20$,1DDN ',( 620,7 $/6 r527(,1Ok17(5$.7,216(/(0(17 )81*,(57P hcff %(67(+7 1(%(1 '(5 NN'($7+ '20$,1DD 35$.7,6&+ 185 $86 (,1(5 :(,7(5(1 u758.785N '(5 62*(1$117(1 NN'($7+ (5(&725 '20$,1DDP f,(6( f20>1( 67(//7 /(7=7/,&+ ',( x(5%,1'81* '(6 c'$37(502/(.@/6 hcff =85 e$6O 3$6( Z +(5N (,1( k17(5$.7,21N ',( '(5 x(50,77/81* (,1(6 :(,7(5(1 h$.7256N h ncuj *(1$117N %('$5)P f$6 u8%675$7 '(5 e$63$6( Z 6&+/,(M/,&+ ,67 ',( e$63$6( UN ',( '$11 ',( g;(.87,21 '(5 c323726(N :,( 2%(1 %(6&+5,(%(1N ,1 i$1* 6(7=(1 .$11P f,( d('(8781* '(6 hcuBhcu nOu<67(06 ,1 '(5 o(',=,1 hcu :,5' 8%,48,7>5 (;35,0,(57N :2+,1*(*(1 hcu n +$8376>&+/,&+ $8) &<7272;,6&+(1 vO |(//(1 JevnK 81' p$7@5/,&+(1 m,//(5=(//(1 JpmK *()81'(1 :,5'P p$&+ '(5 d,1'81* '(5 $17,*(135>6(17,(5(1'(1 |(//( '85&+ evn6 @%(5 '(1 c17,*(1BojeBvetOm203/(; .2007 (6 $8&+ =8 (,1(5 hcuOhcu nOk17(5$.7,21P f$5$86 5(68/7,(57 ',( c.7,9,(581* 921 hcu 0,7 '(5 c323726( '(5 $17,*(135>6(17,(5(1'(1 |(//(P f$5@%(5 +,1$86 :,5' hcu n $8&+ $8) %(67,007(1 |(//3238/$7,21(1 '(5 c8*(1 81' v(67(6 62:,( ,1 (,1,*(1 v8025(1 (;35,0,(57P k17(5(66$17(5:(,6( *(+?5(1 c8*(1 81' v(67(6 =8 '(1 NN,0081(

SWV

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

35,9,/(*(' 6,7(6DDN $/62 =8 '(1 q5*$1(1N ',( *(*(1 &<7272;,6&+( g5(.7( 921 vO|(//(1 (,1(1 (5+?+7(1 u&+87= %(6,7=(1P f(0 hcuBhcu nOu<67(0 6&+(,17 '$%(, (,1( :,&+7,*( h81.7,21 =8=8)$//(1P f85&+ ',( g;35(66,21 921 hcu n $8) '(1 |(//(1 ',(6(5 q5*$1( :(5'(1 ',( hcuOt(=(3725(1 '(5 (,1:$1'(51'(1 vOn<03+2&<7(1 $.7,9,(57 81' 62 '(O 5(1 |(//72' (,1*(/(,7(7P k1 c1/(+181* $1 ',(6(6 r5,1=,3 (;35,0,(5(1 %(67,007( v8O 025(1 hcu n 81' (17=,(+(1 6,&+ 62 '(5 |(567?581* '85&+ pmO|(//(1P g6 :,5' $1O *(1200(1N '$M ',(6(5 r52=(M =8 '(0 NN,0081( (6&$3(DD 921 v8025(1 %(,75>*7P c/6 /(7=7(6 d(,63,(/ )@5 ',( d('(8781* '(5 t(=(3725O9(50,77(/7(1 c323726( ,1 '(5 o(',=,1 62// 6&+/,(M/,&+ ',( c866&+@7781* 921 /?6/,&+(0 vph '85&+ v8025( $1*()@+57 :(5'(1P f,(6 )@+57 @%(5 ',( c.7,9,(581* '(6 8%,48,7>5 (;35,0,(57(1 vphOt(=(37256 =8 (,1(5 6<67(0,6&+(1 $323727,6&+(1 i(:(%(6&+>',*81*P f,(6(5 r52=(66 :,5' )@5 '(1 .$&+(.7,6&+(1 |867$1' 921 v80253$7,(17(1 0,79(5$17:257/,&+ *(0$&+7P f(5 e<72&+520 &Ou,*1$/:(* y>+5(1' ',( k1'8.7,21 '(5 c323726( '85&+ ',( vphOt(=(3725)$0,/,( 35,0>5 @%(5 (,1(1 u,*1$/:(* (5)2/*7N '(5 $8) ',5(.7(1 r527(,1:(&+6(/:,5.81*(1 921 t(=(3725N c'$37253527(,1(1 81' g5(.725&$63$6(1 %(58+7N *,%7 (6 (,1(1 $1'(5(1 u,*1$/:(*N '(5 $/6 =(175$/(1 k1)250$7,216@%(575>*(5 '$6 e<72&+520 & %(187=7P g6 ,67 12&+ 1,&+7 92//67>1',* *(6,&+(57N :(/&+( 352O$323727,6&+(1 u7,08/, 35,0>5 @%(5 e<72&+520 & :(,7(5*(/(,7(7 :(5'(1N $%(5 :$+56&+(,1/,&+( m$1','$7(1 6,1' 8P $P ',( u,*1$/(N ',( 1$&+ fpcOu&+>',*81* $86 '(0 |(//.(51 *(6(1'(7 :(5'(1 J(7:$ 1$&+ g,1:,5.81* 921 uOu75$+/81* 2'(5 1$&+ *(1272;,6&+(5 e+(027+(5$3,(KP f$5@%(5 +,1$86 :(,6(1 $//( %,6 +(87( 817(568&+7(1 u,*1$/:(*( '(5 c323726( ,0 g1'67$',80 (,1( =86>7=/,&+( c.7,9,(581* '(6 e<72&+520 &Ou,*1$/:(*(6 $8)P f,(6(5 d()81' ,03/,=,(57 (,1( 63>7( c03/,7=,(581*6)81.7,21 921 e<72&+520 & )@5 ',( c.7,9,(581* '(5 c323726( ,0 $//*(0(,1(1 81' 817(5675(,&+7 6(,1( %(621'(5( d('(8781*P e<72&+520 & ,67 ,1 o,72&+21'5,(1 /2.$/,6,(57 81' '257 $/6 g/(.7521(175$163257(5 $1 '(5 d(5(,767(//81* %,2&+(0,6&+(5 g1(5*,( ,1 h250 921 cvr %(7(,/,*7P w1$%+>1*,* '$921 .2117( (6 $%(5 @%(55$6&+(1'(5:(,6( $8&+ $/6 d(67$1'7(,/ '(6 NN$323727,& 352O 7($6( $&7,9$7,1* )$&725DD JcrchK ,0 e<7262/ $3237,(5(1'(5 |(//(1 1$&+*(:,(6(1 :(5O '(1P f,( :(,7(5( c1$/<6( ',(6(6 d()81'(6 (5*$% )2/*(1'(6 d,/'\ p$&+ ,1,7,$/(5 c.O 7,9,(581* '(5 c323726( *(/,1*7 e<72&+520 & $86 '(1 o,72&+21'5,(1 ,1 '$6 e<723O /$60$P f257 %,1'(7 (6 $1 crchOSN '$6 6,&+ $/6 '$6 /$1* *(68&+7( j202/2* 921 eP (/(*$16 egfOV J6P 2PK +(5$8667(//7(P c8) ',(6( y(,6( $.7,9,(57 e<72&+520 & crchOSP f,(6(5 $.7,9( m203/(; %,1'(7 crchOUN :(/&+(6 $/6 c'$37(5&$63$6( Je$63$6( [K ',5(.7 g5(.725&$63$6(1 =8 $.7,9,(5(1 9(50$*P c8) ',(6(5 g%(1( 6&+/,(M/,&+ .219(5*O ,(5(1 ',( hcuBhcu nO 81' e<72&+520 &Ou,*1$/:(*( Jc%%P UPYVKP g6 .2117( $8&+ *(=(,*7 :(5'(1N '$M '(5 h$6nOu,*1$/:(* @%(5 (,1( c.7,9,(581* '(6 denOh$0,/,(10,7*/,('(6 dkf '85&+ e$63$6( Z =85 f(67$%,/,6,(581* '(5 o,72O &+21'5,(10(0%5$1 %(,75>*7 Jc%%P UPYUKP f$'85&+ .$11 (6 $8&+ ,0 hcuBhcu nOu,O c%%P UPYU u&+(0$7,6&+( f$567(//81* '(6 hcuBhcun u,*1$/:(*(6P f,( c.7,9,(581* '(6 0(0O 7 %5$167>1',*(1 hcuOt(=(37256 )@+57 @%(5 m233/81*63527(,1( =85 k1'8.7,21 '(5 r52&$63$6( ZP f,( $.7,9( e$63$6( Z .$11 (17:('(5 ',5(.7 ',( g5(.725&$63$6( U $.7,9,(5(1 2'(5 @%(5 '$6 r527(,1 dkf '(1 e<72&+520 &Ou,*1$/:(* $.7,9,(5(1 J6,(+( v(;7 )@5 (,1( '(7$,//,(57( d(6&+5(,O %81* ',(6(6 u,*1$/:(*(6KP

UPZ c323726(

SWW

FAS L

FAS

Zellmembran Death Domain FLASH FAD D Death Effektor Domain

A Procaspase 8 B

(Autoproteolyse) A B

Caspase 8

Procaspase 3

A

B

Cytochrom c Signalweg

A Caspase 3

BID

B

Apoptose

SWX

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

innere Mitochondrienmembran

äußere Mitochondrienmembran

Cytochrom c

proapoptotisches Signal

Cytochrom c

APAF 1

Caspase 9

Procaspase 9 A

B

Procaspase 3

Caspase 3

Apoptose

c%%P UPYV u&+(0$7,6&+( f$567(//81* '(6 e<72&+520 &Ou,*1$/:(*(6P e<72&+520 & :,5' 1$&+ (,1(0 352$323727,6&+(1 u,*1$/ $86 '(1 o,72&+21'5,(1 )5(,*(6(7=7P |86$00(1 0,7 crhS 81' r52&$63$6( [ %,/'(7 (6 '(1 NN$323727,& 3527($6( $&7,9$7,1* )$&725DDP f,( c66(0%/,(581* ',(6(6 h$.7256 )@+57 =85 c.7,9,(581* '(5 e$63$6( [N ',( '$11 ',5(.7 =85 k1'8.7,21 921 g5(.725O &$63$6(1 81' =85 g,1/(,781* '(5 c323726( )@+57P c/7(51$7,9 .$11 (6 =80 c8675,77 921 e
UPZ c323726(

SWY

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innere Mitochondrienmembran

H+ Cytochrom c K+

Cytochrom c

H+

H+ K+ K+

antiapoptotisch BCL 2 BCL-XL BCL-W MCL-1 E1B BHRF1

proapoptotisch BAX BAK BAD BID BIK 1 BCL-XS

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SWZ

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

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UPZ c323726(

SW[

genomischer Streß Onkogenaktivierung

DNA Schäden

MYC

ATM

ABL

E2F

RAS

P14 ARF

P53

P73

BCL2 Seneszenz (s. 3.6.4.)

? ?

Zellzyklusarrest (s. 3.6.4.)

DNA-Reparatur (s. 3.7.4.)

BAX

Apoptose

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SXR

U o2/(.8/$50(',=,1,6&+( r+<6,2/2*,( 81' d,2&+(0,(

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UP[ u,*1$/@%(575$*81*

SXS

v$%P UPSR d(,63,(/( )@5 (;75$=(//8/>5( u,*1$/6725( h$.725

o2/(.@/./$66( h81.7,21

u,*1$/35,1=,3

p(59(1O y$&+67806)$.725

r527(,1

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i/<&,1

c0,126>85(

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p(85275$160,77(5

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u7,08/$7,21 '(5 r52/,)(5$7,21

y$&+67806)$.725

k168/,1

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i/8.26($8)1$+0(N u7,08/$7,21 '(5 r527(,1O 6<17+(6(

j25021

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j25021

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+ +

Endothelzellen

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L-Arg

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Physiologie

+ sGC

glatte Gefäßmuskulatur

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Nitro-Vasodilatatoren

(b)

Endothelzellen

NO Pharmakologie NO

glatte Gefäßmuskulatur

+ +

sGC

GTP cyclo GMP Relaxation

Cytokine

(c)

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L-Arg

--

Endothelzellen

Induktion Cytokine

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glatte Gefäßmuskulatur

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NOS + sGC L-Arg GTP NO + Relaxation

cyclo GMP

Pathophysiologie

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PY

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SMP a!3)37%2+:%5'% SMPMP u%+4/2%. :52 j,/.)%25.' 6/. cm` i581'6>7=/,&+ 0@66(1 9,(5 d(',1*81*(1 (5)@//7 6(,1N 80 63(=,76&+( fpcOh5$*0(1O 7( ./21,(5(1 =8 .?11(1P c/6 (567(6 0@66(1 y(*( *()81'(1 :(5'(1N ',( fpc ,1 d$.7(5,(1 2'(5 j()(1 (,1=8%5,1*(1] =:(,7(16 08M ',( ,1.25325,(57( fpc 5(3/,=,(57 :(5'(1] '5,77(16 08M 6,( ,1 '(1 |(//(1 67$%,/ (5+$/7(1 %/(,%(1 81' 1$&+ |(//7(,/81*(1 $1 h2/*(*(1(5$7,21(1 :(,7(5*(*(%(1 :(5'(1] 81' 9,(57(16 08M ',( fpc :,('(5 5(O(;75$+,(57 :(5'(1 .?11(1P f,(6( d(',1*81*(1 /$66(1 6,&+ '85&+ m233/81* '(5 (;2*(1(1 fpc $1 62*(1$117( x(.725(1 (5)@//(1P

SMPMPMP o,!3-)$% d(, ',(6(1 u758.785(1 +$1'(/7 (6 6,&+ 80 5,1*)?50,*( fpcOo2/(.@/(N ',( 62:2+/ (,1(1 t(3/,.$7,2168563581*N 'P +P (,1( 63(=,76&+(N 921 d$.7(5,(1 (5.$117( u,*1$/O

SYR

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

6(48(1= =85 fpc t(3/,.$7,21 J6,(+( m$3P UPXPSK $/6 $8&+ c17,%,27,.$Ot(6,67(1=*(1( (17+$/7(1 Jc%%P VPSKP r/$60,'( .?11(1 6,&+ '$+(5 81$%+>1*,* 920 d$.7(5,(1&+52O 02620 $/6 *(1(7,6&+(6 g3,620 9(50(+5(1P f,( v(1'(1= '(5 |(//(N 1,&+7O(66(17,(//( fpc =8 (/,0,1,(5(1N .$11 '85&+ $17,%,27,6&+(1 u(/(.7,216'58&. @%(5:81'(1 :(5O '(1P Insertionsregion für exogene DNA von <10 kb

Antibiotika-Resistenzgen Replikationsursprung (a)

Plasmid

Insertionsregion für exogene DNA von ca. 40 kb

Antibiotika-Resistenzgen Replikationsursprung

cos-Sequenzen Cosmid

Insertionsregion für exogene DNA von ca. 20 kb

essentielle Phagengene

nicht essentielle Phagen-DNA

cos-Sequenzen

cos-Sequenzen

(b)

essentielle Phagengene

Bakteriophage

(c)

genomische DNA

TEL (d)

TRPI

SUP4

URA3

TEL

Yeast artificial chromosome (YAC)

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VPS d$6,6:(5.=(8*( DNA oder RNA als Ausgangsmaterial

SYS

Vektor

rekombinante DNA bakterielle Transformation transformierte bakterielle Klone

Genbank "Screening" der Genbank gesuchter Klon

bakterielle Vermehrung und Extraktion rekombinanter DNA

isolierte rekombinante DNA

c%%P VPT

h/8M',$*5$00 =85 u75$7(*,( '(6 fpcOm/21,(5(16P

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SMPMPMQ a!+4%2)/0(!'%. x,5(1 6,1' %,2/2*,6&+ '$5$8) (,1*(67(//7N ,+5 *(1(7,6&+(6 o$7(5,$/ '85&+ k1)(.7,21 ,1 )5(0'( |(//(1 (,1=8%5,1*(1 J6,(+( m$3P YPTKP h@5 ',( fpcOm/21,(581* 6,1' d$.O 7(5,23+$*(1 '$+(5 2)7 (5,=,(17(5( x(.725(1 $/6 r/$60,'( Jc%%P VPSKP |80 %(66(5(1 x(567>1'1,6 ',(6(5 m/21,(581*6675$7(*,( 62// +,(5 .85= $8) '(1 k1)(.7,216=<./86 (,1(6 r+$*(1 (,1*(*$1*(1 :(5'(1\ f(5 5(,)( r+$*( 6(7=7 6,&+ $1 t(=(3725(1 '(5 d$.7(O

SYT

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

5,(1:$1' )(67 81' ,1-,=,(57 6(,1( fpc ,1 ',( |(//(P f257 :(5'(1 ',( i(1( )@5 6(,1( j@//3527(,1( $%*(/(6(1 81' (;35,0,(57P i/(,&+=(,7,* :,5' '$6 r+$*(1*(120 ,1 9,(/O )$&+(5 c86)(57,*81* $/6 /$1*(6 =86$00(1+>1*(1'(6 o2/(.@/ Jm21.$7(0(5K 5(3/,O =,(57N :2%(, ',( (,1=(/1(1 m23,(1 '85&+ 63(=,76&+( fpcOu(48(1=(1N '(1 62*(1$11O 7(1 &26Ou7(//(1N 921(,1$1'(5 $%*(*5(1=7 6,1'P f$5$8)+,1 :,5' '$6 m21.$7(0(5 $1 '(1 &26Ou7(//(1 *(63$/7(1 81' -(:(,/6 (,1 i(120 ,1 ',( )(57,*(1 j@//(1 9(53$&.7P n(7=7/,&+ 3/$7=7 ',( ,17=,(57( |(//( 81' 6(7=7 (,1( x,(/=$+/ 1(8(5 5(,)(5 d$.7(5,23+$*(1 )5(,N ',( -(7=7 6(/%67 :,('(5 12&+ 1,&+7 ,17=,(57( p$&+%$5=(//(1 ,17=,(5(1P k0 w17(5O 6&+,(' =8 '(1 r/$60,'(1 @%(575>*7 (,1 ,1.25325,(57(5 r+$*( .(,1( c17,%,27,.$5(6,O 67(1=P f,(6(6 u(/(.7,21635,1=,3 67(+7 '$0,7 $8&+ 1,&+7 =85 c15(,&+(581* 75$16)25O 0,(57(5 |(//(1 =85 x(5)@*81*P h@5 ',( w17(56&+(,'81* 921 5(.20%,1$17(1 *(*(1O @%(5 1$7,9(1 r+$*(1 0$&+7 0$1 6,&+ =8187=(N '$M '$6 r+$*(1*(120 (567(16 6(,1( (66(17,(//(1 i(1( $8) 185 .1$33 UR .% (17+>/7N 81' '$M =:(,7(16 185 62/&+( fpcO o2/(.@/( 9(53$&.7 :(5'(1 .?11(1N '(5(1 n>1*( 1,&+7 :(6(17/,&+ 921 '(5 1$7@5/,&+(1 i5?M( '(6 i(1206 '(6 +>87* 9(5:(1'(7(1 d$.7(5,23+$*(1 n$0%'$ 921 &$P VZ .% $%:(,&+7P |85 fpcOm/21,(581* ,1 r+$*(1 .?11(1 ',( 1,&+7O(66(17,(//(1 &$P SZ .% (17)(517 81' '85&+ (;2*(1( fpc (56(7=7 :(5'(1P f,( 5(.20%,1$17( fpc :,5' '$11 ,1 9,752 9(53$&.7 81' *((,*1(7( gP &2/, u7>00( 0,7 '(1 92//67>1',*(1 r+$O *(13$57,.(/1 ,17=,(57P f,( n>1*(163(=,77>7 '(6 x(53$&.81*60(&+$1,6086 %(:,5.7N '$M 1,&+7O5(.20%,1$17( r+$*(1Ofpc :(*(1 '(5 )(+/(1'(1 SZ .% 1,&+7 9(53$&.7 :(5'(1 .$11 81' 620,7 1,&+7 =85 k1)(.7,21 '(5 |(//(1 *((,*1(7 ,67P f(5 x257(,/ '(5 fpcOm/21,(581* ,1 r+$*(1 /,(*7 620,7 '$5,1N '$M ',( 0$;,0$/( n>1*( '(5 (;2*(1(1 fpc (7:$ '233(/7 62 *52M ,67 :,( %(, '(1 r/$60,'(1N 81' '$M gP &2/, |(//(1 '85&+ ',( k1)(.7,21 0,7 r+$*(1 :(,7$86 (5(.7,9(5 75$16)250,(57 :(5'(1 $/6 '85&+ (,1( 3$66,9( c8)1$+0( 921 r/$60,'(1P

SMPMPMR b/3-)$% g,1( +>87* %(187=7( '5,77( c/7(51$7,9( ,67 ',( x(5:(1'81* '(5 1$7@5/,&+(5:(,6( 1,&+7 925.200(1'(1 e260,'( $/6 x(.725(1 Jc%%P VPSKP g6 +$1'(/7 6,&+ +,(5%(, 80 r/$6O 0,'( 0,7 %$.7(5,(//(1 t(3/,.$7,21685635@1*(1 81' c17,%,27,.$Ot(6,67(1=*(1(1N ,1 ',( &26Ou(48(1=(1 $/6 u,*1$/(/(0(17( )@5 '(1 9,5$/(1 x(53$&.81*60(&+$1,6086 (,1O *(6(7=7 :85'(1P f,( (66(17,(//(1 d(67$1'7(,/( 62/&+(5 x(.725(1 6,1' 1,&+7 9,(/ 0(+5 $/6 W .% /$1*P f85&+ k1.25325$7,21 921 6 VR .% J81' ,0 62*(1$117(1 rS e260,' 921 %,6 =8 SRR .%K (;2*(1(5 fpc ,1 (,1 e260,' (1767(+7 (,1( t(.20%,1$17(N ',( ,1 9,752 ,1 r+$*(1+@//(1 9(53$&.7 81' =85 k1)(.7,21 921 gP &2/, %(187=7 :(5'(1 .$11P f$ e260,'( .(,1( i(1( )@5 9,5$/( j@//3527(,1( 2'(5 )@5 ',( t(*8/$7,21 '(6 9,5$/(1 k1)(.7,216=<./86 (17+$/7(1N :,5' ',( |(//( '85&+ ',( v5$16)250$7,21 1,&+7 =(567?57 621'(51 (5:,5%7 (,1( c17,%,27,.8065(6,67(1=N ',( :,( %(, '(5 r/$60,'./2O 1,(581* =85 u(/(.7,21 (,1*(6(7=7 :(5'(1 .$11P o$1 9(5%,1'(7 %(, '(5 e260,'./2O 1,(581* 620,7 ',( x257(,/( '(5 35$.7,6&+ 5(/$7,9 (,1)$&+(5 =8 +$1'+$%(1'(1 r/$60,'( 0,7 '(5 +2+(1 v5$16)250$7,216(5,=,(1= '(5 d$.7(5,23+$*(1P f$5@%(5 +,1$86 (5+?+7 6,&+ ',( 0$;,0$/( n>1*( '(5 ,1 (,1(5 |(//( ./21,(5%$5(1 fpc $8) (7:$ VR .%P c/O /(5',1*6 6,1' ',( *52M(1 e260,'( ,1 '(5 |(//( *(1(7,6&+ 1,&+7 62 67$%,/ :,( r+$*(1 2'(5 r/$60,'(N :$6 *(/(*(17/,&+ =8 t(.20%,1$7,21(1 '(5 ./21,(57(1 fpc )@+5(1 .$11P

VPS d$6,6:(5.=(8*(

SYU

SMPMPMS d802%33)/.36%+4/2%. y(11 0$1 1,&+7 185 ',( i(1$1$/<6(N 621'(51 $8&+ ',( g;35(66,21Bp87=81* '(6 ./21,(57(1 *(1(7,6&+(1 o$7(5,$/6 (55(,&+(1 0?&+7(N 62 %,(7(7 (,1( i5833( 921 gP &2/, x(.725(1 ',( o?*/,&+.(,7N 5(.20%,1$17( i(1( =8 )81.7,21(//(1 r527(,1(1 =8 (;35,0,(5(1P f,( fpc 08M '$=8 =81>&+67 ,16 d$.7(5,80 (,1*(%5$&+7 :(5'(1P y,( ,1 m$3,7(/ UPS 1>+(5 (5/>87(57N %(1?7,*7 (,1 i(1 )@5 6(,1( g;35(66,21 $8M(5 '(1 r527(,1O.2',(5(1'(1 d(5(,&+(1 u7(8(5(/(0(17(P h@5 ',( g;35(66,21 (,1(6 (8.$5<21O 7(1 i(16 ,1 gP &2/, 08M '$6 (;2*(1( i(1 $1 %$.7(5,(//( u7(8(5(/(0(17( *(.233(/7 :(5'(1P f,( v5$16.5,37,21 (5)25'(57 (,1(1 921 '(5 %$.7(5,(//(1 tpc r2/<0(5$6( (5.(11%$5(1 r5202725P c8M(5'(0 .?11(1 d$.7(5,(1 r5,0>575$16.5,37( 1,&+7 63/(,O M(1N 62 '$M 185 k17521O)5(,( (8.$5<217( &fpc ,1 d$.7(5,(1 (;35,0,(57 :(5'(1 .$11P g,1( (5,=,(17( v5$16/$7,21 .$11 ,1 gP &2/, 185 '$11 ,1,7,,(57 :(5'(1N :(11 ',( W^O1,&+7O75$16/$7,(57( t(*,21 (,1( =85 %$.7(5,(//(1 SXu 5tpc .203/(0(17>5( u(O 48(1= (17+>/7P f,( 0(,67(1 (176&+(,'(1'(1 fpcOg/(0(17( )@5 (,1( (5,=,(17( i(O 1(;35(66,21 ,1 gP &2/, /,(*(1 $/62 ,0 W^Od(5(,&+ '(6 i(16P f$+(5 :,5' ',( (;2*(1( fpc '(0 r5202725 (,1(6 gP &2/, i(16 0,7 (,1(0 2'(5 2+1( (,1(1 W^Ov(,/ '(5 .2O ',(5(1'(1 u(48(1=(1 1$&+*(6&+$/7(7P j>87* :,5' +,(5 '$6 tOi$/$&726,'$6(*(1 JtO i$/K 9(5:(1'(7P p$&+ '(5 %$.7(5,(//(1 v5$16)250$7,21 (1767(+(1 '$11 h86,2163O 527(,1( 0,7 (,1(0 tOi$/ c0,12O 81' (,1(0 5(.20%,1$17(1 e$5%2;5 1$7,9 *(%,/'(7 :,5'P c1:(1'81* 71'(7 ',( g;35(66,21 5(.20%,1$17(5 i(1( ,1 d$.7(5,(1 %(, '(5 %,27(&+12/2*,6&+(1 u<17+(6( 921 r527(2+25021(1 :,( k168/,1N y$&+67806+25021 2'(5 g5<7+5232(7,1 2'(5 $8&+ %(, '(5 fpcOm/21,(581*N :(11 63(=,76&+( c17,.?53(5 '$=8 (,1*(6(7=7 :(5'(1 .?11(1N '(1 *(:@16&+7(1 5(.20%,1$17(1 m/21 @%(5 '$6 .2',(57( r527(,1 =8 ,'(17,7=,(5(1 Jg;35(66,216Oi(1%$1.KP

SMPMPMT x%!34 `24)&)#)!, b(2/-/3/-%3 Gx`b3H y,( ,1 m$3,7(/ VPYPW %(6&+5,(%(1 :,5'N )>//7 '(5 r26,7,216./21,(581* (,1( ,00(5 *5?O M(5( d('(8781* %(, '(5 k'(17,7=,(581* 921 m5$1.+(,76*(1(1 =8P f$%(, ,67 (6 0?*/,&+N (,1( &+5202620$/( t(*,21N $8) '(5 '$6 *(68&+7( i(1 /,(*(1 62//7(N '85&+ &26(*5(O *,(5(1'( *(1(7,6&+( o$5.(5 (,1=8*5(1=(1P g,1( 62/&+( t(*,21 80)$M7 2)7 $//(5',1*6 12&+ fpcOc%6&+1,77( ,1 '(5 i5?M(125'181* 921 o(*$%$6(1P g6 ,67 '$+(5 :@1O 6&+(16:(57N &+5202620$/( c%6&+1,77( ,1 ',(6(5 i5?M(125'181* =8 ./21,(5(1N :$6 ,1 e260,'(1 1,&+7 (55(,&+7 :(5'(1 .$11P f,(6 )@+57( =8 '(5 g17:,&./81* 921 {ce6N ',( =86>7=/,&+ =80 j()(O(,*(1(1 i(120 ,1 u$&&+$520<&(6 &(5(9,6,$( 3523$*,(57 :(5O '(1 .?11(1 81' SAT o(*$%$6(1 &+5202620$/(5 fpc $8)1(+0(1 .?11(1 Jc%%P VPSKP {ceOd,%/,27+(.(1 6,1' 6(+5 $8):(1',* =8 (567(//(1 81' =8 $1$/<6,(5(1P f(6+$/% :(5'(1 ',(6( f,(167( ,1 '(5 t(*(/ 921 63(=,$/,6,(57(1 |(175(1 $1*(%27(1P p(%(1 {ceOd,%/,27+(.(1N ',( '$6 *(6$07( i(120 5(35>6(17,(5(1N 67(+(1 $8&+ 62/&+( =85 x(5)@*81*N ',( /(',*/,&+ (,1=(/1( e+5202620(1 2'(5 e+5202620(1$%6&+1,77( $%O '(&.(1N :2'85&+ '(5 d($5%(,781*6$8):$1' (5+(%/,&+ 5('8=,(57 :,5'P f$6 u&5((1,1*

SYV

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

(,1(5 {ceOd,%/,27+(. .$11 =P dP 0,7 '(5 %(.$117(1 u(48(1= (,1(6 *(1(7,6&+(1 o$5O .(56 (5)2/*(1P h@5 :(,7(5( u&+5,77(N :,( =P dP (,1( h(,1.$57,(581*N 08M ',( (;2*(1( fpc (,1(6 ,'(17,7=,(57(1 {ce6 =85 :(,7(5(1 c1$/<6( ,1 ./(,1(5( x(.725(1 Je260,'( 2'(5 d$.7(5,23+$*(1K 68%./21,(57 :(5'(1P f,( u(48(1=,(581* '(5 fpc (5)25'(57 '$11 62*$5 (,1( :(,7(5( u8%./21,(581* ,1 r/$60,'( 2'(5 63(=,(// )@5 ',(6(1 |:(&. 237,0,(57( d$.7(5,23+$*(1P

SMPMQ q%342)+4)/.3%.$/.5+,%!3%. |8 '(1 :,&+7,*67(1 y(5.=(8*(1 '(6 o2/(.8/$5%,2/2*(1 *(+?5(1 (1=<0$7,6&+( NNu&+(5(1DDN 0,7 '(1(1 fpc $1 +2&+63(=,76&+(1 u7(//(1 *(6&+1,77(1 :(5'(1 .$11 Jv$%P VPSN c%%P VPUKP p$7@5/,&+(5:(,6( .200(1 ',(6( g1=<0( ,1 d$.7(5,(1 925N :2 6,( $/6 352.$5<217(6 c%:(+56<67(0 )5(0'( fpc $%%$8(1 81' 62 =80 d(,63,(/ ',( g5(.7,9,7>7 (,1(6 x,586 (,16&+5>1.(1N 5(675,1*,(5(1N 0,7 '(5 (6 (,1 d$.7(5,80 ,17O =,(5(1 .$11P f(5 p$0( '(5 t(675,.7,216(1'218./($6(1 /(,7(7 6,&+ $86 ',(6(5 1$7@5O /,&+(1 h81.7,21 $%P f,( )@5 35$.7,6&+( |:(&.( +(5$865$*(1'( g,*(16&+$)7 '(5 t(675,.7,216(1'218.O /($6(1 ,67 ',( u3(=,77>7 ,+5(5 g5.(1181*66(48(1=(1 921 0(,67 9,(5 %,6 $&+7 d$6(1O 3$$5(1 n>1*( Jv$%P VPSN c%%P VPUKP f,(6 %('(87(7N '$M (,1 %(67,007(6 t(675,.7,21O Spaltung der beiden DNA Stränge an gegenüberliegenden Stellen 5´

G

G

G

C

C

C

3´

5´

G

G

G

3´

5´

C

C

C

3´

3´

C

C

C

G

G

G

5´

3´

C

C

C

5´

3´

G

G

G

5´

G

C

Smal Spaltung der beiden DNA Stränge an versetzten Stellen 5´

C

T

G

C

A

G

3´

5´

C

T

A

3´

G

A

C

G

T

C

5´

3´

G

5´ 3´

A

C

G

A

3´ 5´

G

3´

G

T

C

5´

T

C

C

3´

5´ 3´

G

5´

Pstl

5´

G

G

A

T

C

C

3´

5´

G

3´ 5´

3´

C

C

T

A

G

G

5´

3´

C

C

T

A

G

BamHl

c%%P VPU g1767(+81* 9(56&+,('(1(5 fpcOh5$*0(17(1'(1 1$&+ x(5'$8 0,7 817(56&+,('/,&+(1 v<3(1 921 t(675,.7,216(1=<0(1P g1=<0( :,( u0$k 63$/7(1 ',( %(,'(1 u75>1*( $1 *(*(1@%(5O /,(*(1'(1 u7(//(1N 62 '$M .(,1( .85=(1 (,1=(/675>1*,*(1 g1'(1 (1767(+(1P g1=<0( :,( r67 k 63$/7(1 ',( %(,'(1 u75>1*( $1 9(56(7=7(1 u7(//(1N 62 '$M ',( (1767(+(1'(1 h5$*0(17( $1 ,+5(0 UAOg1'( (,1=(/675>1*,* 6,1'P w0*(.(+57 (1767(+(1 1$&+ x(5'$8 0,7 g1=<0(1 :,( d$0jk fpcOh5$*0(17( 0,7 (,1=(/675>1*,*(1 WAOg1'(1P

VPS d$6,6:(5.=(8*(

SYW

v$%P VPS c86:$+/ 921 t(675,.7,216(1=<0(1 0,7 p$0(16.@5=(/N p$0(16$%/(,781* 81' g5O .(1181*66(48(1= c/8k o%2k d$0jk g&2tk j,1'kkk r67k u0$k p27k

c57+52%$&7(5 /87(86 o25$;(//$ %29,6 d$&,//86 $0
W^OcievOU^ W^OicveOU^ W^OiicveeOU^ W^OiccvveOU^ W^OccievvOU^ W^evieciOU^ W^OeeeiiiOU^ W^OieiieeieOU^

6(1=<0 ',( fpc ,00(5 $1 '(1 */(,&+(1N *(1$8 '(71,(57(1 u7(//(1 63$/7(7P u2 6&+1(,O '(7 (,1 g1=<0 0,7 (,1(5 g5.(1181*66(48(1= 0,7 6(&+6 $8)(,1$1'(5 )2/*(1'(1 p8O ./(27,'(1 J=P dP j,1'kkkK 67$7,67,6&+ $//( VN 6 VRRR %3P c1'(5( g1=<0( 0,7 (,1(5 g5.(1181*66(48(1= 921 185 9,(5 J=P dP o%2kK 2'(5 $&+7 J=P dP p27kK p8./(27,'(1 6&+1(,'(1 (17635(&+(1' +>87*(5 J(7:$ $//( VL 6TWR %3K %=:P 6(/7(1(5 J(7:$ $//( VP6 XWRRR %3KP h@5 ',( fpcOm/21,(581* ,67 (6 2)7 %(621'(56 *@167,*N :(11 (,1 t(675,.7,216(1=<0 ,0 x(.725 185 (,1 (,1=,*(6 o$/ 6&+1(,'(7N :(,/ ',( (;2*(1( fpc '$11 /(,&+7 ,1 '(1 (17635(&+(1' *(?51(7(1 x(.725 (,1*(6(7=7 :(5'(1 .$11P f$%(, ,67 (6 9257(,/+$)7N :(11 ',( '233(/675>1*,*( fpcN :,( 921 9,(/(1 g1=<0(1N 1,&+7 $1 *(1$8 *(*(1@%(5/,(*(1'(1 u7(//(1 621'(51 /(,&+7 9(56(7=7 *(63$/7(1 :,5' Jc%%P VPUKP f$'85&+ (1767(+(1 t(675,.7,216)5$*0(17( 0,7 .85=(1 (,1=(/675>1*,*(1 g1'(1P f$+(5 .?11(1 ,0 $//*(0(,1(1 185 62/&+( h5$*0(17( :,('(5 0,7(,1$1'(5 9(5%81'(1 :(5'(1N ',( $86 (,1(0 x(5'$8 0,7 '(0 */(,&+(1 t(675,.7,216(1=<0 +(5O 925*(*$1*(1 6,1' Jc%%P VPVKP PstI

BamHI G 5´

G

3´

C

C

A

T A BamHI

T G

C

5´

G

3´

C

C

C

T A BamHI

G G

C G

5´

PstI A

C G

T 5´

T

G

G

C

C

A G

3´ A

G

C C

G T PstI

T

3´ A

A C

nicht ligierbar

G G T PstI

3´ 5´

C

BamHI C

ligierbar

G

3´

C

5´

c%%P VPV u&+(0$7,6&+( f$567(//81* '(6 ',5(.7,21$/(1 m/21,(5(16P d(,0 ',5(.7,21$/(1 m/21O ,(5(1 :,5' '(5 x(.725 0,7 =:(, 9(56&+,('(1(1 g1=<0(1 *(?51(7N 62 '$M (17635(&+(1' *(O 6&+1,77(1( (;2*(1( fpcOh5$*0(17( 185 ,1 (,1(5 t,&+781* ,1 '(1 x(.725 /,*,(57 :(5'(1 .?1O 1(1P

SYX

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

t(675,.7,216(1'218./($6(1 .?11(1 $8&+ =85 e+$5$.7(5,6,(581* *(120,6&+(5 fpcN (,16&+/,(M/,&+ ',$*1267,6&+(5 c1:(1'81*(1 9(5:(1'(7 :(5'(1P k0 0(16&+O /,&+(1 i(120 6&+1(,'(7 (,1 g1=<0 0,7 (,1(5 6(&+6 p8./(27,'( /$1*(1 g5.(1181*6O 6(48(1= (7:$ SRN 0$/P f,(6 6&+(,17 $8) '(1 (567(1 d/,&. 5(&+7 81@%(56,&+7/,&+P f$6 g176&+(,'(1'( ,67 -('2&+N '$M (,1 %(67,007(6 t(675,.7,216(1=<0 (,1( %(67,007( fpcOr52%( ,00(5 ,1 *(1$8 ',( */(,&+(1 t(675,.7,216)5$*0(17( =(5/(*7N ',( 62 (,1(5 5(352'8=,(5%$5(1 c1$/<6( =8*>1*/,&+ 6,1'P |85 |(,7 6,1' (,1,*( +81'(57 *(5(,1,*7( t(675,.7,216(1=<0( 0,7 -(:(,/6 817(56&+,('/,&+(1 g5.(1181*66(48(1=(1 .200(5O =,(// (5+>/7/,&+P g6 *,%7 620,7 (,1 67$77/,&+(6N /(,&+7 9(5)@*%$5(6 t(3(572,5( $1 63(O =,76&+(1 (1=<0$7,6&+(1 fpcOu&+(5(1P

SMPMR cm`Lg9"2)$)3)%25.' d(, '(5 c1$/<6( *(120,6&+(5 fpcN '(5 tpc 81' $8&+ %(, '(5 fpcOm/21,(581* ,67 (6 1?7,*N 63(=,76&+( u(48(1=(1 ,1 (,1(5 81@%(56,&+7/,&+(1 o(1*( (,1'(87,* =8 ,'(17,7=,(5(1 81' **)P =8 ,62/,(5(1P f$6 '$%(, $167(+(1'( (1250( $1$/<7,6&+( r52O %/(0 :,5' '(87/,&+N :(11 0$1 %('(1.7N '$M (,1 i(1 921 (7:$ URRR %3 n>1*( 185 (,1 o,//,2167(/ '(6 *(6$07(1 0(16&+/,&+(1 i(1206 $860$&+7P d(, '(5 0(7+2',6&+(1 n?681* ',(6(6 r52%/(06 0$&+7 0$1 6,&+ ',( h>+,*.(,7 '(5 fpc 81' '(5 tpc =85 d$6(13$$581* =8187=(P y,( 6&+21 ,1 m$3,7(/ TPV '(7$,//,(57 (5/>87(57N 6,1' ',( %(,'(1 doppelsträngige DNA 3´ 5´

5´ 3´

Hitze- oder Alkalidenaturierung

radioaktiv markierte Gensonde

3´ 5´ 5´ einzelsträngige DNA

3´

5´ 5´

3´* 5´

3´* 5´

5´

3´*

3´*

3´*

Hybridisierung mit einem Überschuß an markierter Gensonde

3´ 5´

5´

3´*

5´ 3´

Autoradiographie

c%%P VPW u&+(0$7,6&+( f$567(//81* '(5 fpcOj<%5,',6,(581*P f(5 u7(51 .(11=(,&+1(7 ',( o$5.,(581* '(5 i(1621'(P

VPT w17(568&+81* 921 fpc

SYY

g,1=(/675>1*( '(5 fpc f233(/+(/,; ,0 u,11( (,1(5 j<%5,',6,(581* '85&+ y$66(5O 6725%5@&.(1%,1'81*(1 =:,6&+(1 '(1 *(*(1@%(5/,(*(1'(1 d$6(1 i8$1,1 81' e<72O 6,1 %=:P c'(1,1 81' v+<0,1 0,7(,1$1'(5 9(5%81'(1P f,(6( d,1'81*(1 /$66(1 6,&+ '85&+ g5+,7=(1 2'(5 '85&+ c/.$/,%(+$1'/81* '(5 fpc 2+1( :(,7(5(6 /?6(1 81' 817(5 *((,*1(7(1 d(',1*81*(1 :,('(5 +(567(//(1P c1$/<7,6&+ ,67 (6 '$+(5 0?*/,&+N (,1(1 fpc f233(/675$1* ,1 6(,1( g,1=(/675>1*( =8 =(5/(*(1N =8 '(1$785,(5(1 81' =85 t(+<%5,',6,(581* (,1(1 %(56&+8M $1 (,1=(/675>1*,*(5 =P dP 5$',2$.7,9 0$5.,(5O 7(5 5(.20%,1$17(5 2'(5 6<17+(7,6&+(5 fpc '(5 *(68&+7(1 u(48(1= $1=8%,(7(1 Jc%%P VPWKP f,(6( 0$5.,(57( fpc :,5' 0,7 ,+5(1 +202/2*(1 u(48(1=(1 +<%5,',6,(5(1 81' 6,( $8) ',(6( y(,6( $86 (,1(5 .203/(;(1 r238/$7,21 9(56&+,('(1(5 fpcOh5$*O 0(17( 48$6, +(5$86621',(5(1P f,( d(',1*81*(1 ',(6(5 j<%5,',6,(581* .?11(1 '(5$57 63(=,76&+ *(:>+/7 :(5'(1N '$M 185 62/&+( u(48(1=(1 (5.$117 :(5'(1N ',( (,1( 0(+5 $/6 [R @,*( j202/2*,( 0,7 '(5 u21'( $8):(,6(1P k0 h$//( '(5 +>87* %(187=7(1 5$',2$.7,9(1 o$5.,(581* />M7 6,&+ (,1( j<%5,',6,(581* $16&+/,(M(1' '85&+ ',( u&+:>5=81* (,1(6 $8)*(/(*7(1 t?17*(17/06 ,1 '(5 62*(1$117(1 c8725$',2*5$3+,( 1$&+:(,6(1P d(621'(56 5(/(9$17( c1:(1'81*(1 '(5 fpc j<%5,',6,(581* 71'(1 6,&+ %(,0 u287+(51 d/277,1* Jc%%P VPXAVPSVKN %(, '(5 c03/,7=,(581* 63(=,76&+(5 u(48(1=(1 '85&+ ',( r2/<0(5$6( m(77(15($.7,21 J6,(+( m$3P VPTPTN c%%P VPSWKN %(, '(5 f,$*126( 921 r81.7087$7,21(1 '85&+ 63(=,76&+( q/,*218./(27,'( Jc%%P VPSXK 81' %(, '(5 fpcOm/21,(581* =85 k'(17,7=,(581* '(6 *(68&+7(1 m/216 Jc%%P VPUTKP

SMQ t.4%235#(5.' 6/. cm` f,( $1$720,6&+( i(1$1$/<6( ,67 ',( +(87( $0 +>87*67(1 $1*(:(1'(7( 02/(.8/$5O %,2/2*,6&+( w17(568&+81* ,1 '(5 35$.7,6&+O./,1,6&+(1 o(',=,1P u,( ',(17 =85 g5.(1O 181* 921 v5>*(51 9(5(5%7(5 g5.5$1.81*(1 62:,( =85 35>6<03720$7,6&+(1 81' =85 35>1$7$/(1 f,$*126(P g55(*(51$&+:(,6( ,1 '(5 0,.52%,2/2*,6&+(1 f,$*1267,. :(5O '(1 '85&+ 02/(.8/$5%,2/2*,6&+( o(7+2'(1 (5*>1=7P k1 '(5 h25(16,. +$%(1 fpcO c1$/<6(1 ',( u3(=,77>7 '(5 r(5621(1,'(17,7.$7,21 5(92/87,21,(57P o?*/,&+.(,7(1 ./,O 1,6&+(5 c1:(1'81* %(67(+(1 %(, '(5 (5:(,7(57(1 jncOv<3,6,(581* 1,&+7 9(5:$1'7(5 m12&+(10$5.63(1'(5 2'(5 %(, '(5 )5@+(1 g5.(1181* 921 t(=,',9(1 0$/,*1(5 g5O .5$1.81*(1P y(,7(5+,1 ,67 (6 '(1.%$5N '$M ',( k'(17,7.$7,21 '()(.7(5 r527(,1( %(, 9(5(5%7(1 g5.5$1.81*(1 @%(5 '(1 i(1'()(.7 J6,(+( m$3P VPYK 1(8( r(563(.7,9(1 )@5 ',( v+(5$3,( (5?51(7P h@5 '(1 ,1)250,(57(1 c5=7 9,(/(5 h$&+*(%,(7( :,5' (6 '$+(5 921 d('(8781* 6(,1N 6,&+ 0,7 '(1 0(7+2',6&+(1 i581'6>7=(1 '(5 fpcOc1$/<6( 9(575$87 =8 0$&+(1P

SMQMP r/54(%2. a,/44).' f(5 (,*(1:,//,*( p$0( ',(6(5 o(7+2'( *(+7 $8) '(5(1 g571'(5 gP u287+(51 =85@&.N '(5 ,0 l$+5( S[YW 6(,1( o(7+2'( )@5 ',( g5.(1181* 63(=,76&+(5 u(48(1=(1 ,1 *(/O (/(.7523+25(7,6&+ *(75(117(1 fpcOh5$*0(17(1 %(6&+5,(%P o,77(/6 u287+(51 d/27O c1$/<6( ,67 (6 0?*/,&+N ',( n>1*( (,1(6 fpcOh5$*0(17(6 =8 %(67,00(1N '$6 (,1(

SYZ

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

%(67,007( u(48(1= (17+>/7P d(, (,1(5 u3$/781* (;75$+,(57(5 0(16&+/,&+(5 *(120,O 6&+(5 fpc J6,(+( m$3P VPSPTK (7:$ 0,7 '(0 +>87* 9(5:(1'(7(1 t(675,.7,216(1=<0 j,1'kkk (1767(+(1 &$P SRX 817(56&+,('/,&+( t(675,.7,216)5$*0(17(P f,(6( :(5'(1 =8O 1>&+67 '85&+ c*$526(Oi(/(/(.7523+25(6( ,+5(5 i5?M( 1$&+ 921(,1$1'(5 *(75(117P u,( .?11(1 '$11 '85&+ 9825(6=,(5(1'( h$5%6725(N :,( g7+,',80%520,'N 6,&+7%$5 *(0$&+7 :(5'(1 Jc%%P VPXKP f,( h5$.7,21,(581* $//(,1 1$&+ i5?M( '(6 h5$*0(176 ,67 $8)*581' '(5 *52M(1 |$+/ '(5 9(56&+,('(1(1 h5$*0(17( 62 81@%(56,&+7/,&+N '$M '$6 |,(/)5$*0(17 1,&+7 63(=,76&+ (5.$117 :(5'(1 .$11 81' .(,1( t@&.6&+/@66( $8) x(5>1'(581*(1 '(5 *(120,6&+(1 fpc =8/>M7P k0 i(*(16$7= '$=8 :,5' ',( 5(/$7,9 @%(56,&+7/,&+( *(120,6&+( fpc '(6 d$.7(5,23+$*(1 n$0%'$ 921 185 VZ .% '85&+ 9,(/( t(675,.7,216(1=<0( ,1 185 :(1,*( h5$*0(17( =(5/(*7N 62 '$M *(63$/7(1( n$0%O '$Ofpc $/6 i5?M(10$5.(5 %(, u287+(51 d/27Oc1$/<6(1 %(187=7 :(5'(1 .$11 Jc%%P VPXKP f(5 1>&+67( u&+5,77 ,67 '$6 (,*(17/,&+( u287+(51 d/277,1*N %(, '(0 ',( ,0 i(/ /,(*(1'( '233(/675>1*,*( fpc =81>&+67 '85&+ (,1( c/.$/,%(+$1'/81* ,1 ,+5( g,1O =(/675>1*( =(5/(*7 81' '$11 '85&+ .$3,//$5( y,5.81* $/6 (;$.7( t(3/,.$ $8) (,1( 0(&+$1,6&+ 81' &+(0,6&+ 5(6,67(17( o(0%5$1 $86 p,752&(//8/26( 2'(5 p
M

elektrophoretische Wanderungsrichtung

Auftragungsstelle

c%%P VPX g7+,',80%520,'O*()>5%7(6 c*$526(*(/ 0,7 9(5'$8(5 *(120,6&+(5 fpcP f(5 h/825O (6=(1=)$5%6725 g7+,',80%520,' %,1'(7 6,&+ ,1 ',( fpcOf233(/+(/,;N 62 '$M fpc ,1 (,1(0 0,7 wxOn,&+7 75$16,//80,1,(57(1 i(/ 6,&+7%$5 :,5'P f,( 9,(/(1 +81'(577$86(1' %,6 (,1,*( o,/O /,21(1 817(56&+,('/,&+(1 h5$*0(17( '(5 9(5'$87(1 *(120,6&+(1 fpc 9(56&+:,00(1 '$%(, ,1 (,1(5 +202*(1 (56&+(,1(1'(1 u385P g,1 j,1' kkkOx(5'$8 921 n$0%'$Or+$*(1Ofpc (5*,%7 185 :(1,*( t(675,.7,216)5$*0(17( '(71,(57(5 i5?M(N ',( 620,7 $/6 n>1*(10$5.(5 (,1*(6(7=7 :(5'(1 .?11(1 JoN r)(,/(KP

kapillare Flußrichtung

VPT w17(568&+81* 921 fpc kg saugfähiges Filterpapier Nylonmembran Agarosegel saugfähiges Filterpapier Schale mit Puffer

c%%P VPY

SY[

Auflage

u&+(0$7,6&+( f$567(//81* (,1(5 u287+(51 d/27Oc33$5$785P

f(5 .5,7,6&+( u&+5,77 '(5 u287+(51 d/27Oc1$/<6( ,67 ',( 181 )2/*(1'( j<%5,',6,(O 581* (,1(5 UTrO 2'(5 1,&+7O5$',2$.7,9 0$5.,(57(1 i(1621'( J352%(K 0,7 '(5 fpc $8) '(5 o(0%5$1P c/6 i(1621'(1 :(5'(1 0(,67 5(.20%,1$17( fpcOh5$*0(17( %(187=7N ',( (17:('(5 u(48(1=(1 0,7 %(.$117(5 h81.7,21N %(.$117(5 n2.$/,6$7,21 2'(5 $8&+ $121<0( u(48(1=(1 (17+$/7(1 Jc%%P VPZKP w17(5 *((,*1(7(1 d(',1*81*(1 %,1'(7 6,&+ ',( u21'( 35>)(5(1=,(// $1 ,+5( .203/(0(17>5( u(48(1=P r5$.7,6&+ .2007 (6 -('2&+ $8&+ =8 :(1,*(5 67$%,/(1N 8163(=,76&+(1 d,1'81*(1N ',( 63>7(5 %(,0 62*(1$117(1 675,1*(17(1 y$6&+(1 %(, +2+(5 v(03(5$785 81' 1,('5,*(5 u$/=O .21=(175$7,21 *(/?67 :(5'(1P f,( 0$5.,(57( i(1621'( %/(,%7 '$%(, '85&+ ',( y$6O 6(56725%5@&.(1%,1'81*(1 =:,6&+(1 '(1 .203/(0(17>5(1 p8./(27,'(1 63(=,76&+ $1 ,+5(5 |,(/6(48(1= +$)7(1N 62 '$M '85&+ c8725$',2*5$3+,( ',( r26,7,21 %=:P ',( n>1*( '(6 (17635(&+(1'(1 t(675,.7,216)5$*0(17(6 (50,77(/7 :(5'(1 .$11 Jc%%P VPZKP r5,O Agarosegel Agarosegel-GelElektrophorese

Restriktionsverdau

unverdaute chromosomale DNA

--

Auftragungsstelle

verdaute chromosomale DNA +

1

2

3 Southern BlotTransfer

Röntgenfilm

Nylonmembran Hybridisierung mit markierter Gensonde stringentes Waschen und Autoradiographie

1

2

3

1

2

3

c%%P VPZ u&+(0$7,6&+( f$567(//81* (,1(5 fpcOj<%5,',6,(581* 1$&+ u287+(51 d/27Ov5$16)(5 %(, x(5'$8 0,7 '5(, 9(56&+,('(1(1 t(675,.7,216(1<=0(1 JSAUKP

SZR

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

0>5 />M7 6,&+ $86 '(5 u287+(51 d/27Oc1$/<6( $/62 ',( i5?M( '(5 t(675,.7,216)5$*O 0(17( $%/(,7(1N ',( '85&+ '$6 u&+1(,'(1 0,7 '(0 g1=<0 c (1767$1'(1 6,1' 81' .203/(0(17>5(B+202/2*( u(48(1=(1 0,7 '(5 u21'( d (17+$/7(1P f$6 g5*(%1,6 '(5 u287+(51 d/27Oc1$/<6( +>1*7 620,7 921 '(5 9(5'$87(1 fpcN 921 '(0 9(5:(1'(7(1 g1=<0 81' 921 '(5 i(1621'( $%P

SMQMPMP c)!'./34)3#(% `.7%.$5.'%. $%3 r/54(%2. a,/44).' f,( ./,1,6&+ 5(/(9$17( h5$*( ,67 181N :,( ',( '85&+ u287+(51 d/277,1* *(:211(1( r5,0>5,1)250$7,21 ,1 35$.7,6&+ 9(5:(57%$5( f,$*126(1 2'(5 02/(.8/$5O$1$720,O 6&+( g5.(1171,66( 80=86(7=(1 ,67P f,5(.7( g5.(1181* 921 r81.7087$7,21(1 y(11 x(5>1'(581*(1 '(5 p8./(27,'6(48(1= '$6 g5.(1181*66,*1$/ (,1(6 t(675,.O 7,216(1=<06 %(75(5(1N '$11 .$11 ',( o87$7,21 '85&+ '$6 9(5>1'(57( t(675,.7,216O P

V

M

F

SS

AA 1,4kb 1,2kb

Sonde normales ‚ Globingen

GAG

1,2kb

0,2kb

GTG

1,4kb

MstII Schnittstellen

Sichelzellgen

MstII Schnittstellen

c%%P VP[ u&+(0$7,6&+( 81' $8725$',2*5$3+,6&+( f$567(//81* '(5 f,$*126( '(5 u,&+(/=(//08O 7$7,21P p$&+ c*$526(Oi(/(/(.7523+25(6( 81' u287+(51 d/27Ov5$16)(5 o67 kk 9(5'$87(5 fpc ,'(17,7=,(57 (,1( i(1621'( $86 '(0 WAOd(5(,&+ '(6 tOi/2%,1*(16 %(, '(5 1250$/(1 fpc (,1 SNT .% 81' %(, '(5 3$7+2/2*,6&+(1 fpc (,1 SNV .% /$1*(6 h5$*0(17P f,( u,&+(/=(//087$7,21 Jici B iviK =(567?57 ',( o67 kk t(675,.7,21667(//( ,0 e2'21 X '(6 tOi/2%,1*(16P f,( c8725$',2*5$3+,( =(,*7 (,1( r5>1$7$/',$*126(N ',( %(,0 h(786 (,1(1 +202=<*27(1 u,&+(/=(//O *(127<3 )(6767(//7(P r\ j202=<*27(5 r52326,786P x\ j(7(52=<*27(5 x$7(5P o\ j(7(52=<*27( o877(5P h\ j202=<*27(5 h(786P uu\ j202=<*27( tgOm21752//(P cc\ j202=<*27 *(681'( m21752//(P

VPT w17(568&+81* 921 fpc

SZS

0867(5 (5)$M7 :(5'(1P f,( u,&+(/=(//087$7,21 ,0 e2'21 X '(6 tOi/2%,1*(16 62// +,(5 $/6 d(,63,(/ ',(1(1P f$6 t(675,.7,216(1=<0 o67kk 6&+1(,'(7 ',( fpc $1 '(5 u(48(1= W^OeevpciiOU^N ',( 6,&+ $/6 W^Oeev ici iciOU^ ,0 e2'21 X '(6 tO i/2%,1*(16 81' $1 =:(, u7(//(1 (7:$ SNT .% :(,7(5 W^ %=:P (7:$ RNT .% :(,7(5 U^ 71'(7 Jc%%P VP[KP x(5'$87 0$1 ',( fpc (,1(5 r(5621 0,7 1250$/(0 tOi/2%,1*(O 127<3 0,7 ',(6(0 g1=<0N 75(117 ',( (1767(+(1'(1 t(675,.7,216)5$*0(17( 0,77(/6 c*$526(Oi(/(/(.7523+25(6(N 75$16)(5,(57 ',( fpc $8) (,1( o(0%5$1 81' +<%5,',O 6,(57 6,( 0,7 (,1(0 5$',2$.7,9 0$5.,(57(1 W^Ov(,/ '(6 tOi/2%,1*(16 $/6 63(=,76&+( i(1621'(N '$11 6,(+7 0$1 1$&+ c8725$',2*5$3+,( '(5 675,1*(17 *(:$6&+(1(1 o(0O %5$1 (,1 u,*1$/ %(, SNT .% Jc%%P VP[KP f,(6( SNT .% (17635(&+(1 '(0 o67kk t(67O 5,.7,216)5$*0(17N '$6 '(1 1250$/(1 W^Oc%6&+1,77 '(6 tOi/2%,1*(16 (17+>/7P f,( c B v t/ o87$7,21 '(6 e2'216 X JW^Oeev ivi iciOU^K =(567?57 ',( 1250$/( o67kk u7(//(P d(, (,1(0 r$7,(17(1 0,7 '(5 u,&+(/=(//(5.5$1.81* 71'(7 0$1 $8) '(0 u28O 7+(51 d/27 o67kkO9(5'$87(5 fpc 67$77 '(6 SNT .% h5$*0(17(6 620,7 (,1 SNV .% h5$*0(17P d(, (,1(0 j(7(52=<*27(1 6,(+7 0$1 62:2+/ '$6 1250$/( SNT .% $/6 $8&+ '$6 3$7+2/2*,6&+( SNV .% h5$*0(17 Jc%%P VP[KP f,( f,$*126( (,1(5 u,&+(/=(//(5.5$1O .81* .$11 62 '85&+ ',( fpcOc1$/<6( *(67(//7 :(5'(1N :(11 (7:$ %(, (,1(5 r5>O 1$7$/',$*126( d/87 )@5 (,1( j>02*/2%,1(/(.7523+25(6( 1,&+7 =85 x(5)@*81* 67(+7P c0 d(,63,(/ '(5 t/ o87$7,21 />M7 6,&+ -('2&+ $8&+ (,1( 0?*/,&+( h(+/(548(//( %(, '(5 k17(535(7$7,21 (,1(5 fpcOc1$/<6( =(,*(1\ f,( o67kk u7(//( ,0 e2'21 X .$11 1>0/,&+ 1,&+7 185 '85&+ ',( u,&+(/=(//087$7,21 JW^Oeev ivi iciOU^K =(567?57 :(5'(1 621'(51 $8&+ '85&+ (,1( tOv+$/$66>0,(087$7,21 $1 '(5 */(,&+(1 u7(//( JW^O eev iOi iciOU^KP k1 '(5 fpcOc1$/<6( *(%(1 %(,'( $//(5',1*6 (,1 ,'(17,6&+(6 d,/'P g,1( 625*)>/7,*( 3+>127<3,6&+( f,5(5(17,$/',$*126( '(5 %(7525(1(1 h$0,/,( ,67 $/62 1?7,*P f,(6( ./,1,6&+( f,5(5(1=,(581* .$11 02/(.8/$5',$*1267,6&+ :(,7(5 '85&+ ',( c//(/O63(=,76&+( q/,*218./(27,'Oj<%5,',6,(581* 2'(5 '85&+ (,1( fpcO u(48(1=,(581* 817(567@7=7 :(5'(1 J6,(+( m$3P VPTPTPS 81' VPTPVKP g5.(1181* 921 fpcOr2/<0253+,60(1 w17(56&+,('( ,1 '(5 p8./(27,'6(48(1= 0@66(1 6,&+ 1,&+7 81%(',1*7 )81.7,21(// $86O :,5.(1P d(, (,1(5 h5(48(1= ,1',9,'8(//(5 x$5,$7,21(1 921 g,1=(/%$6(1 921 (7:$ SBTRR %,6 SBURR ,67 ',(6 62*$5 (+(5 6(/7(1 '(5 h$//P y(,7(5+,1 .?11(1 6,&+ c%6&+1,77( 0,7 5(3(7,7,9(1 g/(0(17(1 ,1 ,+5(5 n>1*( 80 (,1,*( .% 921(,1$1'(5 817(56&+(,'(1P c86 m219(17,21 %(=(,&+1(7 0$1 )81.7,21(// 1(875$/( x(5>1'(581*(1 $/6 r2/<0253+,6O 0(1N 62)(51 0$1 '$6 6(/7(1(5( c//(/ (,1(5 62/&+(1 x$5,$7,21 %(, 0(+5 $/6 S @ '(5 k1',9,'8(1 (,1(5 %(67,007(1 r238/$7,21 71'(7P i(%(1 6,&+ fpcOr2/<0253+,60(1 '85&+ ',( |(567?581* 2'(5 p(8%,/'81* 921 t(675,.7,21667(//(1 %=:P '85&+ ',( x(5O >1'(581* (,1(6 t(675,.7,2160867(56 =8 (5.(11(1N 62 635,&+7 0$1 921 t(675,.7,216O h5$*0(17On>1*(1Or2/<0253+,60(1 Jthnr6KP o(',=,1,6&+( c1:(1'81* 71'(1 fpcOr2/<0253+,60(1N :(11 6,( :(*(1 ,+5(5 $1$720,6&+(1 p>+( =8 3$7+23+<6,2/2*,6&+ :,&+7,*(1 u758.785(1 $/6 *(1(7,6&+( o$5O .(5 ',(1(1 .?11(1 J6,(+( m$3P VPYKP c8M(5'(0 6,1' 0$1&+( 32/<0253+( n2&, '(5$57 9$5,$%(/N '$M 6,(N (,1(0 h,1*(5$%'58&. >+1/,&+N =85 r(5621(1,'(17,7.$7,21 %(187=7 :(5'(1 .?11(1 J6,(+( m$3P VPTWKP f,( ',$*1267,6&+( c866$*(.5$)7 '85&+ u287+(51 d/27Oc1$/<6( ,'(17,7=,(57(5 fpcOr2/<0253+,60(1 62// $1 =:(, 5(35>6(17$7,9(1 d(,O 63,(/(1 (5/>87(57 :(5'(1P g6 817(56&+(,'(1 6,&+ +,(5%(, 1,&+7 185 ',( 0(',=,1,6&+(1

SZT

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

h5$*(67(//81*(1 621'(51 $8&+ ',( 02/(.8/$5%,2/2*,6&+(1 u75$7(*,(1 '(5 fpcOc1$O /<6(P g,1)$&+( thnr6 d(, 9,(/(1 9(5(5%7(1 m5$1.+(,7(1 ,67 '$6 3$7+2*(1(7,6&+ 5(/(9$17( i(1 12&+ 81%(O .$117P d(, $1'(5(1 +(5(',7>5(1 m5$1.+(,7(1 .(117 0$1 =:$5 '$6 %(7525(1( i(1 81' ,1 '(1 0(,67(1 h>//(1 '$11 $8&+ (,1,*( '(5 )@5 '$6 m5$1.+(,76%,/' 9(5$17:257O /,&+(1 o87$7,21(1P c//(5',1*6 ,67 ',( 02/(.8/$5( r$7+2/2*,( 7527= '(5 +(87( 9(5)@*O %$5(1 v(&+12/2*,( =85 u(48(1=,(581* 2)7 =8 .203/(;N 80 ,1 -('(0 ,1',9,'8(//(1 h$// '(1 (;$.7(1 i(1'()(.7 )@5 ',$*1267,6&+( |:(&.( %(67,00(1 =8 .?11(1P d(,O 63,(/( 71'(1 6,&+ +,(5 %(, '(1 j>023+,/,(1 81' %(, '(5 o86.(/'<67523+,( 920 v<3 f8&+(11(P g,1)$&+( thnr6 .?11(1 ,1 62/&+(1 h>//(1 ,0 u,11( (,1(5 m233/81*6O $1$/<6( =85 *(1(7,6&+(1 o$5.,(581* (,1(6 i(16 %=:P '(5 x(5(5%81* 6(,1(6 1250$/(1 2'(5 3$7+2/2*,6&+ 087,(57(1 c//(/6 ,1 (,1(0 u7$00%$80 ',(1(1 Jc%%P VPSRAVPSTKP Markerlocus 2

Genlocus 1

Markerlocus 3

Allel A

Allel P

Allel a

Allel B

Allel N

Allel b

c%%P VPSR u&+(0$7,6&+( f$567(//81* '(5 m233/81* (,1(6 3$7+23+<6,2/2*,6&+ 5(/(9$17(1 i(1O /2&86 Ji(1/2&86 SK $1 =:(, 32/<0253+( o$5.(5/2&, T 81' UP f(5 i(1/2&86 S .2007 '$%(, ,1 (,1(0 3$7+2/2*,6&+(1 c//(/ r 81' ,1 (,1(0 1250$/(1 c//(/ p 925P f$6 c//(/ r ,67 $1 ',( c//(/( c 81' $ '(5 o$5.(5/2&, T %=:P U 81' '$6 c//(/ p $1 ',( c//(/( d 81' % *(.233(/7P

P N

P N

A-a B-b

A-a B-b

P P

P N

N P

N N

A-a A-a

A-a B-b

A-a B-b

B-b B-b

c%%P VPSS u&+(0$7,6&+( f$567(//81* (,1(5 m233/81*6$1$/<6( ,1 (,1(5 h$0,/,(P f,( o$5.(5O $1$/<6( %(,0 +202=<*27 %(7525(1(1N 3+>127<3,6&+ $85>//,*(1 m,1' JrBrK 81' %(, 6(,1(1 g/7(51 JrBpK (5/$8%7 ',( h(67/(*81* '(5 m233/81* =:,6&+(1 '(1 o$5.(5$//(/(1 81' '(1 c//(/(1 '(6 i(1/2&86 J+,(5 cOrO$] dOpO%KP u20,7 .$11 '85&+ ',( o$5.(5$1$/<6( %(, $1'(5(1 m,1'(51N $8&+ 35>1$7$/N '(5 i(127<3 $0 (,*(17/,&+ ,17(5(66,(5(1'(1 i(1/2&86 %(67,007 :(5'(1P

VPT w17(568&+81* 921 fpc 2/2

1/1

SZU

1/2 Allel 1 Allel 2

einfacher RFLP

Allel 1

Allel 2

c%%P VPST u&+(0$7,6&+( f$567(//81* 81' c8725$',2*5$3+,( (,1(6 thnrP k1 '(5 p>+( (,1(6 5(/(9$17(1 i(1/2&86 J6&+:$5=(6 t(&+7(&.K %(71'(1 6,&+ t(675,.7,21667(//(1 (,1(6 %(67,007(1 g1=<06 Jr)(,/(KP g,1( ',(6(5 t(675,.7,21667(//(1 J%/$8K ,67 32/<0253+P f,( c//(/( S 81' T =(,&+O 1(1 6,&+ 620,7 '85&+ '$6 h(+/(1 %=:P '85&+ ',( i(*(1:$57 (,1(5 t(675,.7,21667(//( '(6 9(5O :(1'(7(1 g1=<06 $86P f$6 ,'(17,7=,(57( h5$*0(17 '(6 c//(/6 S ,67 620,7 />1*(5 $/6 '$6 '(6 c//(/6 T 81' (56&+(,17 '$+(5 $1 (,1(5 r26,7,21N ',( 1>+(5 $0 w563581* '(5 g/(.7523+25(6( /,(*7P f,( r52%$1'(1 $8) '(5 $%*(%,/'(7(1 c8725$',2*5$3+,( 6,1' +202=<*27 )@5 '$6 c//(/ T JTBTKN '$6 c//(/ S JSBSK 2'(5 +(7(52=<*27 JSBTKP

f$=8 ,67 ',( *(6,&+(57( ./,1,6&+( f,$*126( =80,1'(67 (,1(6 +202=<*27(1 r$7,(17(1 81' '$0,7 '(5 *(6,&+(57( %(575>*(567$786 6(,1(5 %(,'(1 g/7(51 (5)25'(5/,&+P c8M(5O '(0 %(1?7,*7 0$1 (,1(1 thnr ,1 '(5 w0*(%81* '(6 (,*(17/,&+ ,17(5(66,(5(1'(1 i(16N '(66(1 c//(/( '85&+ u287+(51 d/27Oc1$/<6( 810,77(/%$5 ,'(17,7=,(57 :(5'(1 .?11(1P k0 u7$00%$80 :,5' '$11 ',( m233/81* =:,6&+(1 '(1 c//(/(1 '(6 thnr 81' '(1 @%(5 '(1 r+>127<3 %(67,00%$5(1 c//(/(1 '(6 3$7+2*(1(7,6&+ 5(/(9$17(1 i(16 )(67*(/(*7P y(6(17/,&+ ,67 '$%(,N '$M '$6 i(1 6(/%67 2'(5 ',( (;$.7( p$785 '(5 o87$7,21 1,&+7 %(.$117 6(,1 08MP c%%,/'81* VPSS '(021675,(57 ',( ',$*1267,6&+( p@7=/,&+.(,7 ',(6(6 x(5)$+5(16P f(5 i(1/2&86 S /,(*7 +,(5 ,1 (,1(5 1250$/(1 JpK 81' ,1 (,1(5 ,0 f(7$,/ 81%(.$117(1 3$7+2/2*,6&+(1 JrK h250 925P f(5 32/<0253+( o$5.(5/2&86 T +$7 =:(, 9(56&+,('(1( ',5(.7 (5.(11%$5( c//(/(N c 81' dP c 81' d 6,1' p2509$5,$17(1 81' +$%(1 6(/%67 .(,1( 3$7+2*(1(7,6&+( d('(8781*P k1 '(0 925/,(*(1'(1 d(,63,(/ :,5' '$6 c//(/ r '(6 i(1/2&86 S *(.233(/7 0,7 '(0 c//(/ c '(6 o$5.(5/2&86 T 9(5(5%7P g5.(11%$5 ,67 '$6 '$5$1N '$M '(5 +202=<*27( k1'(;3$7,(17 JrBrK $8&+ '$6 o$5.(5$//(/ c +2O 02=<*27 81' 6(,1( g/7(51 $/6 +(7(52=<*27( %(575>*(5 JrBpK 62:2+/ '$6 o$5.(5$//(/ c $/6 $8&+ d 75$*(1N $/62 $8&+ +(7(52=<*27 )@5 '(1 o$5.(5/2&86 6,1'P f(5 d58'(5 '(6 k1'(;3$7,(17(1 ,67 +202=<*27 )@5 '$6 o$5.(5$//(/ dP g5 ,67 $/62 +202=<*27 *(681' JpBpKP y(,7(5+,1 (5/$8%7 (,1( 62/&+( m233/81*6$1$/<6( ,1 ',(6(5 h$0,/,( (,1( 35>1$7$/( f,$*126( '85&+ ',( w17(568&+81* )(7$/(5 fpcN =80 d(,63,(/ $86 e+25,21=277(1P g6 ,67 :,&+7,* )(67=8+$/7(1N '$M (,1( 62/&+( d(67,0081* 185 )@5 ',( ,1',9,'8(//( h$0,/,( *,/7 81' ',( m233/81* =:,6&+(1 o$5.(5$//(/(1 81' '(1 c//(/(1

SZV

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

'(6 3$7+2*(1(7,6&+ :,&+7,*(1 i(16 ,1 -('(5 h$0,/,( 1(8 %(67,007 :(5'(1 08MP f$5O @%(5 +,1$86 (5*,%7 6,&+ (,1( :,&+7,*( g,16&+5>1.81* '(5 ',$*1267,6&+(1 u,&+(5+(,7 ',(6(5 o(7+2'( $86 '(5 o?*/,&+.(,7 '(5 t(.20%,1$7,21 =:,6&+(1 '(0 i(1/2&86 81' '(0 o$5.(5/2&86P y>+5(1' '(5 o(,26( .2007 (6 =80 u7@&.$867$86&+ =:,O 6&+(1 '(1 %(,'(1 +202/2*(1 e+5202620(1N ',(N 0(&+$1,67,6&+ *(6(+(1N $1 >48,O 9$/(17(1 u7(//(1 %5(&+(1 81' 5(=,352. 9(5%81'(1 :(5'(1 Je5266,1*O29(5N c%%P VPSUKP g5(,*1(7 6,&+ ,1 '(0 +,(5 *(=(,*7(1 d(,63,(/ %(, (,1(0 '(5 g/7(51 (,1 62/&+(6 e526O 6,1*O29(5 =:,6&+(1 '(0 i(1/2&86 S 81' '(0 o$5.(5/2&86 TN 62 ,67 $8) '(0 1(8 $55$1*,(57(1 e+5202620 '$6 o$5.(5$//(/ c 0,7 '(0 1250$/(1 c//(/ p '(6 i(16 81' '$6 o$5.(5$//(/ d 0,7 '(0 3$7+2/2*,6&+(1 c//(/ r *(.233(/7P f,( y$+56&+(,1O /,&+.(,7 (,1(6 '$5$86 5(68/7,(5(1'(1 h(+/(56N =P dP %(, (,1(5 35>1$7$/(1 f,$*1267,. =80 c866&+/8M '(6 i(127<36 rBr +>1*7 920 $1$720,6&+(1 c%67$1' =:,6&+(1 '(0 o$5.(5/2&86 81' '(0 i(1/2&86 %=:P 921 '(5 p(,*81* '(5 %(7(,/,*7(1 fpcOc%O 6&+1,77( =85 t(.20%,1$7,21 $%P l( :(,7(5 o$5.(5 81' i(1 $86(,1$1'(5 /,(*(1 81' -( +?+(5 ',( t(.20%,1$7,2165$7( ,1 ',(6(0 d(5(,&+ ,67N '(672 6&+/(&+7(5 ,67 '(5 o$5O .(5 )@5 ',$*1267,6&+( |:(&.( *((,*1(7P i87( o$5.(5N :,( 6,( '85&+ ',( h2576&+5,77( '(6 j80$1*(120352-(.7(6 J6,(+( m$3P VPZK ,1=:,6&+(1 )@5 ',( 0(,67(1 g5.5$1.81O *(1 =85 x(5)@*81* 67(+(1N +$%(1 (,1( t(.20%,1$7,2165$7( 0,7 '(0 i(1/2&86 921 1,&+7 0(+5 $/6 S@P f,( ',$*1267,6&+( u,&+(5+(,7 /,(*7 '$11 %(, [[ @P f,( ',$*1267,6&+( u,&+(5+(,7 327(1=,(57 6,&+ '85&+ ',( x(5:(1'81* 921 o$5.(5/2&, $8) %(,'(1 u(,7(1 '(6 i(16P k1 '(0 +,(5 *(=(,*7(1 d(,63,(/ Jc%%P VPSRK /,(*7 '(5 o$5.(5/2&86 U $8) '(5 $1'(5(1 u(,7( '(6 i(16 $/6 '(5 o$5.(5/2&86 T 81' +$7 ',( $//(/(1 h250(1 $ 81' %P k1 '(5 h$0,/,( ,67 '$6 3$7+2/2*,6&+( c//(/ r '(6 i(1/2&86

rekombinierte Chromosomen in den Keimzellen

Crossing-over bei der Paarung der homologen Chromosomen während der Meiose

Allel A

Allel P

Allel a

Allel A

Allel P

Allel a

Allel B

Allel N

Allel b

Allel B

Allel N

Allel b

Allel A

Allel P

Allel a

Allel A

Allel N

Allel b

Allel B

Allel P

Allel a

Allel B

Allel N

Allel b

c%%P VPSU u&+(0$7,6&+( f$567(//81* (,1(6 e5266,1*O29(5 =:,6&+(1 '(0 i(1/2&86 81' '(1 32/<0253+(1 o$5.(5/2&,P g,1 e5266,1*O29(5 :>+5(1' '(5 o(,26( 5(.20%,1,(57 ',( m233/81* '(5 c//(/( '(6 i(1/2&86 0,7 '(1 o$5.(5/2&, 81' .$11 62 =8 h(+/',$*126(1 )@+5(1P

VPT w17(568&+81* 921 fpc

SZW

S 0,7 '(0 c//(/ $ '(6 o$5.(5/2&86 U *(.233(/7P c8) '(0 e+5202620 0,7 '(0 3$7+2/2*,6&+ 9(5>1'(57(1 i(1 71'(7 6,&+ $/62 ',( c//(/.20%,1$7,21N '(5 j$3/27<3 cOrO$ 81' $8) '(0 1250$/(1 e+5202620 '(5 j$3/27<3 dOpO%P g,1( t(.20%,1$O 7,21 $8) (,1(5 u(,7( '(6 i(1/2&86 7(/( +,(5 '85&+ (,1( x(5>1'(581* '(5 m233/81* =:,6&+(1 '(1 ',5(.7 (5.(11%$5(1 o$5.(5$//(/(1 $8)P k1 816(5(0 d(,63,(/ )>1'( 0$1 181 ',( o$5.(5$//(/( c 81' % %=:P d 81' $ =86$00(1 $8) (,1(0 e+5202620P k1 (,1(0 62/&+(1 h$// 6,1' .(,1( 6,&+(5(1 t@&.6&+/@66( $8) '(1 |867$1' '(6 i(1/2&86 0?*/,&+P l( 1$&+ r26,7,21 '(5 t(.20%,1$7,21 .?117( '(5 1(8 (1767$1'(1( j$3/27<3 cOpO% 2'(5 cOrO% 6(,1P u7(+(1 12&+ :(,7(5( o$5.(5/2&, =:,6&+(1 '(1 n2&, S 81' T %=:P =:,6&+(1 T 81' U =85 x(5)@*81*N 62 ,67 (6 (9(178(// 0?*/,&+ =8 (176&+(,'(1N $8) :(/&+(5 u(,7( '(6 i(1/2&86 ',( t(.20%,1$7,21 67$77*()81'(1 +$7 81' 62 12&+ =8 (,1(5 6,&+(5(1 f,$*126( =8 .200(1P c1'(51)$//6 ,67 (,1( 6,&+(5( f,$*126( $86O *(6&+/266(1P |8 (,1(5 h(+/',$*126( '85&+ m233/81*6$1$/<6( .2007 (6 -(7=7 185 '$11N :(11 =:(, 921(,1$1'(5 81$%+>1*,*( t(.20%,1$7,216(5(,*1,66( =:,6&+(1 n2O &86 S 81' T 62:,( =:,6&+(1 S 81' UN 'P +P %(,'6(,76 '(6 i(16 (1767(+(1P f,( m233/81* =:,6&+(1 '(1 o$5.(5/2&, %/(,%7 181 %(67(+(1P f(5 *(6$07( j$3/27<3 >1'(57 6,&+ $//(5',1*6 =8 cOpO$ %=:P =8 dOrO%P o,7 $1'(5(1 y257(1N '(5 925+(5 0,7 '(0 *(O 681'(1 c//(/ '(6 i(1/2&86 *(.233(/7( o$5.(5+$3/27<3 dO% ,67 181 0,7 '(0 3$7+2O /2*,6&+(1 c//(/ *(.233(/7 81' 80*(.(+57P y(11 -('(6 '(5 t(.20%,1$7,216(5(,*1,66( (,1( y$+56&+(,1/,&+.(,7 921 (7:$ S @ +$7N 62 ,67 185 ,1 RNRS @ '(5 h>//( =8 (5:$57(1N '$M %(,'( e5266,1*O29(5 %(, '(5 6(/%(1 o(,26( $%/$8)(1P f,( ',$*1267,6&+( u,&+(5+(,7 67(,*7 %(, '(5 x(5:(1'81* 921 o$5.(5/2&, $8) %(,'(1 u(,7(1 '(6 i(1/2&86 '$0,7 921 [[ @ $8) [[N[[ @P c86 '(1 +,(5 '$5*(67(//7(1 %(5/(*81*(1 (5*,%7 6,&+N '$M 6,&+ ',$*1267,6&+( c86O 6$*(1 185 '$11 75(5(1 /$66(1N :(11 ',( x$7(56&+$)7 ,0 ,1',9,'8(//(1 h$// *(6,&+(57 ,67P f,(6 />M7 6,&+ 35,1=,3,(// (17:('(5 $1$01(67,6&+ 2'(5 02/(.8/$5*(1(7,6&+ '85&+ |8+,/)(1$+0( '(6 *(1(7,6&+(1 h,1*(5$%'58&.6 J6,(+( m$3P VPTPWK ./>5(1P c8M(5'(0 0@66(1 9(56&+,('(1( c//(/( '(6 o$5.(5/2&86 -(:(,/6 $1 '$6 *(681'( %=:P $1 '$6 3$7+2/2*,6&+( i(1 *(.233(/7 6(,1P h,1'(7 6,&+ ,1 '(5 %(7525(1(1 h$0,/,( 185 (,1 c//(/ '(6 o$5.(56N 62 /$66(1 6,&+ '$5$86 .(,1( ,1',5(.7(1 t@&.6&+/@66( $8) '(1 |8O 67$1' '(6 i(16 =,(+(1P f,( h$0,/,( ,67 %(=@*/,&+ ',(6(6 o$5.(56 1,&+7 ,1)250$7,9P h@5 (,1( 6,1192//( g5:(,7(581* '(5 ,1',5(.7(1 02/(.8/$5*(1(7,6&+(1 f,$*1267,. 9(5O (5%7(5 g5.5$1.81*(1 6,1' $/62 62/&+( o$5.(5/2&, $0 %(67(1 *((,*1(7N ',( %(, 0?*O /,&+67 9,(/(1 %(575>*(51 ,1 +(7(52=<*27(5 h250 925/,(*(1P j<3(59$5,$%/( t(*,21(1 JjxtK f,( 2%(1 %(6&+5,(%(1(1 (,1)$&+(1 thnr6 .200(1 ,1 =:(, $//(/(1 h250(1 925N ',( '85&+ '$6 x25.200(1 %=:P '85&+ '$6 h(+/(1 (,1(5 t(675,.7,21667(//( %(67,007 :(5'(1P y(*(1 ,+5(5 *(5,1*(1 $//(/(1 x,(/)$/7 /,()(57 (,1 62/&+(6 185 ',0253+(6 o$5O .(56<67(0 ,1 9,(/(1 h>//(1 .(,1( ,1)250$7,9( m2167(//$7,21N 62 '$M )@5 63(=,76&+( ',$*1267,6&+( |:(&.( 0(+5(5( (,1)$&+( thnr6 %(67,007 :(5'(1 0@66(1P f$5@%(5 +,1$86 $662=,,(5(1 6,&+ 1$+( %(,(,1$1'(5 /,(*(1'( thnr6 ,1 (,1(5 r238/$7,21 2)7 =8 (,1(5 *(5,1*(1 |$+/ 921 j$3/27<3(1N :$6 ',( $//(/( x,(/)$/7 $8&+ .203/(;(5(5 32/<0253+(5 u<67(0( (,16&+5>1.7P c86 ',(6(0 i581'( 6,1' (,1=(/1( 32/<0253+( n2&, 0,7 0(+5(5(1 c//(/(1 *(1(7,6&+ 0(,67 :(,7$86 ,1)250$7,9(5 81' $8&+ ',$*12O 67,6&+ %(66(5 187=%$5P g6 *,%7 ,0 0(16&+/,&+(1 i(120 u(48(1=$%6&+1,77(N ',( 6,&+

SZX

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

$86 .85=(1 g,1=(/(/(0(17(1 921 :(1,*(1 d$6(13$$5(1 =86$00(16(7=(1P f,(6( g,1O =(/(/(0(17( 6,1' ,1',9,'8(// 817(56&+,('/,&+ 2)7 $1(,1$1'(5 *(5(,+7P k+5( c1=$+/ 9$O 5,,(57 2)70$/6 67$5.N 62 '$M (6 ,1 (,1(5 r238/$7,21 1,&+7 185 =:(,N 621'(51 (,1( x,(/O =$+/ 921 c//(/(1 ',(6(6 n2&86 *,%7 Jc%%P VPSVKP g,1 o(16&+ ,67 '$580 185 6(/7(1 +202=<*27 )@5 (,1(6 ',(6(5 c//(/( 621'(51 0(,67 +(7(52=<*27 )@5 =:(, 9(56&+,('(1(P f$+(5 %(=(,&+1(7 0$1 ',(6( u758.785(1 $/6 +<3(59$5,$%/( t(*,21(1 JjxtKN $/6 NN9$O 5,$%/( 180%(5 2) 7$1'(0 5(3($76DD JxpvtK 2'(5 $8&+ $/6 o,1,6$7(//,7(1 J6,(+( m$3P VPTPWKP f$6 0(7+2',6&+( 81' .21=(37,21(//( x25*(+(1 817(56&+(,'(7 6,&+ +,(5 1,&+7 6(+5 920 x25*(+(1 %(, (,1)$&+(1 thnr6P o$1 63$/7(7 ',( fpc 0,77(/6 t(67O 5,.7,216(1=<0(1 $1 %(,'(1 u(,7(1 '(5 jxtN 75(117 ',( h5$*0(17( '(5 i5?M( 1$&+ ,1 (,1(0 c*$526(*(/ $8)N 7;,(57 ',( fpc ,0 i(/ 1$&+ u287+(51 d/27Ov5$16)(5 $8) (,1(5 p1*7 ',( n>1*( '(6 0$5.,(57(1 h5$*0(17(6 $86 '(5 *(120,6&+(1 fpc '$%(, $//(5',1*6 1,&+7 921 '(5 r5>6(1= (,1(5 t(675,.O 7,21667(//(N 621'(51 921 '(5 c1=$+/ '(5 5(3(7,7,9(1 g/(0(17( ,1 '(5 jxt =:,6&+(1 =:(, .2167$17(1 t(675,.7,21667(//(1 $%P g6 *,%7 620,7 1,&+7 185 =:(, c//(/( :,( %(, '(1 (,1)$&+(1 thnr6N 621'(51 62 9,(/( :,( ',( 817(56&+,('/,&+( c1=$+/ '(5 5(3(O 7,7,9(1 g/(0(17(P x,(/( jxt6 +$%(1 0(+5(5( +81'(57 9(56&+,('(1( c//(/(N 62 '$M '(5 /,0,7,(5(1'( ',$*1267,6&+( h$.725 1,&+7 62 6(+5 ',( %,2/2*,6&+( $//(/( x,(/)$/7 '(6 n2&86N 621'(51 (+(5 '$6 c89?681*69(50?*(1 '(5 u287+(51 d/27Oc1$/<6( ,67P r5$.7,6&+ (5*,%7 6,&+ '$5$86N '$M ,1 62 *87 :,( -('(5 h$0,/,( 0,7 (,1(5 jxt ,1 '(5 p>+( '(6 3$7+2*(1(7,6&+ 5(/(9$17(1 i(1/2&86 '$6 3$7+2/2*,6&+( 920 1250$/(1 i(1 '85&+ ',( x(5:(1'81* (,1(6 (,1=(/1(1 32/<0253+(1 o$5.(56 817(56&+,('(1 :(5'(1 .$11P

hypervariable Region

Allel 1

Allel 2

Allel 3

Allel 4

c%%P VPSV u&+(0$7,6&+( f$567(//81* (,1(5 +<3(59$5,$%/(1 t(*,21 JjxtKP f$6 9(5:(1'(7( t(675,.7,216(1=<0 63$/7(7 ',( fpc $1 .2167$17(1 u7(//(1 J&KP f$=:,6&+(1 %(71'(1 6,&+ -(O '2&+ 5(3(7,7,9( g/(0(17( J 7KN ',( 817(56&+,('/,&+ 2)7 +,17(5(,1$1'(5*(6&+$/7(7 6(,1 .?11(1 81' 620,7 '(1 c%67$1' =:,6&+(1 '(1 .2167$17(1 t(675,.7,21667(//(1 81' ',( n>1*( '(5 (17O 67(+(1'(1 h5$*0(17( 9(5>1'(51P

VPT w17(568&+81* 921 fpc

SZY

SMQMQ o/,9-%2!3% j%44%.2%!+4)/. GobqH c8&+ ',( *5?M7(1 i(1( 5(35>6(17,(5(1 185 (,1(1 9(56&+:,1'(1' ./(,1(1 v(,/ '(6 *(6$07(1 i(1206P f,( 0(,67(1 02/(.8/$5*(1(7,6&+(1 o(7+2'(1 (5)25'(51 '$+(5 (,1(1 1,&+7 81(5+(%/,&+(1 $1$/<7,6&+(1 c8):$1'P u2 ,67 ',( fpcOm/21,(581* %(, $//(1 %,6 +,(5+(5 %(6&+5,(%(1(1 o(7+2'(1 =85 c15(,&+(581* 81' k62/$7,21 %(67,00O 7(5 u(48(1=(1 81$%',1*%$5 1?7,*P f,( r2/<0(5$6( m(77(15($.7,21 Jret )@5 NN32O /<0(5$6( &+$,1 5($&7,21DDK )@+57 (1=<0$7,6&+ 81' ,1 9,752N 'P +P 2+1( (,1(1 |:,6&+(1O 6&+5,77 ,1 d$.7(5,(1N =8 (,1(5 (;321(17,(//(1 c03/,7.$7,21 (,1(6 '(71,(57(1 fpcO h5$*0(17(6 Jc%%P VPSWKP f,( r27(1= ',(6(5 o(7+2'( ,67 '(5$57N '$M 6,( ',( u287+(51 5´ 3´

3´ 5´

95°C Denaturierung

5´

3´

3´

56°C Zugabe von Oligonukleotiden als Primer

5´ 3´

3´ 5´

3´ 72°C Zugabe von DNA Polymerase

5´ 3´ 3´

5´

5´ 5´

5´ 3´ 5´ 3´ 3´ 5´

doppelsträngige chromosomale DNA

einzelsträngige chromosomale DNA

hybridisierte Primer

zweifache Amplifikation

2. Zyklus 5´ 3´ 3´

3´

5´ 3´ 5´

5´ 5´ 3´ 5´

5´

3´

3´

vierfache Amplifikation

3´ 5´

3. bis 30. Zyklus 5´

3´ bis 107 fache Amplifikation

3´

5´

c%%P VPSW u&+(0$7,6&+( f$567(//81* '(6 r5,1=,36 '(5 r2/<0(5$6( m(77(15($.7,21 JretKP c86*(+(1' 921 '(5 &+5202620$/(1 fpc .$11 817(5 x(5:(1'81* *((,*1(7(5 q/,*218./(27,'( $/6 r5,0(5 81' +,7=(67$%,/(5 fpcOr2/<0(5$6( ,1 :(1,*(1 u781'(1 (,1( %,6 =8 SRYO)$&+( c0O 3/,7.$7,21 (,1(6 fpcOh5$*0(17(6 (55(,&+7 :(5'(1N '$6 6,&+ $8) '(0 e+5202620 =:,6&+(1 '(1 %(,'(1 r5,0(51 %(71'(7P

SZZ

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

d/27Ov(&+1,. 81' ',( .219(17,21(//( fpcOm/21,(581* %(, (,1(5 t(,+( 921 c1:(1O '81*(1 %(5(,76 9(5'5>1*7 +$7P f,( ret 5(35>6(17,(57 (,1( '(5 ',$*1267,6&+ %('(87O 6$067(1 p(8(581*(1 '(5 02/(.8/$5*(1(7,6&+(1 o(7+2',. '(5 /(7=7(1 l$+5(P c/6 u7$570$7(5,$/ %(1?7,*7 0$1 *(5,1*67( o(1*(1 +80$1(5 2'(5 $8&+ 9,5$/(5 *(O 120,6&+(5 fpcN ',( 1,&+7 (,10$/ 81%(',1*7 '85&+ .219(17,21(//( o(7+2'(1 *(O 5(,1,*7 :(5'(1 08MN 621'(51 ,1 |(///<6$7(1 (17+$/7(1 6(,1 .$11P |85 *(120,6&+(1 fpc :(5'(1 .85=( 6<17+(7,6&+( q/,*218./(27,'(N (7:$ TR0(5(N =86$00(1 0,7 (,1(5 +,7=(67$%,/(1 fpcOr2/<0(5$6( =8*(*(%(1P f,( u(48(1= '(5 q/,*218./(27,'( ,67 62 *(:>+/7N '$M 6,&+ ,+5( -(:(,/,*(1 .203/(0(17>5(1 u(48(1=(1 ,1 '(5 |,(/Ofpc $8) '(1 *(*(1@%(5/,(*(1'(1 u75>1*(1 '(5 f233(/+(/,; ,1 (,1(5 g17)(5181* 921 (,1,*(1 +81'(57 2'(5 $8&+ :(1,*(1 7$86(1' d$6(13$$5(1 %(71'(1P c/6 x25,1)250$7,21 08M $/62 ',( p8./(27,'6(48(1= '(6 =8 $03/,7=,(5(1'(1 h5$*0(17(6 %=:P 6(,1(5 810,7O 7(/%$5(1 p$&+%$56&+$)7 %(.$117 6(,1P f,( ret ,67 (,1 6,&+ :,('(5+2/(1'(5 f5(,6&+5,77352=(M Jc%%P VPSWKP k0 (567(1 u&+5,77 :,5' ',( fpc '85&+ j,7=( '(1$785,(57N 'P +P ,1 ,+5( (,1=(/675>1*,*( h250 @%(5)@+57P k0 =:(,7(1 u&+5,77 />M7 0$1 ',( ,0 %(56&+8M 925/,(*(1'(1 q/,*218.O /(27,'( '85&+ v(03(5$7856(1.81* $1 ,+5( .203/(0(17>5(1 u(48(1=(1 +<%5,',6,(5(1N 62 '$M ',( fpc $1 ',(6(1 u7(//(1 181 :,('(5 '233(/675>1*,* 925/,(*7P k0 '5,77(1 u&+5,77 '(5 t($.7,21 (5.(117 ',( fpcOr2/<0(5$6( ',(6( .85=(1 '233(/675>1*,*(1 g/(0(17( $/6 u7$576,*1$/( Jr5,0(5K 81' %(*,117N ',( %(1$&+%$57( (,1=(/675>1*,*( fpc .203/(0(17>5 =80 f233(/675$1* ,1 '(5 W^ B U^ t,&+781* =8 (5*>1=(1P c0 g1'( '(6 '5,77(1 u&+5,77(6N 81' '$0,7 '(6 (567(1 |<./86 '(5 retN ,67 ',( fpc ',(6(5 t(*,21 $/62 9(5'233(/7 :25'(1P f85&+ y,('(5+2/81* ',(6(5 |<./(1 />M7 6,&+ 620,7 (,1( (;321(17,(//( c03/,7.$7,21 '(5 fpc =:,6&+(1 '(1 q/,*218./(27,'(1 (55(,&+(1P g,1( *(:?+1/,&+ 2+1( :(,7(5(6 (55(,&+%$5( SRYO)$&+( c03/,7.$7,21 (,1(6 SRRR %3 /$1*(1 +80$1(1 *(120,6&+(1 fpcOh5$*0(17(6 %(',1*7N '$M ',(6 67$77 (,1(6 c17(,/6 921 :(1,*(5 $/6 (,1(0 o,//,2167(/ '(5 c86*$1*6Ofpc 181 0(+5 $/6 [R @ '(5 i(6O $07Ofpc ,0 $03/,7=,(57(1 o$7(5,$/ $860$&+7P f,( ret )@+57 620,7 )$67 =8 (,1(5 fpcOm/21,(581* ,1 9,752 81' (5/$8%7 ',( c1:(1'81* 02/(.8/$5*(1(7,6&+(5 ',$O *1267,6&+(5 o(7+2'(1N ',( 62167 185 $1 5(.20%,1$17(5 fpc '85&+*()@+57 :(5'(1 .?11(1P f,(6 6&+/,(M7 ',( ',5(.7( u(48(1=,(581* $03/,7=,(57(5 fpc (,1P c8M(5'(0 (5/$8%7 ',( ret (,1( w17(568&+81* *(5,1*67(5 o(1*(1 %,2/2*,6&+(1 o$7(5,$/6 %,6 =8 g,1=(/=(//(1P c8&+ 0@66(1 6,&+ ',( 817(568&+7(1 r52%(1 1,&+7 ,1 (;=(//(17(0 %,2&+(0,6&+(1 |867$1' %(71'(1\ retOc1$/<6(1 6,1' 6&+21 $1 -$+5(=(+17($/7(1 3$5$5,17;,(57(1 +,672/2*,6&+(1 r5>3$5$7(1 81' $1 i(:(%(1 >*<37,6&+(5 o80,(1 (5)2/*5(,&+ '85&+*()@+57 :25'(1P g,1( d(6&+5>1.81* '(5 ret /,(*7 ,1 '(5 0$;,0$/(1 n>1*( '(6 $03/,7=,(5%$5(1 h5$*0(17(6N ',( 5287,1(0>M,* ,1 '(5 i5?M(125'181* 921 :(1,*(1 .% /,(*7P c8M(5O '(0 (5)25'(57 ',( (;321(17,(//( p$785 '(5 t($.7,21 %(, (,1(5 s8$17,7=,(581* '(5 $03/,7=,(57(1 u(48(1=(1 ,0 c86*$1*60$7(5,$/ %(621'(5( x(5)$+5(1P f,( (1250( u(16,7,9,7>7 81' '$6 (;321(17,(//( r5,1=,3 '(5 (1=<0$7,6&+(1 t($.7,21 ,67 (,1(56(,76 '(5 *52M( x257(,/ '(5 o(7+2'(N 0$&+7 6,( $1'(5(56(,76 $%(5 $8&+ *$1= %(621'(56 (0371'/,&+ )@5 m217$0,1$7,21(1 185 *(5,1*67(1 c860$M(6P y,5' ',( ret =P dP (,1*(6(7=7N 80 fpc (7:$ 921 jkx 2'(5 j(3$7,7,69,5(1 ,1 ./,1,6&+(1 r52%(1 1$&+O =8:(,6(1N 62 5(,&+7 (,1( m217$0,1$7,21 (,1(6 (,1=,*(1 x,5863$57,.(/6 $86N 80 (,1 )$/6&+ 326,7,9(6 g5*(%1,6 =8 352'8=,(5(1P u2:2+/ %(, '(5 r52%(1(171$+0( $/6 $8&+

VPT w17(568&+81* 921 fpc

SZ[

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SMQMQMP `,,%,L30%:)&)3#(% n,)'/.5+,%/4)$Lg9"2)$)3)%25.' f,( fpc :,5' '85&+ y$66(56725%5@&.(1%,1'81*(1 =:,6&+(1 '(1 *(*(1@%(5/,(*(1O '(1 p8./(27,'(1 i 81' e %=:P c 81' v ,1 ,+5(5 &+$5$.7(5,67,6&+(1 '233(/675>1*,*(1 m217*85$7,21 *(+$/7(1 J6,(+( m$3P TPVPTKP f,(6 *,/7 62:2+/ )@5 ',( u,78$7,21 ,1 9,92 $/6 $8&+ ,1 9,752 )@5 $1 ',( |,(/Ofpc +<%5,',6,(57( i(1621'(1P f(5 f233(/675$1* ,67 '$%(, 8062 67$%,/(5N -( %(66(5 ',( %(,'(1 j<%5,',6,(581*63$571(5 =8(,1$1'(5 3$6O 6(1P d(, x(5:(1'81* 921 5$',2$.7,9 0$5.,(57(1 q/,*218./(27,'621'(1 )@+5(1 (,1O =(/1(N 1,&+7 .203/(0(17>5( *(*(1@%(5/,(*(1'( p8./(27,'( =8 (,1(5 '(87/,&+(1 f(O 67$%,/,6,(581* '(6 j<%5,'6P u2 .?11(1 675,1*(17( (;3(5,0(17(//( d(',1*81*(1 *(O )81'(1 :(5'(1N ',( '$6 q/,*218./(27,' 0,7 ',(6(5 (,1=(/1(1 h(+/3$$581* 921 '(5 |,(/Ofpc /?6(1N (,1 92//67>1',* .203/(0(17>5(6 j<%5,' -('2&+ '233(/675>1*,* %(O /$66(1P f,(6( ',5(5(1=,(57(1 3+<6,.2O&+(0,6&+(1 g,*(16&+$)7(1 '(5 fpc 0$&+7 0$1 6,&+ %(, '(5 c//(/O63(=,76&+(1 q/,*218./(27,'Oj<%5,',6,(581* =8187=(N 80 fixierte amplifizierte DNA mit der Zielsequenz im Wildtyp

fixierte amplifizierte DNA mit einer mutierten Zielsequenz

ACGTGGTACCTGGATGC

ACGTGGTATCTGGATGC markierte Oligonukleotidsonde TGCACCATGGACCTACG*

ACGTGGTACCTGGATGC TGCACCATGGACCTACG*

ACGTGGTATCTGGATGC TGCACCAT GACC TACG* G stringentes Waschen

ACGTGGTACCTGGATGC TGCACCATGGACCTACG* stabiles Hybrid positives Signal

ACGTGGTATCTGGATGC

instabiles Hybrid kein Signal

CC GA T A CC G CA TG

G* TAC

c%%P VPSX u&+(0$7,6&+( f$567(//81* '(6 r5,1=,36 '(5 c//(/O63(=,76&+(1 q/,*218./(27,'Oj1',* =8(,1$1'(5 3$66(1'( fpcOj<%5,' %/(,%7 '$*(*(1 67$%,/ 81' .$11 $8725$',2*5$3+,6&+ 6,&+7%$5 *(0$&+7 :(5'(1P

S[R

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r81.7087$7,21(1 ,1 3$7+23+<6,2/2*,6&+ ,17(5(66$17(1 i(1(1 (,1'(87,* =8 ,'(17,7O =,(5(1P c%%,/'81* VPSX =(,*7 '$6 r5,1=,3 ',(6(5 o(7+2'(P |81>&+67 :,5' (,1 *(12O 0,6&+(6 fpcOh5$*0(17 '85&+ ret $03/,7=,(57N '$11 '85&+ j,7=( '(1$785,(57 81' $8) (,1( p1*,*(5 h250 $8) '(5 o(0%5$1 7;,(57 81' .$11 0,7 .203/(0(17>5(1 (,1=(/675>1*,*(1 u(48(1=(1 $/6 i(1621'(1 +<%5,',6,(57 :(5'(1P c/6 u21'(1 ',(1(1 &+(0,6&+ 6<17+(7,6,(57( q/,*218./(27,'(N ',( ,1 TR p8./(27,'(1 n>1*( ',( r26,7,21 '(5 *(68&+7(1 o87$7,21 81' '(5(1 810,77(/%$5( p$&+%$56&+$)7 (17+$/7(1P g,1(6 ',(6(5 q/,*218./(27,'( (17635,&+7 '$%(, '(5 1250$/(1 81' (,1 $1'(5(6 '(5 087,(57(1 u(48(1=P f,( %(,'(1 q/,*218./(27,'( 817(56&+(,'(1 6,&+ $/62 $1 (,1(5 (,1=,*(1 u7(//(P d(,'( :(5'(1 181 '85&+ c1+>1*(1 (,1(6 5$',2$.7,9(1 r+263+$75(67(6 JUTrK $1 ,+5(5 WAOu(,7( 0$5.,(57 81' 0,7 '(5 7;,(57(1 |,(/Ofpc +<%5,',6,(57P c16&+/,(M(1' :(5'(1 ',( o(0%5$1(1 %(, '(71,(57(1 d(',1*81*(1 %(=@*/,&+ v(03(5$785 81' u$/=.21O =(175$7,21 *(:$6&+(1N 62 '$M 185 62/&+( j<%5,'( 67$%,/ 81' $8) '(5 o(0%5$1 7;,(57 %/(,%(1N ',( SRR@,* =8(,1$1'(5 3$66(1P g,1( (,1=,*( h(+/3$$581* )@+57 '$=8N '$M ',( u21'( 921 '(5 o(0%5$1 $%6&+:,007P g,1( c8725$',2*5$3+,( '(5 o(0%5$1 .$11 620,7 ',(-(1,*(1 r52%(1 ,'(17,7=,(5(1N ',( 0,7 '(5 u21'( ,'(17,6&+( %=:P 92// .203/(0(17>5( u(48(1=(1 (17+$/7(1P g,1 q/,*218./(27,' 0,7 '(5 p250$/6(48(1= :,5' $/62 (,1 u,*1$/ 0,7 +202=<*27 1250$/(1 2'(5 0,7 +(7(52=<*27(1 fpcOr52%(1 *(%(1P c1$/2* *,%7 '$6 087,(57( q/,*218./(27,' 0,7 (,1(5 +202=<*27 087,(57(1 62:,( (%(1)$//6 0,7 (,1(5 +(7(52=<*27(1 r52%( (,1 u,*1$/P g,1( 3$5$//(/( j<%5,',O 6,(581* 0,7 %(,'(1 u21'(1 (5/$8%7 $/62 (,1( (,1'(87,*( d(67,0081* '(6 i(127<36 $1 ',(6(5 u7(//(P f,( ',$*1267,6&+( u,&+(5+(,7 )@5 ',( k'(17,7.$7,21 (,1(5 %(67,007(1 o87$7,21 /,(*7 $/62 %(, 1$+(=8 SRR @P |8 %('(1.(1 ,67 -('2&+N '$M (,1( 62/&+( c1$O /<6( 185 (,1( c866$*( @%(5 (,1( %(67,007( o87$7,21 $1 (,1(5 *(1$8 '(71,(57(1 u7(//( (5/$8%7P g,1( o87$7,21 185 :(1,*( d$6(13$$5( (17)(517N 2'(5 (,1( $1'(5( o87$7,21 $1 '(56(/%(1 u7(//( :,5' 1,&+7 (5.$117P o?*/,&+( c1:(1'81*(1 '(5 c//(/O63(=,76&+(1 q/,*218./(27,' j<%5,',6,(581* 71O '(1 6,&+ =P dP %(, '(5 f,$*1267,. (5(5%7(5 m5$1.+(,7(1 %=:P '(5(1 %(575>*(567$786N %(, '(5 f,$*1267,. 921 k1)(.7,216.5$1.+(,7(1 81' $8&+ %(, '(5 w17(568&+81* 921 620$7,6&+(1 o87$7,21(1N (7:$ ,0 t$+0(1 '(5 v8025,*(1(6(P f$6 r5,1=,3 '(5 c//(/O 63(=,76&+(1 q/,*218./(27,'Oj<%5,',6,(581* /,(*7 $8&+ '(5 g17:,&./81* 921 fpcO e+,36 =8*581'( J6,(+( m$3P VPYKN %(, '(5 ',( u21'(1 -('2&+ $1 ',( o(0%5$1 7;,(57 6,1' 81' 0,7 '(5 r52%( ,1 '(5 h/@66,*3+$6( +<%5,',6,(57 :(5'(1P

SMQMQMQ q%342)+4)/.3!.!,93% obqL!-0,)&):)%24%2 cm` c1$/2* '(5 u287+(51 d/27Oc1$/<6( *(120,6&+(5 fpc .$11 $8&+ $03/,7=,(57( fpc (,1(5 t(675,.7,216$1$/<6( 817(5=2*(1 :(5'(1N 80 r81.7087$7,21(1 2'(5 fpcOr2O /<0253+,60(1 =8 (5.(11(1P f$=8 :,5' ',( fpc 80 ',( 5(/(9$17( u7(//( +(580 '85&+ ',( ret $03/,7=,(57N 0,7 '(5 *(:@16&+7(1 t(675,.7,216(1'218./($6( 9(5'$87 81' (/(.7523+25(7,6&+ $8)*(75(117 Jc%%P VPSYKP k0 i(*(16$7= =85 u287+(51 d/27O c1$/<6( *(120,6&+(5 fpc .?11(1 ',( h5$*0(17( 1$&+ '(5 67$5.(1 c03/,7=,(581* ',5(.7N 'P +P 2+1( j<%5,',6,(581* 0,7 5$',2$.7,9 0$5.,(57(1 i(1621'(1 $8) (,1(0 0,7 g7+,',80%520,' *()>5%7(1 c*$526(*(/ 6,&+7%$5 *(0$&+7 :(5'(1P f$'85&+ 6,1O .(1 |(,7O 81' m267(1$8):$1' (5+(%/,&+P

VPT w17(568&+81* 921 fpc I

‚

‚

A

104

S

104

S[S

II

180

201

381

88

89

88

89

864

381

201/180 100/90

M

AA

F

P

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S[T

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SMQMR r#2%%.).'-%4(/$%. &=2 o5.+4-54!4)/.%. f,( k'(17,7=,(581* 921 o87$7,21(1 (,1=(/1(5 p8./(27,'326,7,21(1 ,67 (,1( '(5 *5?M7(1 j(5$86)25'(581*(1 %(, '(5 e+$5$.7(5,6,(581* 921 i(1'()(.7(1P |,(/ '(5 c1$/<6(1 ,67 ',( k'(17,7=,(581* 62/&+(5 f()(.7( 0,7 +2+(5 u(16,7,9,7>7 J'P +P ',( x(50(,'81* 921 )$/6&+ 1(*$7,9(1 g5*(%1,66(1K %(, *87(5 r5$.7,.$%,/,7>7 J'P +P %(, $.=(37$%/(0 g,1O 6$7= 921 t(66285&(1KP f,( x(5)@*%$5.(,7 '(5 retOv(&+1,. J6,(+( m$3P VPTPTK +$7 62/&+( c1$/<6(1 $8) %5(,7(5 g%(1( (50?*/,&+7P f$6 r5,1=,3 =:(,(5 62/&+(5 c1$/<6(1N 1>0/,&+ '(5 w17(568&+81* '85&+ NN6,1*/(O675$1'O&21)250$7,21 32/<0253+,60DD JuuerK 81' '(5 NN7(03(5$785(O*5$',(17O*(/ (/(&7523+25(6,6DD JviigK 62// ,0 h2/*(1'(1 925*(67(//7 :(5'(1P d(,'( w17(568&+81*(1 %$8(1 $8) '(5 c1$/<6( 921 '85&+ ret $03/,7=,(57(1 u8%)5$*0(17(1 921 i(1(1 2'(5 &fpc $8) 81' 6,1' u&5((1,1*Oo(7+2'(1P f$6 +(,M7N (6 .$11 0,7 y$+56&+(,1/,&+.(,7 (,1( c866$*( @%(5 '$6 x25+$1'(16(,1 (,1(5 r81.7O 087$7,21 *(0$&+7 :(5'(1P g6 ,67 -('2&+ 1,&+7 0?*/,&+N '(1 d$6(1$867$86&+ (;$.7 =8 /2.$/,6,(5(1P f(6+$/% 08M 1$&+ 326,7,9(5 uuer %=:P viig '$6 (17635(&+(1'( fpcOh5$*0(17 ,1 -('(0 h$//( 6(48(1=,(57 :(5'(1P nicht mutierte DNA

mutierte DNA Denaturierung

single-stranded confirmation

unterschiedliches Laufverhalten einzelsträngiger DNA in nicht-denaturierendem Gel. wt

m

c%%P VPSZ u&+(0$ '(5 uuerOc1$/<6(P f,( w17(568&+81* *(+7 921 (,1(0 @%(5 ret $03/,O 7=,(57(1 fpc h5$*0(17 $86P x(5*/(,&+(1' :,5' (,1 1,&+7 087,(57(6 h5$*0(17 0,7 '(0 =8 $1$/<6,(5(1'(1 81' 327(17,(// 087,(57(1 h5$*0(17 3$5$//(/ 817(568&+7P p$&+ f(1$785,(581* '(5 fpc $'237,(5(1 ',( fpcOg,1=(/675>1*( (,1( m21)250$7,21 J6,1*/(O675$1'(' &21)250$O 7,21KN ',( 921 ,+5(5 r5,0>56(48(1= $%+>1*,* ,67P g17635(&+(1' 817(56&+,('/,&+ :$1'(51 08O 7,(57( J0K 81' 1,&+7 087,(57( J:7K r52%(1 ,0 1,&+7 '(1$785,(5(1'(1 i(/P

VPT w17(568&+81* 921 fpc

S[U

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SMQMRMQ s%-0%2!452Lf2!$)%.4%.Lf%,Ld,%+42/0(/2%3% GsffdH c8&+ ',( viig %$6,(57 $8) '(5 c1$/<6( 921 '85&+ ret *(1(5,(57(1N @%(5/$33(1'(1 i(1)5$*0(17(1N ',( %(, 817(56&+,('/,&+(5 d$6(1=86$00(16(7=81* 63(=,76&+( w1O 7(56&+,('( ,0 (/(.7523+25(7,6&+(1 n$8)9(5+$/7(1 =(,*(1P f85&+ ',( x(5:(1'81* (,1(5 63(=,(//(1 i(/.$00(5 81' =:(,(5 y$66(5%>'(5N ',( ',( n$8)385(5/?681* $1 c12'( 81' m$7+2'( 817(56&+,('/,&+ 7(03(5,(5(1N :$1'(51 ',( '233(/675>1*,*(1 c03/,7.$7( ,0 (/(.75,6&+(1 h(/' *(*(1 (,1(1 67(,*(1'(1 v(03(5$785*5$',(17(1P f,(6 )@+57 :>+5(1' '(5 g/(.7523+25(6( =8 806&+5,(%(1(1 u75$1*75(1181*(1 Jf(1$785,(O 581*(1K ,0 c03/,7.$7N ',( (,1( 6,*1,7.$17( }1'(581* '(5 n$8)*(6&+:,1',*.(,7 9(5O 856$&+(1 Jc%%P VPS[KP g,1( 92//.200(1( n26/?681* '(5 %(,'(1 fpcOu75>1*( :,5' '$%(, '85&+ ',( x(5:(1'81* (,1(5 &+(0,6&+(1 m/$00(5 $0 WAOg1'( (,1(5 '(5 %(,'(1 r5,0(5 9(5+,1'(57P w17(56&+,('( ,0 n$8)9(5+$/7(1 =:,6&+(1 u7$1'$5' 81' c1$/<6( )@+5(1 =80 p$&+:(,6 925+$1'(1(5 o87$7,21(1P y,( $8&+ %(, '(5 uuer 08M ',( n2.$/,6$7,21 '(5 o87$7,21 '85&+ u(48(1=,(581* 1$&+*(:,(6(1 :(5'(1P f,( viig ,67 (,1( x$5,$17( '(5 fiig J'(1$785,1* *5$',(17 *(/ (/(&7523+25(6,6KP g17635(&+(1' '(5 %(, '(5 viig '85&+ v(03(5$785$167,(* (55(,&+7(1 f(1$785,(581* .$11 ',( f(1$785,(581* %(, '(5 fiig @%(5 &+(0,6&+( i5$',(17(1 Jj$516725 2'(5 h250$0,'K (55(,&+7 :(5'(1P d(, $'>48$7(5 c03/,7.$7*5?M( J%,6 =8 WRR %3K /,(*7 ',( u(16,7,9,7>7 ',(6(5 o(7+2'(1 %(, [RA[W @P f,(6(0 x257(,/ '(5 viig 67(+7 -('2&+ (,1( $8):(1',*( q37,0,(581* '(5 x(568&+6%(',1*81*(1 *(*(1@%(5P

S[V

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

nicht mutierte DNA

mutierte DNA

Denaturieren und Mischen

Hetero- und Homoduplex DNA

Elektrophorese in Temperaturgradienten unterschiedliches Schmelzverhalten der Doppelstränge

wt

(a)

wt + m

(b)

1

2

3

4

c%%P VPS[ u&+(0$7,6&+( f$567(//81* 81' d(,63,(/ (,1(5 viigOc1$/<6(P y,( ',( uuer %(58+7 $8&+ ',( viig $8) '(5 c1$/<6( 921 '85&+ ret $03/,7=,(57(1 fpcOh5$*0(17(1P x25 '(0 i(//$8) :(5'(1 ',( m21752//O J1,&+7 087,(57( fpcK 81' v(67$03/,7.$7( J327(17,(// 087,(57( fpcK -('2&+ '(1$785,(57N *(0,6&+7 81' :,('(5 5(1$785,(57P d(, '(0 x25/,(*(1 921 o87$7,21(1 (5*(%(1 6,&+ '$11 9,(5 817(56&+,('/,&+( fpcOf233(/675$1*.20%,1$7,21(1P l('(5 ',(6(5 81O 7(56&+,('/,&+(1 f233(/675>1*( =(,*7 ,1 (,1(0 v(03(5$785*5$',(17(1*(/ (,1 817(56&+,('/,&+(6 n$8)9(5+$/7(1P g,1 1,&+7 087,(57(6 h5$*0(17 5(68/7,(57 '(6+$/% ,1 185 (,1(5 d$1'( 352 i(/N :2+,1*(*(1 %(,0 925/,(*(1 (,1(5 o87$7,21 ,0 *@167,*67(1 h$// 9,(5 d$1'(1 ./$5 817(56&+,('(1 :(5'(1 .?11(1P f$6 5(/$7,9( n$8)9(5+$/7(1 921 087,(57(1 81' 1,&+7 087,(57(1 o2/(.@/(1 .$11 '$%(, 921 w17(568&+81* =8 w17(568&+81* 9$5,,(5(1 81' +>1*7 921 '(5 r5,0>56(48(1= '(5 817(568&+7(1 i(1$%6&+1,77( $%P f$6 i(/ =(,*7 '$6 g5*(%1,6 (,1(5 viigOc1$/<6( 921 (,1(0 fpcOc%6&+1,77 $86 '(0 h,%5,//,1*(1 (,1(6 r$7,(17(1 0,7 o$5)$1 u<1'520P f$6 x25O /,(*(1 (,1(5 o87$7,21 ,67 '(87/,&+ $1 '(0 5(7$5',(57(1 n$8)9(5+$/7(1 '(5 c03/,7.$7( 921 u2+1 Ju385 UK 81' x$7(5 Ju385 TK =8 (5.(11(1P f,( fpc '(5 o877(5 Ju385 VK :(,67 '$6 */(,&+( n$8)9(5+$/7(1 :,( '$6 '(5 1,&+7 087,(57(1 m21752//Ofpc Ju385 SK $8)P Jf,( c%%,/'81* :85'( )5(81'/,&+(5:(,6( 921 f5P rP pP t2%,1621 =85 x(5)@*81* *(67(//7K

VPT w17(568&+81* 921 fpc

S[W

SMQMS cm`Lr%15%.:)%25.' f,( +?&+67( c89?681* '(5 fpc r5,0>56758.785 (5*,%7 ',( d(67,0081* '(5 t(,O +(1)2/*( '(5 p8./(27,'(N ',( fpcOu(48(1=,(581*P p85 1$&+ (,1(5 u(48(1=,(581* =P dP (,1(5 &fpc .?11(1 t@&.6&+/@66( $8) ',( c0,126>85(6(48(1= 81' ',( u(.81O '>56758.785 '(6 .2',(57(1 r527(,16 *(=2*(1 :(5'(1P u,( (5?51(7 '$0,7 1,&+7 185 '(7$,//,(57( g,1%/,&.( ,1 ',( 02/(.8/$5( c1$720,(N r+<6,2/2*,( 81' r$7+23+<6,2/2*,( '(6 0(16&+/,&+(1 i(1206N 621'(51 ,67 6(,7 x(5)@*%$5.(,7 '(5 ret $8&+ ./,1,6&+O ',$*1267,6&+ 187=%$5P q%:2+/ 9(56&+,('(1( u75$7(*,(1 =85 x(5)@*81* 67(+(1N +$7 6,&+ ',( (1=<0$7,6&+( o(7+2'( 1$&+ u$1*(5 )$67 81,9(56(// '85&+*(6(7=7 Jc%%P VPTRKP f,(6( 62// +,(5 ,1 ,+5(0 r5,1=,3 %(6&+5,(%(1 :(5'(1P f(5 .21=(37,21(//( m(51 /,(*7 ,1 '(5 h>+,*.(,7 '(5 fpcOr2/<0(5$6(N (,1=(/675>1*,*( fpc 921 (,1(0 '233(/675>1*,*(1 u7$57381.7 J35,0(5K $86 '85&+ (,1(1 *(75(8(1 .203/(0(17>5(1 u75$1* =8 (,1(0 f233(/675$1* =8 (5*>1=(1P f,( u<17+(6(5,&+781* ,67 '$%(, 921 WA 1$&+ UA 25,(17,(57P f,( fpcO r2/<0(5$6( .$7$/<6,(57 $/62 ',( d,/'81* '(6 r+263+2',(67(56 =:,6&+(1 '(5 WAOr+26O 3+$7 81' '(5 UAOqjOi5833( '(5 '(62;O +,*.(,7 '(5 fpcOr2/<0(5$6( (176&+(,'(1'N $8&+ 1$7@5/,&+(5:(,6( 1,&+7 925.20O 0(1'( ','(62;1*(581*N '$ ,+1(1 ',( UAOqjOi5833( $/6 d,1'(*/,(' =80 r+263+$7 '(6 1>&+67(1 p8./(27,'6 )(+/7P c/6 u7$570$7(5,$/ %(1?7,*7 0$1 5(&+7 *52M( o(1*(1N 'P +P SAU ~* ,62/,(57(5 81' *(5(,1,*7(5 fpc 921 (,1,*(1 +81'(57 %,6 :(1,*(1 7$86(1' d$6(13$$5(1N ',( (17:('(5 '85&+ fpcOm/21,(581* 2'(5 '85&+ ',( ret *(:211(1 :,5'P f,(6( :,5' '(1$785,(57 81' (,1 r5,0(5 '85&+ c1/$*(581* ,1 h250 (,1(6 q/,*218./(27,'6 ,1 810,77(/%$5(5 p$&+%$56&+$)7 '(5 =8 %(67,00(1'(1 u(48(1=(1 $1*(/$*(57P d(, 5(O .20%,1$17(5 fpc .$11 '(5 r5,0(5 ,0 x(.725 ',5(.7 1(%(1 '(5 k16(57,21667(//( '(5 (;2*(1(1 fpc /,(*(1P d(, retO$03/,7=,(57(5 fpc .$11 (,1(6 '(5 q/,*218./(27,'( %(187=7 :(5'(1N '$6 6&+21 =85 c03/,7=,(581* ',(17(P f,(6( fpc :,5' '$11 ,1 9,(5 9(56&+,('(1( i()>M( $8)*(7(,/7N ',( -(:(,/6 $//( 9,(5 '(62;1*(N '(5(1 u<17+(6( -(:(,/6 %(,0 g,1%$8 (,1(6 ''cvr6 $%*(%52&+(1 :85'( 81' 620,7 '(1 c%67$1' 920 r5,0(5 =8 -('(0 (,1*(%$87(1 c'(126,1 $1=(,*(1P g17635(&+(1'(6 *,/7 )@5 ',( $1'(5(1 '5(, t($.7,21(1 0,7 ''evrN ''ivr 81' ''vvrP d(, +2&+$89?6(1'(5 (/(.7523+25(7,O 6&+(5 v5(1181* '(5 ,1 '(1 9,(5 t($.7,21(1 (167$1'(1(1 o2/(.@/( 1(%(1(,1$1'(5 .$11 0$1 1$&+ c8725$',2*5$3+,( @%(5 ',( 817(56&+,('/,&+( m(77(1/>1*( ',( 5(/$7,9( r26,7,21 '(5 9,(5 p8./(27,'( =8(,1$1'(5 ,1 ,+5(5 u(48(1= %(67,00(1P x21 (,1(0 r5,0(5 $86*(+(1' .$11 0$1 (,1,*( +81'(57 d$6(13$$5( 6(48(1=,(5(1P |85 u(48(1O =,(581* :(,7(5 (17)(517 /,(*(1'(5 fpc 08M 0$1 (17:('(5 ',( 1(8 *(:211(1( k1O )250$7,21 =85 u<17+(6( 1(8(5 r5,0(5Oq/,*218./(27,'( 9(5:(1'(1N 2'(5 9(56&+,('(O 1(N 6,&+ ,1 ,+5(5 (;2*(1(1 fpc @%(5/$33(1'( t(.20%,1$17(1 6&+$5(1N ',( 920 6(/%(1 r5,0(5 $86 6(48(1=,(57 :(5'(1P

S[X

V o2/(.8/$50(',=,1,6&+( o(7+2'(1 5´- Primer 3´

A–Reaktion dATP* dCTP, dGTP, dTTP DNA Polymerase ddATP

5´3´ 5´3´ 5´3´

ACTTTGGCAAA-5´

C–Reaktion dATP* dCTP, dGTP, dTTP DNA Polymerase ddCTP

5´3´ 5´3´

TGAAACCdd* ACTT TGGCAAA- 5´ TGAAACdd* ACT T TGGCAAA- 5´

TGAAAdd* ACT T T GGCAAA -5´ TGAAdd* ACTT TGGCAAA-5´ TGAdd* ACT T TGGCAAA -5´

G–Reaktion dATP* dCTP, dGTP, dTTP DNA Polymerase ddGTP

T–Reaktion dATP* dCTP, dGTP, dTTP DNA Polymerase ddTTP

5´3´

5´3´ 5´3´ 5´3´

TGAAACCGdd* ACTT TGGCAAA-5´

TGAAACCGTTdd* ACTT TGGCAAA - 5´ TGAAACCGT T Tdd* ACT T TGGCAAA - 5´ TGAAACCGTdd* ACT T TGGCAAA - 5´

5´3´

TGdd* AC T T TGGCAAA-5´ 5´3´

Tdd* ACT T TGGCAAA - 5´

denaturierende Polyacrylamid-Gel-Elektrophorese A

C

G

T

A

C

G

T

gelesene Sequenz: 5´-TGAAACCGTTT-3´ analysierte Sequenz: 3´-ACTTTGGCAAA-5´

c%%P VPTR u&+(0$7,6&+( f$567(//81* 81' c8725$',2*5$3+,( (,1(5 fpcOu(48(1=,(581*P g,1 (7:$ TR %3 /$1*(6 q/,*218./(27,' Jr5,0(5K :,5' ,1 810,77(/%$5(5 p$&+%$56&+$)7 =85 ,17(5(6O 6,(5(1'(1 fpc +<%5,',6,(57N 62 '$M (,1 c16$7=381.7 )@5 ',( fpcOr2/<0(5$6( (1767(+7P f$6 'cvr ,67 5$',2$.7,9 0$5.,(57 J"KP

VPT w17(568&+81* 921 fpc

S[Y

o2'(51( v(&+12/2*,(1 =85 fpcOu(48(1=,(581* 9(5:(1'(1 9825(6=,(5(1'( r5,O 0(5N ',( (,1( $8720$7,6,(57( u(48(1=$1$/<6( ,1 (17635(&+(1'(1 t2%27(51 =8/$66(1P f,( x(5)@*%$5.(,7 ',(6(5 v(&+12/2*,( ,67 (,1( '(5 :(6(17/,&+(1 x25$866(7=81*(1 )@5 ',( ,0 *52M(1 w0)$1* '85&+*()@+57( fpcOu(48(1=,(581* (7:$ ,0 t$+0(1 '(5 k'(17,7.$7,21 921 i(1(1 J6,(+( m$3P VPYK 2'(5 '(6 j80$1*(120352-(.7(6 J6,(+( m$3P VPZKP

SMQMT `.!,93% (/#(0/,9-/20(%2 l!2+%2 o2/(.8/$5*(1(7,6&+( c1$/<6(1 +$%(1 ',( o(',=,1 5(92/87,21,(57P f,(6 *,/7 ,1 %(621O '(5(0 o$M( )@5 ',( g17:,&./81* 921 ,1',9,'8$/63(=,76&+(1 o$5.(56<67(0(1P f,( w56$&+(1 '$)@5 6,1' 925 $//(0 ,1 '(5 (1250(1 x$5,$%,/,7>7 '(5 1,&+7O.2',(5(1'(1 u(48(1=%(5(,&+( '(6 i(1206 81' ,1 ,+5(0 '$0,7 9(5%81'(1(1 5,(6,*(1 k1',9,'8$O /,6,(581*6327(17,$/N ,1 '(5 5(/$7,9(1 u7$%,/,7>7 '(5 fpcOo2/(.@/( *(*(1@%(5 3267O 0257$/(1 c%%$8352=(66(1 81' w0:(/7(,19@66(1 81' ,1 '(5 (5+?+7(1 u(16,7,9,7>7 '(5 p$&+:(,67(&+1,. ,16%(621'(5( 1$&+ g,1)@+581* '(5 r2/<0(5$6( m(77(15($.7,21 =8 68&+(1P c1:(1'81* 71'(1 ',(6( k1',9,'8$/,6,(581*69(5)$+5(1 ,1 '(5 ./,1,6&+(1 f,$*12O 67,.N ,1 '(5 *(5,&+7/,&+(1 o(',=,1 81' 1$7@5/,&+ $8&+ ,1 '(5 0(',=,1,6&+(1 i581'O /$*(1)256&+81* %(, '(5 m$57,(581* 921 i(1(1 J6,(+( m$3P VPYKP k0 f,(167( '(5 ./,O 1,6&+(1 o(',=,1 :(5'(1 k'(17,7=,(581*(1 921 d/87O 81' i(:(%(352%(1 %(, q3(O 5$7,216O 2'(5 d,236,(O 81' +,672/2*,6&+(1 r5>3$5$7(1 '85&+*()@+57 81' e+,0>5,6O 0(1 1$&+ v5$163/$17$7,21(1 '(7(.7,(57P k1 '(5 )25(16,6&+(1 u385(1$1$/<6( ',(1(1 6,( ,1 (567(5 n,1,( '(5 m/>581* 675$)5(&+7/,&+(5 h5$*(1N %(,63,(/6:(,6( ,1 6385(1.81'O /,&+(1 i87$&+7(1N %(, u(;8$/'(/,.7(1N k'(17,7=,(581*(1 921 n(%(1'(1 2'(5 v27(1N i(:(%(1 81' m?53(59@66,*.(,7(1P f$5@%(5 +,1$86 /$66(1 6,&+ '$0,7 $8&+ =,9,/5(&+7O /,&+( h5$*(1 ,1 c%67$0081*6*87$&+7(1 ./>5(1P q%:2+/ retO*(67@7=7( x(5)$+5(1 0,7 ,+5(5 +2+(1 u(16,7,9,7>7 81' *(5,1*(1 f(*5$'$7,216$1)>//,*.(,7 6&+21 c1)$1* '(5 1(81=,*(5 l$+5( ',( j<%5,',6,(581*67(&+1,.(1 0,7 u,1*/(O 81' o8/7,/2&86Ou1*7(1N +$%(1 /(7=7(5( )@5 63(=,76&+( c1:(1'81*(1 $8&+ +(87( 12&+ ,+5( d('(8781*P

SMQMTMP cm`Ll5,4),/#53Lr934%-% GlkrH f(5 d(*5,5 h,1*(5$%'58&. J(1*/P\ NN71*(535,17DDK :85'( 85635@1*/,&+ )@5 '(1 c%O '58&. '(5 )@5 -('(1 o(16&+(1 &+$5$.7(5,67,6&+(1 r$3,//$5/,1,(1 '(5 h,1*(5%((5( 9(5O :(1'(7 81' )$1' 6(,1 02/(.8/$5%,2/2*,6&+(6 r(1'$17 ,0 *(1$862 )@5 -('(6 k1',9,O '880 63(=,76&+(1 j<%5,',6,(581*60867(5 '(5 o,77( '(5 $&+7=,*(5 l$+5( (17:,&.(/7(1 fpcOo8/7,/2&86Ou21'(1P f(5 r52727<3 ',(6(6 u21'(17<36 (17+>/7 0(+5)$&+ $1(,O 1$1'(5*(5(,+7 '$6 o,1,6$7(//,7(1 NN&25(DDOo27,9 J(,1 +>87* :,('(5.(+5(1'(6 ieO5(,O &+(6 u(48(1=027,9K 81' (5)$M7 9,(/( +<3(59$5,$%/( fpcOn2&, */(,&+=(,7,*P f,(6( */(,&+=(,7,*( g5.(1181* (,1(5 x,(/=$+/ 921 r2/<0253+,60(1 0$&+7 '(1 +2+(1 k1O )250$7,216*(+$/7 ',(6(5 o(7+2'( $86P k1 '(5 h2/*(=(,7 :85'(1 :(,7(5( o8/7,/2&86O u21'(1 (17:,&.(/7N %,6 +,1 =8 &+(0,6&+ 6<17+(7,6,(57(1 q/,*218./(27,'(1 0,7 5(3(O 7,7,9(1 o27,9(1 921 =:(, %,6 9,(5 d$6(13$$5(1P c// ',(6( u<67(0( '(7(.7,(5(1 5(3(O

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c%%P VPTV w17(568&+81* '(6 e+,0>5,6086 1$&+ m12&+(10$5.Ov5$163/$17$7,21 ,1 (,1(0 uvtOu<67(0P c8720$7,6,(57( c1$/<6( '(5 h/825(6=(1=O0$5.,(57(1 retOr52'8.7(P SR\ fpc '(6 r$7,(17(1 925 v5$163/$17$7,21N SS\ fpc '(6 u3(1'(56N ST\ fpc '(6 r$7,(17(1N Z y2&+(1 1$&+ v5$163/$17$7,21N =86>7=/,&+ SRAST\ fpc (,1(6 ,17(51(1 u7$1'$5'6P f,( h5$*0(17/>1*(1 6,1' ,1 %3 $1*(*(%(1P f,( fpc '(6 r$7,(17(1 =(,*7 1$&+ '(5 v5$163/$17$7,21 (,1(1 *(0,6&+7(1 e+,0>5,6086 ,0 x(5+>/71,6 S \ Z Jg03)>1*(5\u3(1'(5OfpcKP f,(6(5 *(0,6&+7( e+,0>5,6086 .2117( 925 '(5 ./,1,6&+(1 f,$*126( NNv5$163/$17$79(56$*(1DD %=:P NNt(=,',9DD '(5 i581'(5.O 5$1.81* %(2%$&+7(7 :(5'(1P

TRV

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

./(>5(1 c1$/<6( (5./>57 J6,(+( v$%P VPTPKP u2 .2007 ',( 07fpcOc1$/<6( =P dP ,1 '(5 h25(16,. ,00(5 '$11 =80 g,16$7=N :(11 $//( $1'(5(1 x(5)$+5(1 1,&+7 (5)2/*5(,&+ 6,1'N :,( %(, (;+80,(57(0 n(,&+(10$7(5,$/N 080,7=,(57(1 2'(5 6.(/(77,(57(1 n(,&+(1O 7(,/(1BO.?53(51P f$5@%(5 +,1$86 6,1' 07fpcOc1$/<6(1 =85 t(.216758.7,21 921 x(5O :$1'76&+$)769(5+>/71,66(1 @%(5 0(+5(5( i(1(5$7,21(1 1@7=/,&+N '$ 07fpc $86O 6&+/,(M/,&+ 0$7(51$/ 9(5(5%7 :,5'P r5>+,6725,6&+( r52%(1 J7SRX l$+5( 81' >/7(5K 6,1' -('2&+ $8&+ 0,7 ',(6(5 u75$7(*,( 35$.7,6&+ 1,&+7 0(+5 $1$/<6,(5%$5N 81' *(/(*(17/,&+( d(5,&+7( @%(5 (5)2/*5(,&+( c1$/<6(1 0@66(1 ,16*(6$07 .5,7,6&+ %(75$&+7(7 :(5'(1P

SMR t.4%235#(5.' 6/. qm` y,// 0$1 @%(5 ',( 02/(.8/$5( c1$720,( +,1$86 ',( h81.7,21 921 i(1(1 817(568O &+(1N 62 %(1?7,*7 0$1 k1)250$7,21(1 @%(5 ',( c57 81' o(1*( '(5 *(%,/'(7(1 tpc ,1 (,1(0 %(67,007(1 i(:(%(P f,( 0(',=,1,6&+ 5(/(9$17(1 c1:(1'81*(1 '(5 tpcO c1$/<6( (5675(&.(1 6,&+ =85 |(,7 $8) w17(568&+81*(1 '(5 i(13+<6,2/2*,( %=:P r$O 7+23+<6,2/2*,(N $8) ',( f,$*1267,. 921 tpcOx,5(1 81' $8) ',( g;35(66,21 3$7+2O *(1(7,6&+ 5(/(9$17(5 i(1( (7:$ %(, 0$/,*1(1 g5.5$1.81*(1P

SMRMP m/24(%2. a,/44).' f$6 r5,1=,3 '(6 p257+(51 d/277,1* 817(56&+(,'(7 6,&+ 1,&+7 6(+5 921 '(0 '(6 u28O 7+(51 d/277,1*P f,( c1$/2*,( ',(6(5 %(,'(1 o(7+2'(1 '5@&.7 6,&+ 0,7 (,1(0 *(:,66(1 j8025 $8&+ ,1 '(5 p$0(16*(%81* $86P |,(/ '(6 p257+(51 d/277,1* ,67 (6N ',( n>1*( 81' $8&+ ',( o(1*( (,1(5 tpc =8 %(67,00(1N ',( j202/2*,(1 0,7 (,1(5 %(67,007(1 i(1621'( $8):(,67P f$=8 :,5' ',( tpc =81>&+67 $86 '(0 i(:(%( ,62/,(57P o(7+2',6&+ ,67 ',(6 $8)O :(1',*(5 81' 67?5$1)>//,*(5 $/6 ',( k62/$7,21 921 fpcP f,(6 /,(*7 (,10$/ '$5$1N '$M ',( (,1=(/675>1*,*( tpc ,1 %(621'(5(0 o$M( 18./($6((0371'/,&+ ,67P f$6 +(,M7N ',( k17(*5,7>7 '(6 tpcOo2/(.@/6 :,5' '85&+ (,1( (,1=,*( j<'52/<6( (,1(5 r+263+2',(67(5%,1'81* 810,77(/%$5 =(567?57N :>+5(1' (,1 (,1=(/675>1*,*(5 d58&+ '(5 fpc =81>&+67 '85&+ '(1 ,17$.7(1 *(*(1@%(5/,(*(1'(1 u75$1* NN*(6&+,(17DD :,5'P y(,7(5+,1 ,67 ',( t,%218./($6( (,1 @%(5$86 67$%,/(6 g1=<0 81' 185 6(+5 6&+:(5 =8 ,1$.7,9,(5(1N :>+5(1' ',( f(62;<5,%218./($6( 6(+5 (0371'/,&+ ,67P f,( ,62/,(57( tpc :,5' '$11N >+1/,&+ :,( ',( 9(5'$87( fpc %(,0 u287+(51 d/27O 7,1*N ,+5(5 i5?M( 1$&+ (/(.7523+25(7,6&+ $8)*(75(117N 1$&+ .$3,//$5(0 v5$16)(5 920 i(/ $8) (,1(5 0(&+$1,6&+ 67$%,/(1 o(0%5$1 7;,(57N 0,7 (,1(5 0$5.,(57(1 i(1621'( +<%5,',6,(57 81' 1$&+ 675,1*(17(0 y$6&+(1 $8725$',2*5$3+,(57 Jc%%P VPTWKP f$6 (17O 67(+(1'( u,*1$/ *,%7 c8)6&+/@66( @%(5 ',( n>1*( 81' ',( o(1*( '(6 v5$16.5,37(6 ,1 '(0 -(:(,/,*(1 817(568&+7(1 i(:(%(P f$6 p257+(51 d/277,1* (,*1(7 6,&+ 620,7 $/6 25,(17,(5(1'( 48$/,7$7,9( 81' 48$17,7$7,9( w17(568&+81* '(5 tpcOg;35(66,21P h@5 63(=,(//( c1:(1'81*(1 67(+(1 63(=,76&+(5( o(7+2'(1N :,( '(5 uS p8./($6( 81' '(5 tp$6( r527(.7,216$66$< =85 x(5)@*81*N ',( +,(5 $//(5',1*6 185 0,7 ,+5(0 p$0(1 *(1$117 6(,1 62//(1P g0371'/,&+(5 $/6 '(5 p257+(51 d/27 ,67 ',( ,0 h2/*(1'(1 %(6&+5,(%(1( tvOretP

VPU w17(568&+81* 921 tpc

TRW

RNA-Extraktion

denaturierende Agarose-Gelelektrophorese

Transfer auf eine Nylonmembran

Hybridisierung mit einer spezifischen Gensonde

stringentes Waschen und Autoradiographie

c%%P VPTW

h/8M',$*5$00 '(6 p257+(51 d/277,1*P

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TRX

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

62//7(1 ',( 63(=,76&+(1 r5,0(5 '(5 retOt($.7,21 0?*/,&+67 k17521Bg;21*5(1=(1 @%(563$11(1P g,1( 0?*/,&+( m217$0,1$7,21 '85&+ ',( c03/,7=,(581* *(120,6&+(5 u(48(1=(1 .$11 '$11 @%(5 '$6 *5?M(5( c03/,7.$7 '(5 *(120,6&+(1 fpc ,1./86,9( '(5 ,1 '(5 0tpc 1,&+7 (17+$/7(1(1 k175216 1$&+*(:,(6(1 %=:P $86*(6&+/266(1 :(5O '(1P f,( tvOret +$7 (,1( %(621'(5( d('(8781* %(,0 p$&+:(,6 6(/7(1(5 v5$16.5,37(P k1 '(5 ./,1,6&+(1 f,$*1267,. :,5' 6,( =80 d(,63,(/ =80 p$&+:(,6 3$7+2/2*,6&+(5 v5$16.5,37( (,1*(6(7=7N :,( 6,( %(, v5$16/2.$7,21(1 ,1 817(56&+,('/,&+(1 v8025(1 *()81'(1 :(5'(1 J6,(+( m$3P XPSRN c%%P XPYKP f$5@%(5 +,1$86 (50?*/,&+7 ',( fpc $/6 r52'8.7 '(5 tvOretOt($.7,21 $8&+ (,1( ',5(.7( o87$7,216$1$/<6( 75$16.5,O %,(57(5 i(1(P f,(6( .$11 (17:('(5 @%(5 u&5((1,1*Oc1$/<6(1 :,( uuer 81' viig J6,(+( m$3P VPTPUK 2'(5 ',( ',5(.7( u(48(1=,(581* J6,(+( m$3P VPTPVK (5)2/*(1 81' 71'(7 ,1 '(5 f,$*1267,. +>87*( c1:(1'81*(1P

SMS s2!.3&%+4)/. 6/. %5+!29/.4%. y%,,%. o$1&+( :,&+7,*( c8)6&+/@66( @%(5 ',( h81.7,21 921 i(1352'8.7(1 %=:P @%(5 ',( c86:,5.81* 63(=,76&+(5 $1$720,6&+(5 fpcOx(5>1'(581*(1 .$11 0$1 185 '$11 *(:,11(1N :(11 5(.20%,1$17( fpc ,1 (8.$5<217(1 h5(0'=(//(1 :,( .8/7,9,(57(1 |(//,1,(1 2'(5 j()(=(//(1 =85 g;35(66,21 *(%5$&+7 :,5'P f$=8 *(+?5(1 =P dP ',( w1O 7(568&+81* '(5 i(15(*8/$7,21 0,7 '(5 k'(17,7.$7,21 921 u7(8(55(*,21(1N ',( c1$/<6( '(5 %,2&+(0,6&+(1 t(/(9$1= 921 c0,126>85(68%67,787,21(1 ,1 3+$50$.2/2*,6&+ 81' $8&+ 3+<6,2/2*,6&+ :,&+7,*(1 r527(,1(1 62:,( c1:(1'81*(1 ,1 '(5 d,27(&+O 12/2*,(P k1 ',(6(0 m$3,7(/ 62//(1 (,1,*( 0(7+2',6&+( r5,1=,3,(1 ',(6(6 (;3(5,0(1O 7(//(1 c16$7=(6 '$5*(67(//7 :(5'(1P g,1( i581'925$866(7=81* )@5 ',( g;35(66,21 )5(0'(5 i(1( ,1 (,1(5 (8.$5<217(1 |(//( ,67 (6N ',( (;2*(1( fpc ,1 ',( .8/7,9,(57( |(//( (,16&+/(86(1 =8 .?11(1 Jc%%P VPTXKP f(1 d(*5,5 '(5 v5$16)(.7,21 +$7 0$1 *(:>+/7N 80 ',(6(1 x25*$1* $8&+ 635$&+/,&+ 921 '(5 v5$16)250$7,21 352.$5<217(5 |(//(1 $%=8*5(1=(1 J6,(+( m$3P VPSPSKP

rekombinante DNA

kultivierte Zellen –Elektroporation –Ca-Phosphatfällung –Virusinfektion transfizierte Zellen

permanente Inkorporation und Expression exogener DNA

c%%P VPTX /(1P

transiente Inkorporation und Expression exogener DNA

h/8M',$*5$00 '(5 g;35(66,21 (;2*(1(5 fpc 1$&+ v5$16)(.7,21 (8.$5<217(5 |(/O

VPV v5$16)(.7,21 921 (8.$5<217(1 |(//(1

TRY

i581'6>7=/,&+ 817(56&+(,'(7 0$1 181 =:,6&+(1 (,1(5 75$16,(17(1 v5$16)(.7,21 (,1(5O 6(,76N %(, '(5 ',( (;2*(1(1 i(1( 185 )@5 u781'(1 %,6 :(1,*( v$*( ,1 '(5 |(//( 9(5%/(,%(1 81' (;35,0,(57 :(5'(1 81' (,1(5 3(50$1(17(1 v5$16)(.7,21 $1'(5(56(,76N %(, '(5 ',( (;2*(1( fpc 67$%,/ ,1 '$6 y,576*(120 ,17(*5,(57 :,5'P f,( x257(,/( '(5 c1$/<6( 75$16,(17 ,1.25325,(57(5 81' (;35,0,(57(5 (;2*(1(5 fpc /,(*(1 ,1 '(5 m@5=( '(5 %(O 1?7,*7(1 |(,7 62:,( '(5 /(,&+7(1 (;3(5,0(17(//(1 t(352'8=,(5%$5.(,7P c8M(5'(0 (17O )$//(1 1,&+7 .21752//,(5%$5( g,19@66(N ',( 921 %(1$&+%$57 /,(*(1'(5 (1'2*(1(5 fpc $86*(+(1P c//(5',1*6 6,1' 75$16,(17( g;35(66,216(;3(5,0(17( 81%5$8&+%$5N :(11 '$6 x(5+$/7(1 921 i(1(1 @%(5 />1*(5( |(,7 %(2%$&+7(7 :(5'(1 62//P c8&+ )(+/7 %(, '(5 75$16,(17(1 k1.25325$7,21 (,1( '(5 *(120,6&+(1 fpc 9(5*/(,&+%$5( g,1%,1'81* 921 fpc ,1 e+520$7,1N 62 '$M 6,&+(5 1,&+7 $//( g%(1(1 '(5 i(15(*8/$7,21 (;3(5,0(17(// (5)$M7 :(5'(1 .?11(1P u&+/,(M/,&+ :(5'(1 %(, '(5 75$16,(17(1 v5$16)(.7,21 ,1 '(5 t(*(/ 0(+5 $/6 SRV r/$60,'02/(.@/( 921 '(5 |(//( $8)*(1200(1N 62 '$M (6 =8 6(+5 +2+(1 ,175$=(//8/>5(1 m21=(175$7,21(1 '(6 i(1352'8.7(6 .2007P f,(6 +$7 =85 h2/*(N '$M ',( =(//(,*(1(1 o(&+$1,60(1 '(5 c.7,9,7>76.21752//( ',(6(5 r527(,1( 185 6(+5 (,1*(6&+5>1.7 *5(,)(1 .?11(1 81' (17635(&+(1' .$80 0(M%$5 6,1'P k0 i(*(16$7= '$=8 ,67 ',( 67$%,/( k17(*5$7,21 921 x(.725(1 (,1 6(/7(1(6 g5(,*1,6N 62 '$M ,1 '(5 t(*(/ 185 :(1,*( m23,(1 '(5 x(.725(1 352 |(//( ,1 '$6 i(120 ,17(*5,(57 :(5'(1P g,1( 3(50$1(17( v5$16)(.7,21 6(7=7 ,1 $//(5 t(*(/ 925$86N '$M (,1 u(/(.7,2160$5O .(5 $1 ',( (;2*(1( fpc *(.233(/7 :,5'P f$6 r5,1=,3 ,67 '(0 '(5 $17,%,27,6&+(1 u(/(.7,21 ,0 t$+0(1 '(5 %$.7(5,(//(1 v5$16)250$7,21 >+1/,&+ J6,(+( m$3P VPSPSKP g,1 +>87* 9(5:(1'(7(5 o$5.(5 ,67 '$6 p(20<&,1Oc&(77 (,1( (8.$5<217( |(//( *(*(1 '$6 p(20<&,1$1$/2*21 iVSZ 5(6,67(17 :(5'(1 />M7P y,5' ',( m8/785 181 '(0 u(/(.7,216'58&. $86*(6(7=7N 62 @%(5/(%(1 185 ',( |(//(1N ',( '(1 u(/(.7,2160$5.(5 81' ',( '$5$1 *(.233(/7( (;2*(1( fpc 67$%,/ ,1.25325,(57 +$%(1P f,( (;2*(1( fpc ,67 1$&+ '(0 u(/(.7,216925*$1* ,1 '$6 e+52O 0$7,1 '(5 y,576=(//( (,1*(%$87 81' 817(5/,(*7 '$0,7 $8&+ 3+<6,2/2*,6&+(1 t(*8/$O 7,2160(&+$1,60(1P d,6+(5 9(5)@*%$5( u7$1'$5'0(7+2'(1 )@+5(1 $//(5',1*6 =85 =8O )>//,* ,0 i(120 9(57(,/7(1 k1.25325$7,21 81' |(//7<3O81$%+>1*,*(1 g;35(66,21 921 i(1(1N 62 '$M 63(=,76&+(N 185 /2.$/ :,5.6$0( t(*8/$7,216(%(1(1 (17:('(5 1,&+7 (5)$M7 :(5'(1 2'(5 81.21752//,(57 81' 813+<6,2/2*,6&+ $8) ',( (;2*(1( fpc :,5O .(1P k1 '(1 /(7=7(1 l$+5(1 (17:,&.(/7( o(7+2'(1 =85 *(=,(/7(1 k1.25325$7,21 (;2O *(1(5 i(1( $1 ,+5( 3+<6,2/2*,6&+(1 u7(//(1 ,0 i(120 81' ',( |(//7<3O63(=,76&+( g;35(66,21 921 i(1(1 J*(1( 7$5*(7,1*K 6,1' *((,*1(7N 9,(/( p$&+7(,/( =8 @%(5:,1'(1 81' ',( (;2*(1( fpc '(1 :(6(17/,&+(1 3+<6,2/2*,6&+(1 t(*8/$7,2160(&+$1,60(1 '(5 y,576=(//( =8 817(5:(5)(1P g,1( +>87* 9(5:(1'(7( g17:,&./81* ,1 ',(6( t,&+781* ,67 '$6 ,1 m$3,7(/ VP[ %(6&+5,(%(1( e5(B/2;r u<67(0P y(11 (;2*(1(6 o$7(5,$/ ,1 (,1( (8.$5<217( |(//( (,1*(%5$&+7 :(5'(1 62//N '$11 67(//7 ',( r/$60$0(0%5$1 ',( (176&+(,'(1'( d$55,(5( '$5P f,(6( .$11 (17:('(5 '85&+ r,12Br+$*2&<726( 2'(5 $8&+ '85&+ (,1( 75$16,(17( 3+<6,.$/,6&+( u&+>',*81* @%(5O :81'(1 :(5'(1P o(7+2',6&+ 6,1' +(87( -( 1$&+ 9(5:(1'(7(0 |(//7<3 (,1( '(5 )2/O *(1'(1 x(5)$+5(1 '(5 v5$16)(.7,21 $0 *(%5>8&+/,&+67(1P d(, '(5 m$/=,80Or+263+$7 h>//81* :,5' ',( (;2*(1( fpc 0,7 '(0 u$/= &2O35>=,3,7,(57P o$1 />M7 '$6 r5>=,3,7$7 6,&+ $8) (,1(5 $'+>5(17 :$&+6(1'(1 |(//,1,( $%6(7=(1N :25$8)+,1 (6 921 (,1(0 v(,/ '(5 |(//(1 '85&+ r+$*2&<726( ,1.25325,(57 :,5'P f,( g/(.752325$7,21 9(5:(1'(7 0$1 925=8*6:(,6( %(, |(//,1,(1N ',( 0,77(/6 m$/O =,80Or+263+$7 h>//81* 1,&+7 (5,=,(17 75$16)(.7,(5%$5 6,1'P f$%(, +$1'(/7 (6 6,&+

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VPW r527(,1$1$/<6( S 1

2

3

4

5

6

P

N

7

8

TSU

RB/E2F

E2F

freie Sonde

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TSV

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

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VPX u75$7(*,(1 =85 fpcOm/21,(581* Faktor A

Faktor B

VP16

POL II

LEX A (a)

TSW

lac z-Gen

LEX A Bindungsstelle

Faktor A

cDNA

VP16

cDNA

VP16

cDNA VP16

POL II

LEX A

lac z-Gen

LEX A Bindungsstelle

(b)

• Verifizierung der Interaktion • Sequenzierung • Datenbankabgleich • funktionelle Analyse

Isolierung

cDNA

VP16

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TSX

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

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SMUMP #cm` d(, '(5 &fpcOm/21,(581* :,5' (,1( m23,( '(5 0tpc '(6 |,(/*(16 ./21,(57 Jc%%P VPURKP f,( t(.20%,1$17( (17+>/7 $/62 185 ',( .2',(5(1'(1 62:,( ',( WAO 81' UAO 1,&+7O75$16/$7,(57(1 u(48(1=(1N $%(5 .(,1( k175216P f,( &fpcOu(48(1= (5/$8%7 '$+(5 (,1'(87,*( t@&.6&+/@66( $8) ',( r5,0>56758.785 '(6 .2',(57(1 r(37,'6 81' '$921 $%*(/(,7(7 $8&+ (9(178(// t@&.6&+/@66( $8) ',( u(.81'>56758.785 81' h81.O 7,21 '(6 r527(,16P f,( &<723/$60$7,6&+( 0tpc :,5' 0,77(/6 t(9(56(5 v5$16.5,37$6( ,1 9,752 ,1 .203/(0(17>5( fpc J&fpcK @%(56&+5,(%(1P g6 +$1'(/7 6,&+ %(, '(5 t(9(56(1 v5$16.5,37$6( 80 (,1 5(7529,5$/(6 g1=<0N '$6 ',( 80*(.(+57( v5$16.5,3O 7,21 '(5 tpc =8 fpc .$7$/<6,(57 J6,(+( m$3P YPTKP d(, '(5 5(9(56(1 v5$16.5,37,21 921 0tpc (1767(+7 $/62 =81>&+67 (,1 0tpcBfpc j<%5,'N '$6 $1 6(,1(0 UAOtpcB WAOfpcOg1'( (,1(1 r2//7P f85&+ x(5'$8

VPX u75$7(*,(1 =85 fpcOm/21,(581*

AA A AAAAAA AAAAAAAAA A AAAAAAAAAAA AA

CAP

CAP CAP CAP

AA

AA

AA

A AA

AA

TSY

AAAAAA

P

CA

AAAAA

AAA

AAA

CAP

AAA

AA

isolierte mRNA reverse Transkriptase + Oligo dT-Primer 5´ 3´

CAP

AAAAAAAAAAA T T T T T TT TT T T

3´ 5´ Ribonuklease H

3´

T T T T T TT TT T T

5´

1.Strang cDNA DNA-Polymerase + Random Primer 5´ 3´

AAAAAAAAAAA T T T T T TT TT T T

2.Strang cDNA

3´ 5´ DNA-Ligase + Linkerfragmente mit spezifischen Segmenten von Restriktionsschnittstellen

T T T T T TT TT T T AAAAAAAAAAA

Ligierung in einen mit Restriktionsendonukleasen geöffneten Vektor rekombinante cDNA Transformation cDNA Genbank „Screening” isolierte cDNA

c%%P VPUR

u&+(0$7,6&+( f$567(//81* '(5 &fpcOm/21,(581*P

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TSZ

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

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SMUMQ f%./-)3#(% cm` d(, (,1(5 t(,+( 921 c1:(1'81*(1 ,67 (6 (17:('(5 1?7,* 2'(5 6,1192//N 6,&+ 1,&+7 $8) ',( c1$/<6( .2',(5(1'(5 fpc %=:P 921 &fpc =8 %(6&+5>1.(1P u2 71'(1 6,&+ 3+<6,2/2*,6&+( t(*8/$7,216(/(0(17( 2'(5 3$7+2*(1(7,6&+ 5(/(9$17( o87$7,21(1 +>8O 7* ,1 '(1 k175216 2'(5 ,1 '(1 WAO 81' UAO 9$1.,(5(1'(1N 1,&+7 75$16.5,%,(57(1 u(O 48(1=(1P c8M(5'(0 67$00(1 9,(/( '(5 *(*(1:>57,* )@5 ',( 326,7,21(//( m/21,(581* J6,(+( m$3P VPYK %(187=7(1 fpcOu21'(1 $86 ,17(5*(1(1 d(5(,&+(1 '(6 i(1206P h@5 ',( m/21,(581* 921 *(120,6&+(5 fpc %5$8&+7 0$1 '$+(5 $1'(5(6 c86*$1*60$O

c%%P VPUS

i()>//7( *(120,6&+( fpc ,1 }7+$12/P

VPX u75$7(*,(1 =85 fpcOm/21,(581*

TS[

7(5,$/ $/6 )@5 ',( &fpcOm/21,(581*P |,(/ ,67 (6 +,(5N '$6 *(6$07( 2'(5 (,1(1 '(71,(57(1 v(,/ '(6 i(1206N 81*($&+7(7 921 '(66(1 g;35(66,21 ,1 (,1(5 i(1%$1. $1=8/(*(1 81' ',( *(:@16&+7(1 u(48(1=(1 =8 ,'(17,7=,(5(1 81' =8 ,62/,(5(1P c/6 c86*$1*60$7(5,$/ ',(17 *(120,6&+( fpcN ',( 35,1=,3,(// $86 (,1(0 %(/,(%,*(1 i(:(%( ,1 0?*/,&+67 +2&+02/(.8/$5(5 h250 *(:211(1 :,5'P f$=8 :(5'(1 ',( |(/O /(1 =81>&+67 0,7 (,1(0 f(7(5*(1= /<6,(57N ',( r527(,1( '$11 0,7 (,1(5 r527(,1$6( 81' ',( tpc 0,7 (,1(5 tp$6( 9(5'$87 81' ',( $/,3+$7,6&+(1 d(67$1'7(,/( 0,7 25O *$1,6&+(1 n?681*60,77(/1 (;75$+,(57P f(5 fpc :,5' '85&+ u$/= 81' c/.2+2/ ,+5 n?681*6:$66(5 (17=2*(1 81' 62 *()>//7 Jc%%P VPUSKP x(.725(1 =85 fpcOm/21,(581* .?11(1 185 %(*5(1=7( o(1*(1 (;2*(1(5 fpc $8)1(+0(1 Jc%%P VPSKP f,( *(120,6&+( fpc 08M '$+(5 ,1 h5$*0(17( (,1(5 $8) '(1 x(.725 $1*(3$M7(1 n>1*( =(5/(*7 :(5'(1P f,(6 .$11 $0 %(67(1 '85&+ (,1(1 3$57,(//(1 x(5'$8 0,7 (,1(0 +>87* 6&+1(,'(1'(1 t(675,.7,216(1=<0 (55(,&+7 :(5'(1P f(5 x257(,/ ',(6(6 x25*(+(16 %(67(+7 *(*(1@%(5 (,1(5 92//67>1',*(1 u3$/781* 0,7 (,1(0 6(/7(1(5 6&+1(,'(1'(1 g1=<0 '$5,1N '$M (,1( r238/$7,21 921 6,&+ @%(56&+1(,O '(1'(1 fpcOh5$*0(17(1 (1767(+7P g,1 62/&+(5 3$57,(//(5 t(675,.7,216$16$7= 08M $//(5',1*6 62 .21752//,(57 :(5'(1N '$M +$8376>&+/,&+ fpc h5$*0(17( '(5 *(:@16&+O 7(1 i5?M( (1767(+(1N ',( 0,7 '(0 *(:>+/7(1 x(.725 /,*,(57 81' =85 v5$16)250$7,21 %(187=7 :(5'(1P g,1( i(1%$1.N 'P +P ',( i(6$07+(,7 $//(5 5(.20%,1$17(1 m/21(N ',( '$6 *(6$07( ',3/2,'( i(120 921 (7:$ X4SR[ %3 %(,63,(/6:(,6( ,1 (,1(0 e26O 0,'9(.725 5(35>6(17,(5(1 62//N 08M $/62 5(&+1(5,6&+ SNW4SRW t(.20%,1$17(1 0,7 VR .% (;2*(1(5 fpc (17+$/7(1P g5)$+581*6*(0>M %(1?7,*7 0$1 )@5 (,1( 6,&+(5 5(35>6(17$7,9( i(1%$1. $//(5',1*6 (7:$ =:(,O %,6 '5(,0$/ 629,(/( t(.20%,1$17(1 %=:P 75$16)250,(57( gP &2/, m/21(P |85 k'(17,7.$7,21 '(6 *(:@16&+7(1 h5$*0(17(6 .$11 0(,67 ',( =8*(+?5,*( &fpc 2'(5 0$1&+0$/ (,1( %(.$117( u(48(1= ,1 '(5 810,77(/%$5(1 p$&+%$56&+$)7 %(187=7 :(5'(1 Jc%%P VPUTN c%%P VPUUKP

c%%P VPUT h272 (,1(5 c*$53/$77( 0,7 d$.7(5,(1.2/21,(1 $/6 v(,/ (,1(5 i(1%$1. J$KP c872O 5$',2*5$3+,( 1$&+ u&5((1,1* '(5 i(1%$1. 0,7 (,1(5 i(1621'(P f,( *(68&+7(1 m/21( :(5'(1 1$&+ 63(=,76&+(5 j<%5,',6,(581* 81' 675,1*(17(0 y$6&+(1 '85&+ u&+:>5=81* '(6 t?17*(1O 7/06 /2.$/,6,(57 J%KP f,( r)(,/63,7=(1 =(,*(1 ',( r26,7,21 '(5 *(68&+7(1 m/21( $8) '(5 c*$53/$77( $1P

TTR

V o2/(.8/$50(',=,1,6&+( o(7+2'(1 Restriktionsverdau

genomische DNA

Restriktionsverdau

Restriktionsfragmente genomischer DNA

geöffneter Vektor

Antibiotika Resistenzgen Vektor

DNA-Ligierung

rekombinante genomische DNA Transformation Antibiotika-Selektion genomische Genbank „Screening“ isolierte genomische DNA

c%%P VPUU

u&+(0$7,6&+( f$567(//81* '(5 m/21,(581* *(120,6&+(5 fpcP

|85 r52'8.7,21 921 i(1621'(1 $/6 *(1(7,6&+( o$5.(5 ,67 (6 2)7 :@16&+(16:(57N fpc %(67,007(5 e+5202620(1 =8 ./21,(5(1P f$=8 .$11 0$1 i(1%$1.(1 $86 o(16&+Bo$86 j<%5,'=(//,1,(1 0,7 (,1=(/1(1 (5+$/7(1(1 0(16&+/,&+(1 e+520262O 0(1 +(567(//(1P d(, x(5:(1'81* 921 +80$1O63(=,76&+(1 5(3(7,7,9(1 fpcOg/(0(1O 7(1 2'(5 $8&+ 727$/(5 0(16&+/,&+(5 fpc $/6 i(1621'( /$66(1 6,&+ ',( t(.20%,O 1$17(1 0,7 0(16&+/,&+(5 (;2*(1(5 fpc 921 '(1(1 0,7 o$86Ofpc ',5(5(1=,(5(1P c1'(5( u75$7(*,(1 =85 m/21,(581* *(120,6&+(5 fpcOh5$*0(17( %(67,007(5 e+52O 02620(1 2'(5 $8&+ 63(=,76&+(5 c%6&+1,77( 921 e+5202620(1 9(5:(1'(1 $/6 c86O *$1*60$7(5,$/ h/825(6=(1=O6257,(57( e+5202620(135>3$5$7,21(1N ',( )@5 (,1 '(7O 1,(57(6 e+5202620 $1*(5(,&+(57 6,1' 2'(5 $8&+ 0,.52',66(.7,(57(N (,1=(/1( e+52O 02620(1$%6&+1,77( $/6 c86*$1*6OfpcP

SMUMQMP b(2/-/3/-% 7!,+).' 5.$ *5-0).' d(, '(5 c1$/<6( .203(;(5 i(1/2&, ,67 (6 2)7 1?7,*N *5?M(5( fpcOc%6&+1,77( =8 &+$5$.7(5,6,(5(1N $/6 (,1 (,1=(/1(6 5(.20%,1$17(6 e260,' $8)1(+0(1 .$11P u2 6,1' *52M( i(1(N :,( (7:$ '$6 i(1 )@5 '(1 i(5,1181*6)$.725 xkkkN )@5 '$6 f<67523+,1 2'(5 )@5 '$6 c32/,323527(,1 d (,1,*( +81'(57 2'(5 0(+5 $/6 7$86(1' .% /$1*P k1

VPX u75$7(*,(1 =85 fpcOm/21,(581* Ausschnitt genomischer DNA tertiär isolierter Klon DNA-Klone einer Genbank

zunächst isolierter DNA Klon

TTS

10kb tertiär isolierter Klon

Gensonden sekundär isolierte DNA Klone

c%%P VPUV u&+(0$7,6&+( f$567(//81* '(6 &+5202620( :$/.,1*P c86*(+(1' 921 (,1(0 =8O 1>&+67 ,62/,(57(1 fpcOm/21 :,5' $86 (,1(5 *(120,6&+(1 i(1%$1. (,1 *5?M(5(5N =86$00(1O +>1*(1'(5 c866&+1,77 '(5 *(120,6&+(1 fpc J&217,*K ,1 h250 921 @%(5/$33(1'(1 5(.20O %,1$17(1 h5$*0(17(1 ,62/,(57 81' &+$5$.7(5,6,(57P

',(6(1 h>//(1 (50?*/,&+7 ',( u75$7(*,( '(6 62*(1$117(1 NN&+5202620( :$/.,1*DD (,1( m/21,(581* =86$00(1+>1*(1'(5 *(120,6&+(5 fpc Jc%%P VPUVKP c/6 c86*$1*6381.7 %(1?7,*7 0$1 (,1 5(.20%,1$17(6 e260,' 2'(5 d$.7(5,23+$O *(1N '(5 %(,63,(/6:(,6( 0,7 (,1(5 &fpc '(6 817(568&+7(1 i(16 $/6 u21'( $86 (,1(5 *(120,6&+(1 i(1%$1. ,62/,(57 :85'(P f$6 &+5202620( :$/.,1* (5/$8%7 181N @%(5O /$33(1'( m/21( $8) %(,'(1 u(,7(1 '(6 c86*$1*6./216 =8 ,62/,(5(1P f$=8 68&+7 0$1 ,1 '(0 925/,(*(1'(1 m/21 1$&+ 6,1*/( &23< u(48(1=(1N ',( '$11 $/6 u21'( )@5 (,1(1 (51(87(1 |8*$1* ,1 ',( i(1%$1. ',(1(1P f,( d(6&+5>1.81* $8) 6,1*/( &23< u(48(1O =(1 $/6 u21'( ,67 :,&+7,*N :(,/ h5$*0(17( 0,7 5(3(7,7,9(1 u(48(1=(1 m/21( 0,7 6(+5 817(56&+,('/,&+(5 *(120,6&+(5 n2.$/,6$7,21 (5.(11(1 :@5'(1P f,( k'(17,7=,(581* 5(3(7,7,9(5 u(48(1=(1 ,1 (,1(5 t(.20%,1$17( .$11 '85&+ (,1( u287+(51 d/27Oc1$O /<6( (5)2/*(1N %(, '(5 (,1 ./21,(57(6 5(3(7,7,9(6 g/(0(17 $/6 u21'( ',(17P h5$*0(17( 0,7 $866&+/,(M/,&+ 6,1*/( &23< u(48(1=(1 +<%5,',6,(5(1 0,7 ',(6(5 u21'( 1,&+7 81' *(%(1 620,7 .(,1 u,*1$/P f,(6( 1,&+7 u,*1$/O*(%(1'(1 h5$*0(17( :(5'(1 '$11 ,62O /,(57 81' $/6 u21'( %(187=7P f$6 c860$M '(5 %(5/$3381* =:,6&+(1 '(0 $/7(1 81' '(1 1(8 ,62/,(57(1 m/21(1 />M7 6,&+ '85&+ t(675,.7,2169(5'$8 '(5 9(56&+,('(1(1 t(O .20%,1$17(1 $%6&+>7=(1P y,('(5+2/81*(1 ',(6(6 u&+5,77(6 '(6 &+5202620( :$/.,1* )@+5(1 =85 m/21,(581* (,1(5 6,&+ 1$&+ %(,'(1 u(,7(1 '(6 c86*$1*6./216 $86'(+1(1'(1 =86$00(1+>1*(1O '(1 t(*,21 *(120,6&+(5 fpcN (,1(6 62*P e217,*6P c8) ',(6( y(,6( .?11(1 620,7 $8&+ *5?M(5( i(1( 0,76$07 k175216 81' 1,&+7 75$16.5,%,(57(1 t(*8/$7,216(/(0(17(1 92//67>1',* ./21,(57 :(5'(1P o,7 -('(0 u&+5,77 '(6 &+5202620( :$/.,1*6N ',( -(:(,/6 ,17(16,9( n$%25$5%(,7 (5)25'(51N %(:(*7 0$1 6,&+ 0$;,0$/ VR .% $8) '(0 e+5202620 925:>576P d(, (,1,O *(1 c1:(1'81*(1N :,( (7:$ %(, '(5 r26,7,216./21,(581* J6,(+( m$3P VPYKN 0@66(1 817(5 w067>1'(1 (,1,*( +81'(57 .% @%(5:81'(1 :(5'(1N 80 921 (,1(0 i(10$5.(5 =80 i(1 6(/%67 =8 .200(1P k1 ',(6(1 h>//(1 ,67 '$6 &+5202620( :$/.,1* 6&+21 :(*(1 6(,1(5 *(5,1*(1 i(6&+:,1',*.(,7 (,1( 185 6&+:(5/,&+ 35$.7,.$%/( u75$7(*,(P c8M(5'(0 (17+>/7 '$6 0(16&+/,&+( i(120 u(48(1=(1N ',( $86 817(56&+,('/,&+(1 i5@1'(1 1,&+7 ./21,(5%$5 6,1'P u2/&+( u(48(1=(1 .?11(1 (,1(1 &+5202620( :$/. '85&+$86 67233(1 81' (,1( e+$5$.7(5,6,(581* '(5 fpc -(16(,76 (,1(5 62/&+(1 t(*,21 9(5+,1'(51P d(,'( r52%/(0( /?67 ',( 7(&+1,6&+ $//(5',1*6 6(+5 $16358&+692//( u75$O 7(*,( '(6 NN&+5202620( -803,1*6DD Jc%%P VPUWKP

TTT

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

partieller Verdau mit dem 1. Restriktionsenzym und Größenselektion

genomische DNA

mehrere hundert kb

Selektionsmarker

DNA-Ligierung

vollständige Spaltung mit dem 2. Restriktionsenzym

wenige kb Transformation „Jumping“ Genbank „Screening“ isolierte „Jumping“ Klone

c%%P VPUW u&+(0$7,6&+( f$567(//81* '(6 &+5202620( -803,1*P p$&+ 3$57,(//(0 t(675,.O 7,2169(5'$8 (1767(+(1 0(+5(5( +81'(57 .% *52M( fpcOh5$*0(17(N ',( 817(5 g,16&+/8M (,1(6 u(/(.7,2160$5.(56 =81>&+67 =,5.8/$5,6,(57 :(5'(1P k1 (,1(0 =:(,7(1 u&+5,77 :,5' (,1 :(1,*( .% *52M(6 fpcOh5$*0(17 ./21,(57N '$6 1(%(1 '(0 u(/(.7,2160$5.(5 u(48(1=(1 (17+>/7N ',( ,0 i(120 (,1,*( +81'(57 .% 921(,1$1'(5 (17)(517 $8) '(06(/%(1 e+5202620 /,(*(1P f,( =:,6&+(1 ,+1(1 /,(*(1'( fpc :,5' '$%(, NN@%(563581*(1DDP

f$%(, :(5'(1 /$1*( *(120,6&+( fpcOh5$*0(17( 921 %(,63,(/6:(,6( SWR .%N ',( (17:('(5 '85&+ (,1(1 3$57,(//(1 x(5'$8 0,7 (,1(0 +>87* 6&+1(,'(1'(1 2'(5 '85&+ 92//67>1',*( u3$/781* 0,7 (,1(0 6(/7(1 6&+1(,'(1'(1 t(675,.7,216(1=<0 (1767$1'(1 6,1' 0,7 (,1(0 %$.7(5,(//(1 u(/(.7,2160$5.(5 /,*,(57P f$11 :(5'(1 ',( g1'(1 '(6

VPY i(1.$57,(581* 81' i(1,'(17,7=,(581*

TTU

5(.20%,1$17(1 o2/(.@/6 0,7(,1$1'(5 9(5%81'(1P f$'85&+ (1767(+7 (,1 5,1*)?50,O *(6 fpcOo2/(.@/N ,1 '(0 ,1 '(5 *(120,6&+(1 fpc :(,7 921(,1$1'(5 (17)(517 /,(*(1'( u(48(1=(1 (1* %(1$&+%$57 81' 185 '85&+ '(1 u(/(.7,2160$5.(5 921(,1O $1'(5 *(75(117 6,1'P k0 1>&+67(1 u&+5,77 :,5' '(5 fpcOt,1* 0,7 (,1(0 =:(,7(1 t(675,.7,216(1=<0 *(6&+1,77(1 81' ',( (1767(+(1'(1 h5$*0(17( ,1 (,1(1 x(.725 /,O *,(57P |85 v5$16)250$7,21 .2007 (6 185 '85&+ ',( c8)1$+0( '(5 o2/(.@/( 0,7 '(0 u(/(.7,2160$5.(5P f,( (1767(+(1'( i(1%$1. (17+>/7 $/62 t(.20%,1$17(1N '(O 5(1 (;2*(1( u(48(1=(1 ,1 '(5 *(120,6&+(1 fpc :(,7 921(,1$1'(5 (17)(517 $%(5 $8) '(0 6(/%(1 e+5202620 /,(*(1'( fpc (17+$/7(1P c86*(+(1' 921 (,1(5 %(.$11O 7(1 u(48(1= .$11 0$1 62 ,1 '(5 :(,7(5(1 p$&+%$56&+$)7 /,(*(1'( h5$*0(17( ,62O /,(5(1N .$57,(5(1 81' &+$5$.7(5,6,(5(1P o,7 '(0 &+5202620( -803,1* (55(,&+7 0$1 620,7 (,1( +?+(5( i(6&+:,1',*.(,7 '(5 e+$5$.7(5,6,(581* *5?M(5(5 c%6&+1,77( (,1(6 e+52026206 81' .$11 '$5@%(5 +,1$86 1,&+7 ./21,(5%$5( u(48(1=(1 @%(5635,1*(1P f85&+ &+5202620( -803,1* ,62O /,(57( m/21( .?11(1 :(,7(5+,1 $/6 u7$57381.7( )@5 (,1 &+5202620( :$/.,1* $8) '(5 %(1$&+%$57(1 fpc ',(1(1P c/6 :2+/ %,6+(5 :,&+7,*67( 0(',=,1,6&+( c1:(1'81* *(/$1* '85&+ (,1( m20%,1$7,21 921 &+5202620( :$/.,1* 81' -803,1* ',( k'(1O 7,7.$7,21 '(6 i(1'()(.7(6 %(, '(5 o8.29,6=,'26(P

SMV f%.+!24)%25.' 5.$ f%.)$%.4)&):)%25.' f,( 02/(.8/$5( c1$/<6( '(6 0(16&+/,&+(1 i(1206 ,67 ,0 /(7=7(1 l$+5=(+17 =8 (,1(0 (66(17,(//(1 d(67$1'7(,/ '(5 0(',=,1,6&+(1 h256&+81* 81' f,$*1267,. *(:25'(1P g567 '85&+ ',( c8)./>581* '(5 02/(.8/$5(1 r$7+2/2*,( +(5(',7>5(5 81' (5:25%(1(5 g5O .5$1.81*(1 .2117( ,1 9,(/(1 h>//(1 (,1 x(567>1'1,6 '(5 *581'/(*(1'(1 r$7+2*(1(6( (55(,&+7 :(5'(1P k1 (,1,*(1 h>//(1 :$5 ',(6 $8&+ (,1 (567(5 c16$7=381.7 )@5 ',( g17:,&./81* 1(8(5 2'(5 9(5%(66(57(5 .219(17,21(//(5 v+(5$3,()250(1P j,(5 62//(1 9(56&+,('(1( u75$7(*,(1 =85 m$57,(581*N k'(17,7=,(581* 81' e+$5$.7(5,6,(581* 921 0(16&+/,&+(1 i(1(1 (5/>87(57 :(5'(1 Jc%%P VPUXKP f$6 0(16&+/,&+( i(120 (17+>/7 (7:$ SVRPRRR i(1(P f(0*(*(1@%(5 6,1' 185 (7:$ YPRRR +(5(',7>5( m5$1.+(,7(1 '(6 o(16&+(1 .$7$/2*,6,(57 Jo&m86,&.I6 o(1O '(/,$1 k1+(5,7$1&( ,1 o$1KP f,(6( f,6.5(3$1= ,67 =80 (,1(1 '$'85&+ (5./>5%$5N '$M %(, 9,(/(1 g5.5$1.81*(1 (,1( *(1(7,6&+( m20321(17( +(87( 12&+ 1,&+7 (7$%/,(57 ,67P |80 $1'(5(1 ,67 =8 (5:$57(1N '$M 9,(/( i(1( ,0 i(120 +,16,&+7/,&+ ,+5(5 h81.7,21 5('81'$17 6,1' 81' $1'(5( i(1352'8.7( (,1(1 0?*/,&+(1 f()(.7 .203(16,(5(1 .?11(1P c8&+ *,%7 (6 i(1'()(.7(N ',( 6,&+ %(5(,76 ,1 '(5 g0%5<21$/O 2'(5 h(7$/=(,7 8163(=,76&+ $/6 n(7$/)$.725(1 0$1,)(67,(5(1P c8M(5'(0 :,5' ',( |825'181* 921 i(127<3 81' ./,1,6&+(0 m5$1.+(,76%,/' '$'85&+ .203/,=,(57N '$M (,1( t(,+( 921 g5.5$1.81*(1 '85&+ o87$7,21(1 ,1 817(56&+,('/,&+(1 i(1(1 9(5856$&+7 :,5'P f(0O *(*(1@%(5 .?11(1 9(56&+,('(1( o87$7,21(1 ,1 (,1(0 i(1 *$1= 817(56&+,('/,&+( m5$1.+(,7(1 +(592558)(1P f,(6( m203/(;,7>7 :,5' 12&+ '$'85&+ *(67(,*(57N '$M ',( 08/7,)$.725,(//(1 m5$1.+(,7(1 (567 %(, 0(+5(5(1 i(1'()(.7(1 (1767(+(1 2'(5 921 w0:(/7)$.725(1 %((,198M7 :(5'(1P v527= ',(6(5 u&+:,(5,*.(,7(1 .2117(1 %,6+(5 (7O :$ SR@ '(5 ,1 o&m86,&.I6 o(1'(/,$1 k1+(5,7$1&( ,1 o$1 .$7$/2*,6,(57(1 m5$1.O +(,7(1 (,1(0 i(1'()(.7 =8*(25'1(7 :(5'(1P c86 ',(6(0 |$+/(19(5+>/71,6 :,5' $8&+

TTV

V o2/(.8/$50(',=,1,6&+( o(7+2'(1 Positionsklonierung

funktionelle Klonierung

reverse Genetik

Phänotyp

bekannter biochemischer Defekt (Enzym)

Gen mit unbekannter Funktion

genetische Kartierung

Isolation des Gens

in vitro Mutagenese

Isolation des Gens

Identifizierung von Mutationen

Phänotyp

Identifizierung von Mutationen

Funktionsanalyse

c%%P VPUX u75$7(*,(1 =85 c1$/<6( 921 i(127<3Or+>127<3 y(&+6(/:,5.81*(1N ',( ,1 '(5 02O /(.8/$5(1 o(',=,1 c1:(1'81* 71'(1P f,( r26,7,216./21,(581* (50?*/,&+7N ,0 i(*(16$7= =85 )81.7,21(//(1 m/21,(581*N ',( k'(17,7=,(581* 921 o87$7,21(1 2+1( 925+(5,*( m(1171,6 '(6 %,2&+(0,6&+(1 f()(.76 J6,(+( v(;7KP g,1 d(,63,(/ )@5 ',( 5(9(56( i(1(7,. ,67 ',( N.12&.O287 o87$*(1(6(D ,1 (0%5<21$/(1 u7$00=(//(1 '(5 o$86N :2%(, (,1 i(1 0$1,38/,(57 :,5' 81' ,0 c16&+/866 '$5$1 ',( 3+>127<3,6&+(1 c86:,5.81*(1 $1$/<6,(57 :(5'(1 .?11(1P

'(87/,&+N '$M 0$1 6,&+ =81>&+67 $8) ',( c1$/<6( 0212*(1(5 m5$1.+(,7(1 .21=(1O 75,(5(1 :,5'N 80 63>7(5 $8&+ ',( .203/(;(5(1 08/7,)$.725,(//(1 m5$1.+(,7(1 9(5O 67(+(1 =8 .?11(1P

SMVMP j!24)%25.' -/./'%.%2 d2+2!.+5.'%. c/6 (567(5 u&+5,77 =85 k'(17,7=,(581* 921 i(1(1 08M 0(,67 '(5 i(1257 ,0 i(120 .$57,(57 :(5'(1P x(5*/(,&+6:(,6( (,1)$&+ ,67 ',( m$57,(581* ,1 h>//(1 0,7 :(*:(,O 6(1'(1 &<72*(1(7,6&+ $85>//,*(1 d()81'(1N :,( (7:$ v5$16/2.$7,21(1N ',( (,1(1 ',O 5(.7(1 g,167,(* ,1 ',( r26,7,216./21,(581* '(6 5(/(9$17(1 i(16 (5/$8%(1 J6,(+( m$3P VPYPWKP k1 $1'(5(1 h>//(1 08M ',( &+5202620$/( u8%/2.$/,6$7,21 '(6 *(68&+7(1 i(16 =81>&+67 '85&+ (,1( m233/81*6817(568&+81* 0,7 32/<0253+(1 o$5.(51 (5O )2/*(1P k0 r5,1=,3 %(58+7 (,1( 62/&+( m233/81*6$1$/<6( '$5$8)N ',( y(,7(5*$%( '(5 c//(/( (,1(6 32/<0253+(1 n2&86 0,7 %(.$117(5 &+5202620$/(5 n2.$/,6$7,21 ,1 (,O 1(0 u7$00%$80 921 (,1(5 =85 1>&+67(1 i(1(5$7,21 =8 9(5)2/*(1 81' 0,7 '(5 c86O 35>*81* '(6 i(1'()(.7(6 =8 .255(/,(5(1 Jc%%P VPUYN c%%P VPUZKP x25 d(*,11 '(5 6<67(0$7,6&+(1 m$57,(581* '(6 i(1206 0,7 62/&+(1 o$5.(51 J6,(O +( m$3P VPZK :$5 ',( i(6&+:,1',*.(,7 ',(6(5 u75$7(*,( /$1*6$0 81' '(5 g5)2/* :(,7O *(+(1' '(0 |8)$// @%(5/$66(1P f,( (567( .203/(77( *(1(7,6&+( m$57( '(6 0(16&+/,O &+(1 i(1206 :85'( S[ZY 38%/,=,(57P f,( '$)@5 9(5:(1'(7(1 *(1(7,6&+(1 o$5.(5

VPY i(1.$57,(581* 81' i(1,'(17,7=,(581* RFLP-Marker:

TTW

VNTR-Marker:

Restriktions-Schnittstellen Allel 1 (A1)

Allel 1

Allel 2 (A2)

Allel 2 Allel 3

heterozygot (A1/A2) homozygot (A2/A2) homozygot (A1/A1)

DNA-Sonde

Allel 4 Allel 5

Southern-Blot-Analyse

A1/A5

A2/A3

A1/A4

A2/A5

Allel 5

Allel 4

Allel 3

Allel 1 Allel 2

PCR-Primer

Polyacrylamid-Gelelektrophorese

c%%P VPUY w17(56&+,('/,&+( *(1(7,6&+( o$5.(5N ',( =85 m233/81*6$1$/<6( (,1*(6(7=7 :(5'(1 .?11(1P t(675,.7,216Oh5$*0(17On>1*(1Or2/<0253+,60(1 Jthnr6K (5/$8%(1 (,1( w17(56&+(,O '81* '(5 c//(/( $8) '(5 d$6,6 32/<0253+(5 t(675,.7,2166&+1,7767(//(1P f(5 p$&+:(,6 '(5 (,1O =(/1(1 c//(/( (5)2/*7 0,77(/6 u287+(51 d/27Oj<%5,',6,(581* 0,7 (,1(5 fpcOu21'(P k0 i(*(1O 6$7= =80 thnrN '(5 ',( w17(56&+(,'81* 921 185 =:(, c//(/(1 (50?*/,&+7N .?11(1 0,7 j,/)( '(5 unuO 81' uvtOu<67(0( 0(+5(5( c//(/Ox$5,$17(1 '(7(.7,(57 :(5'(1P f,( c1=$+/ '(5 t(3($7O g,1+(,7(1 9$5,,(57 ,1 '(5 r238/$7,21 5(/$7,9 67$5.N 62 '$M (,1( +2+( k1)250$7,9,7>7 0,7 ',(6(1 o$5.(51 *(*(%(1 ,67P f(5 p$&+:(,6 '(5 c//(/( (5)2/*7 @%(5 ',( c8)75(1181* '(5 0,77(/6 r2O /<0(5$6( m(77(15($.7,21 JretK $03/,7=,(57(1 fpcOh5$*0(17( ,1 '(5 i(/(/(.7523+25(6(P

%$6,(57(1 :(,7*(+(1' $8) t(675,.7,216Oh5$*0(17On>1*(1Or2/<0253+,60(1 Jthnr6] 6,(+( m$3P VPTPSKP h@5 (,1( 80)$66(1'( m$57,(581* '(6 0(16&+/,&+(1 i(1206 0,7 32/<0253+(1 o$5.(51 6,1' thnr6 1,&+7 *((,*1(7P |80 (,1(1 6,1' 6,( ,1 185 6(+5 :(,7(1 c%67>1'(1 921(,1$1'(5 1$&+:(,6%$5P f(5 '85&+6&+1,77/,&+( c%67$1' $8) '(5 m$57( 921 S[ZY %(758* SRASW &(17,Oo25*$1 J&oKP f,(6 %('(87(7N '$M (6 %(, SRASW@ $//(5 o(,26(1 =8 (,1(5 t(.20%,1$7,21 =:,6&+(1 ',(6(1 o$5.(51 .2007N :$6 ',( k17(535(7$7,21 (,1(5 m233/81*6$1$/<6( (5+(%/,&+ (56&+:(57P g,1 :(,7(5(5 p$&+7(,/ ',(6(5 thnrOo$5.(5 ,67 ,+5( *(5,1*( k1)250$7,9,7>7P f,(6 /,(*7 '$5$1N '$M (,1( m233O /81*6$1$/<6( 1$7@5/,&+ .5,7,6&+ '$921 $%+>1*7N 2% '(5 32/<0253+( o$5.(5 '$6 0@7O 7(5/,&+( 920 9>7(5/,&+(1 e+5202620 817(56&+(,'(1 .$11P thnr6 +$%(1 185 =:(, c//(/(N ',( '$5@%(5 +,1$86 6(+5 81*/(,&+0>M,* 9(57(,/7 6(,1 .?11(1P f$+(5 6,1' 9,(/( o,7*/,('(5 (,1(6 u7$00%$806 )@5 ',( 0(,67(1 thnr6 +202=<*27N 62 '$M ',( n2O .$/,6$7,21 '(6 *(68&+7(1 i(16 1,&+7 '85&+ ',( y(,7(5*$%( '(5 c//(/( '(6 o$5.(5/2&86 =8*(25'1(7 :(5'(1 .$11P m233/81*6817(568&+81*(1 :(5'(1 '$+(5 1,&+7 0(+5 0,7 thnr6 '85&+*()@+57N 621'(51 0(,67 0,7 +2&+32/<0253+(1 o$5.(51 :,( '(1 ,1 m$3,7(/ VPTPW %(6&+5,(%(1(1 u,1*/(/2&86Ou<67(0(1 JunuK 81' 6+257 7$1'(0 5(3($7

TTX

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

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2

Anlageträger nicht betroffen 3

4

5

6

7

betroffen 8

9

10 11

12

13 14

Genetische Marker-Analyse: 1

2

3

4

5

6

7

8

9

10 11

12 13 14

15

16

17

18

15

16

17

18 Allel 1 Allel 2

Marker 1: keine Kopplung mit der Erkrankung 1

2

3

4

5

6

7

8

9

10 11

12 13 14

15

16

17

18 Allel 1 Allel 2

Marker 2: Kopplung mit der Erkrankung, alle Betroffenen sind homozygot für Allel 1

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TUR

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7,21(//(6 m$1','$7(1*(1P f$5@%(5 +,1$86 ,67 (6 $8&+ 12&+ ,1 '(5 (5:$57(7(1 e+52O 02620(15(*,21 /2.$/,6,(57 81' 67(//7( '$+(5 $8&+ (,1 326,7,21(//(6 m$1','$7(1*(1 '$5P f,( k'(17,7.$7,21 921 o87$7,21(1 '(6 t+2'236,1*(16 %(, r$7,(17(1 0,7 tr %(67>7,*7( '$6 m$1','$7(1*(1P

SMVMT o/3)4)/.3+,/.)%25.' c86*$1*6381.7 ',(6(5 )5@+(5 $/6 NNt(9(56( i(1(7,.DD %(=(,&+1(7(1 u75$7(*,( ,67 ',( m(1171,6 @%(5 ',( n2.$/,6$7,21 '(6 *(1(7,6&+(1 f()(.7(6P f,( h81.7,21 '(6 i(16 63,(/7 +,(5 =81>&+67 .(,1( t2//(P f,( r26,7,216./21,(581* :85'( (5670$/6 (5)2/*5(,&+ S[ZX %(, '(5 e+521,6&+(1 i5$18/20$726( $1*(:$1'7N ',( (567 62 $/6 i(1'()(.7 '(6 e<72&+520 dOm203/(;(6 ,'(17,7=,(57 :(5'(1 .2117(P u(,7+(5 ,67 ',(6( u75$7(*,( %(, (7:$ SRR m5$1.+(,7(1 (5)2/*5(,&+ (,1*(6(7=7 :25'(1P k1 9,(/(1 h>//(1 .2117(1 '$O '85&+ (176&+(,'(1'( m(1171,66( @%(5 ',( d,2&+(0,( 81' ',( r$7+2*(1(6( *(:211(1 :(5'(1P

22.3

Kopplungsintervall

22.2 22.1

Suche nach strukturellen Chromosomenveränderungen (z.B. Deletionen)

Identifizierung von Genen

Mutationsanalyse

21.1 11.4 11.3 11.23 11.22 cen

Kontrolle

21.3

Kontrolle

Xp

Assemblierung überlappender genomischer DNA-Fragmente in contigs

Patienten

Patienten 1 2 3 4 5 6

12

Mutationen

13 21.1

SSCP-Analyse

21.3

Xq

22.1 22.3 23

Southern-Blot-Analyse

24 25 26 27

-2.000 kbp

50 – 500 kbp

1– 200 kbp

einzelne Basenpaare

28

genetische Karte

physikalische Karte

Gen (Transkriptions)-Karte

DNA-Sequenzanalyse

c%%P VPU[ u&+(0$7,6&+( f$567(//81* '(5 9(56&+,('(1(1 v(,/6&+5,77( '(5 r26,7,216./21,(581* $0 d(,63,(/ (,1(6 zO&+5202620$/(1 i(16P c86*$1*6381.7 ,67 ',( f(71,7,21 '(6 m233/81*6O ,17(59$/6 0,7 j,/)( *(1(7,6&+(5 o$5.(5P c16&+/,(66(1' (5)2/*7 ',( c66(0%/,(581* (,1=(/1(5 fpcOh5$*0(17( ,1 (,1(0 e217,*P g,1(6 ',(6(5 h5$*0(17( '(7(.7,(57 f(/(7,21(1 Jx(5/867 921 *(1(7,6&+(0 o$7(5,$/K %(, (,1(0 v(,/ '(5 r$7,(17(1P f,( $16&+/,(66(1'( o87$7,216$1$/<6( =80 d(,63,(/ 0,77(/6 uuerOv(&+1,. J6,1*/( 675$1' &21)250$7,21 32/<0253+,60N 6P m$3P VPTPUPSK (50?*/,&+7 ',( k'(17,7=,(581* :(,7(5(5 o87$7,21(1N ',( 6,&+ ,1 (,1(0 9(5>1'(57(1 n$8)9(5O +$/7(1 >866(51P

VPY i(1.$57,(581* 81' i(1,'(17,7=,(581*

TUS

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TUT

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

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VPY i(1.$57,(581* 81' i(1,'(17,7=,(581* Oligonukleotid-Chip:

GATCCTAGCCTATATCCAG

TUU

normales Allel (N)

CTAGGATCGGATATAGGTC GATCCTAGCATATATCCAG

mutiertes Allel (M)

CTAGGATCGTATATAGGTC Hybridisierung der Patienten-DNA

NN

NM

MM

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Hybridisierung

mRNA aus Normalgewebe a d

b

mRNA aus Tumorgewebe

c

a

b

c

d

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TUV

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

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SMXMQ s2!.3'%.% l;53% i(1(7,6&+( x(5>1'(581*(1 %(, o>86(1 .?11(1 '85&+ (,1( 81*(5,&+7(7( k17(*5$7,21 (;2*(1(5 fpcN (,1(6 62*(1$117(1 v5$16*(16N 925*(1200(1 :(5'(1P f,(6( o>86( :(5'(1 (17635(&+(1' $/6 75$16*(1( o>86( %(=(,&+1(7P c8M(5'(0 .?11(1 $8&+ =,(/O *(5,&+7(7( o87$7,21(1 63(=,76&+(5 i(1( *(1(5,(57 :(5'(1N ',( -( 1$&+ o87$7,2167<3 $/6 NN.12&.O287DD Jh81.7,2169(5/867 '(6 i(16N /266 2) )81&7,21K 2'(5 $/6 NN.12&.O,1DD J1(8( h81.7,21 '(6 i(16N *$,1 2) )81&7,21K o>86( %(=(,&+1(7 :(5'(1P c8) ',(6( 9(56&+,('(1(1 o87$17(1 :,5' ,0 h2/*(1'(1 *(1$8(5 (,1*(*$1*(1P c/6 u$00(/%(O *5,5 9(5:(1'(1 :,5 ,0 h2/*(1'(1 *(1(7,6&+ 9(5>1'(57( o>86(P v5$16*(1( o>86( ,0 (1*(5(1 u,11( :(5'(1 '85&+ x25.(51,1-(.7,21 921 /,1($5(1 fpcOm216758.7(1 ,1 %()58&+7(7( g,=(//(1 (5=(8*7N ',( $86 '(0 g,/(,7(5 921 :(1,*( u781'(1 6&+:$1*(5(1 u3(1'(57,(5(1 35>3$5,(57 :(5'(1P f$6 fpcOm216758.7 (17O +>/7 ,0 $//*(0(,1(1 '$6 v5$16*(1N %(67(+(1' $86 (,1(5 .2',(5(1'(1 u(48(1= )@5 (,1 r527(,1 81' ',( =8 6(,1(5 g;35(66,21 1?7,*(1 5(*8/$725,6&+(1 g/(0(17( Jc%%P VPVT $KP n(7=7(5( .?11(1 (1'2*(1( u(48(1=(1 2'(5 g/(0(17( $1'(5(5 i(1( 6(,1P f$6 v5$16*(1 ,16(5,(57 ,1 $//(5 t(*(/ 67$%,/ $1 0,1'(67(16 (,1(0 q57 ,0 i(120 Ji(1/2&86KN +>87* 0,7 0(+5(5(1 m23,(1 JSASRRKP o,7 ',(6(0 c16$7= .$11 ',( g;O 35(66,21 (1'2*(1(5 i(1( ,1 c%+>1*,*.(,7 '(5 9(5:(1'(7(1 r5202725(1 48$17,7$7,9N 2172*(1(7,6&+ 2'(5 *(:(%(63(=,76&+ 5(*8/,(57 :(5'(1P g%(162 .?11(1 x$5,$17(1 (1'2*(1(5 i(1( 2'(5 i(1( $1'(5(5 u3(=,(6 (;35,0,(57 :(5'(1P h@5 NN*(1( 5(3$,5DD

TVR

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

w17(568&+81*(1 Jm203/(0(17$7,216$16$7=K .?11(1 ,17$.7( i(1( ,1 (,1(0 087$1O 7(1 o$8667$00 (;35,0,(57 :(5'(1P g,1 x257(,/ ',(6(5 o(7+2'( *(*(1@%(5 '(5 817(5 .12&.O,1 o87$17(1 J6,(+( 817(1K %(6&+5,(%(1(1 o(7+2'( ,67N '$M .(,1( |(//.8/785 %(1?7,*7 :,5' 81' '$+(5 $8) (,1 u(/(.7,2160$5.(5*(1 9(5=,&+7(7 :(5'(1 .$11P f$6 fpcOh5$*0(17N :(/&+(6 '$6 v5$16*(1 75>*7N :,5' 817(5 x(5:(1'81* (,1(6 +2&+$89?6(1'(1 o,.526.236 ',5(.7 0,7 j,/)( )(,1 $86*(=2*(1(5 i/$6.$3,//$5(1 ,1 '(1 x25.(51 %()58&+7(7(5 g,=(//(1 ,1-,=,(57 Jc%%P VPVT %KP YW@ '(5 g0%5<21(1 @%(5O /(%(1 ',( k1-(.7,21 81' :(5'(1 1$&+ (,1(5 .85=(1 k1.8%$7,21 ,1 6&+(,16&+:$1*(5( g03)>1*(57,(5( 75$16)(5,(57P u&+(,16&+:$1*(5( c00(17,(5( (5=(8*7 0$1 '85&+ *(O =,(/7( x(53$$581* :(,%/,&+(5 v,(5( 0,7 67(5,/,6,(57(1 0>11/,&+(1 v,(5(1P p$&+ (,1(5 v5$*=(,7 921 (7:$ TR v$*(1 :(5'(1 ',( p$&+.200(1 *(%25(1P g7:$ TRAUR@ '(5 p$&+.200(1 75$*(1 '$6 v5$16*(1 ,1 ,+5(0 i(120P l('(6 v5$16*(1O326,7,9( v,(5 ',(6(5 i(1(5$7,21 5(35>6(17,(57 0,1'(67(16 (,1 81O $%+>1*,*(6 k17(*5$7,216(5(,*1,6N 'P +P '$6 v5$16*(1 ,17(*5,(57 =8)>//,* 81' 81*(5,&+O 7(7 $8) (,1(0 e+5202620P f$+(5 6,1' ',( v,(5( *(1(7,6&+ 1,&+7 ,'(17,6&+P l('(6 ,67 9,(/0(+5 '(5 d(*5@1'(5 J)281'(5K (,1(6 1(8(1 o$8667$00(6P o$1&+0$/ .2007 (6 925N '$M (,1 v(,/ '(5 v5$16*(1.23,(1 ,1 (,1(1 =:(,7(1 i(1/2&86 ,16(5,(57 81' '$+(5 %(,0 1>&+67(1 m5(8=81*66&+5,77 81$%+>1*,* 9(5(5%7 :,5' Ju(*5(*$7,21KP u2 (1767(+(1 '$11 $86*(+(1' 921 (,1(0 75$16*(1(1 h281'(5 =:(, 75$16*(1( u8%/,1,(1P

Transgenkonstrukt

Promotor

pA

mRNA

A (n)

(a) Herstellung transgener Mäuse Injektion von DNA in den Vorkern befruchteter Oozyten Zygote

Übertragung injizierter Oozyten in scheinschwangere Empfängertiere

^ ]

Züchtung transgener „founder”

^ transgener „founder”

Injektionskapillare mit DNA Zona pellucida

Pronuklei

50 % der Nachkommen tragen das Transgen

(b)

c%%P VPVT v5$16*(1( o>86(P J$K u&+(0$7,6&+( f$567(//81* (,1(6 7<3,6&+(1 v5$16*(1)5$*0(1O 7(6 $86 (,1(0 g;35(66,2169(.725 )@5 ',( j(567(//81* 75$16*(1(5 o>86(P 3c\ r2/< cOu,*1$/] cJ1K\ r2/86( 0,77(/6 x25.(51,1-(.7,21 %()58&+7(7(5 g,=(//(1P f,( fpc :,5' ,1 (,1(1 '(5 %(,'(1 r5218./(, ,1-,=,(57P f,( ,1-,=,(57(1 |<*27(1 :(5'(1 $16&+/,(M(1' ,1 '(1 g,/(,7(5 6&+(,16&+:$1*(5(5 g03)>1*(57,(5( @%(575$*(1P

VP[ v,(502'(//(

TVS

SMXMQMP a%)30)%,% f,( d(6&+5(,%81* (,1(5 )@5 '$6 y$&+67806+25021 75$16*(1(1 o$86 625*7( $1)>1*O /,&+ )@5 c8)6(+(1 81' (%1(7( '(1 y(* )@5 ',( 5$6$17( g17:,&./81* ,0 d(5(,&+ '(5 i(175$16)(57(&+12/2*,(P f,(6(5 o$8667$00 (17+>/7 (,1 v5$16*(1 )@5 ',( .2',(5(1'( u(48(1= '(6 y$&+67806+250216 '(5 t$77(N '$6 '85&+ '(1 r5202725 '(6 o(7$//2O 7+,21,1 k i(16 '(5 o$86 J0ovOkK .21752//,(57 :,5'P o>86(N ',( '$6 v5$16*(1 75$*(1N :(5'(1 (7:$ TAV 0$/ 62 *52M :,( k+5( i(6&+:,67(5 2+1( v5$16*(1P g,1(1 :(,7(5(1 u&+8% (5+,(/7 ',(6( h256&+81*65,&+781* $/6 o,77( '(5 $&+7=,*(5 l$+5( ',( t(/(9$1= '(5 g5*(%1,66( 921 ,1 9,752 c1$/<6(1 =85 t2//( 921 q1.2*(1(1 %(, '(5 m5(%6(167(+81* 81' %(,0 v8025:$&+6780 ,1 (,1(0 .203/(77(1 q5*$1,6086 @%(535@)7 :85'(P f,(6(5 c16$7= =(,*7(N '$M q1.2*(1( -(:(,/6 =(//7<363(=,76&+ :,5O .(1 81' (,1 v8025:$&+6780 185 ,1 (,1(0 %(67,007(1 i(:(%( ,1'8=,(5(1P q1.2O *(1( 6,1' 127:(1',* $%(5 1,&+7 +,15(,&+(1' )@5 ',( m5(%6(167(+81* ,0 v,(502'(//N 62*(1$117( v8025352*5(66,216)$.725(1 +$%(1 =86>7=/,&+( (66(17,(//( h81.7,21(1P o,7 j,/)( 75$16*(1(5 o>86( .$11 '$6 63(=,76&+( |86$00(163,(/ 921 q1.2*(1(1 0,7 v8025352*5(66,216)$.725(1 ,1 9,92 0,7 1(8(5 r5>=,6,21 817(568&+7 :(5'(1P f,( *(1(7,6&+( x(5>1'(581* (,1(6 1$7@5/,&+ J63217$1K (1767$1'(1(1 087$17(1 o$8667$00(6 '(5 +3* o$86 Jj<32*21$',6086K ,67 (,1 *87(6 d(,63,(/ )@5 ',( c1O :(1'81* '(5 i(175$16)(57(&+1,. =85 m255(.785 (,1(6 i(1'()(.76 %(, (,1(0 x(5O 68&+67,(5P f(5 j<32*21$',6086 '(5 +3* o$86 ,67 '85&+ (,1( f(/(7,21 ,0 i(1/2&86 '(6 i21$'27523,1O5(/($6,1* j250216 Ji1tjK 9(5856$&+7P i1tj 63,(/7 (,1( %(O '(87(1'( t2//( %(, '(5 g17:,&./81* '(5 i(6&+/(&+7625*$1( 81' '(5(1 h81.7,21P d(, +3* o>86(1 ,67 ',( 32671$7$/( g17:,&./81* '(5 i21$'(1 %/2&.,(57N :$6 ',( w1)58&+7%$5.(,7 '(5 o87$17(1 +(592558)7P f,( g,1.5(8=81* '(6 i1tj y,/'7<3*(16 $/6 '(71,(57(6 v5$16*(1 )@+57( =8 (,1(5 .203/(77(1 t(9(56,21 '(6 087$17(1 r+>O 127<36 0,7 )(57,/(1 0>11/,&+(1 81' :(,%/,&+(1 v,(5(1P

SMXMR j./#+L/54 5.$ +./#+L). l;53% f,( g5=(8*81* 921 o87$17(1 0,7 (,1(5 =,(/*(5,&+7(7(1 *(1(7,6&+(1 x(5>1'(581* ,1 (,1(0 %(67,007(1 i(1/2&86 %$6,(57 $8) '(5(1 g,1)@+581* '85&+ +202/2*( t(.20O %,1$7,21 ,1 (0%5<21$/( u7$00=(//(1 JguO|(//(1K ,0 u,11( (,1(6 NN*(1(O7$5*(7,1*DDP f,(6( o(7+2'( %(58+7 $8) =:(, *581'/(*(1'(1 7(&+1,6&+(1 x25$866(7=81*(1P |80 (,1(1 *(/$1* ',( m8/7,9,(581* (0%5<21$/(5 u7$00=(//(1 JguK 81' '(5(1 g7$%/,(581* $/6 67$%,/( |(//,1,(1P guO|(//(1 67$00(1 85635@1*/,&+ $86 '(5 ,11(5(1 |(//0$66( 921 UNW v$*( $/7(1 o$86(0%5<21(1 JNNd/$672=<67(1DDKN 6,1' 92//67>1',* 81',5(5(1=,(57 81' .?11(1 '$+(5 '(1 c8)%$8 $//(5 i(:(%( (,1(6 6,&+ (17:,&.(/1'(1 q5*$1,6086 9(50,77(/1 JNNq01,327(1=DDKN $8&+ 1$&+'(0 6,( ,1 m8/785 *(+$/7(1 :85O '(1P y(/7:(,7 :(5'(1 185 :(1,*( guO|(//,1,(1 9(5:(1'(7N '$ 48$/,7$7,9 +2&+:(57,*( guO|(//(1N ',( ,+5(1 81',5(5(1=,(57(1 u7$786 (5+$/7(1 +$%(1 81' *87( d(7(,/,*81* $0 m(,0%$+1*(:(%( =(,*(1N 6(/7(1 6,1'P f,( $1'(5( 7(&+1,6&+( x25$866(7=81* )@5 ',( i(1(5,(581* 921 .12&.O287 81' .12&.O,1 o>86(1 ,67 ',( o?*/,&+.(,7 '(5 +2O 02/2*(1 t(.20%,1$7,21 '(5 *(120,6&+(1 u(48(1=(1 0,7 (;2*(1(5 fpc 817(5 *(O (,*1(7(1 d(',1*81*(1P o,77(/6 g/(.75275$16)(.7,21 *(/$1* S[ZY ',( (567( *(=,(/7( g,1)@+581* (,1(5 o87$7,21 '85&+ +202/2*( t(.20%,1$7,21 ,1 guO|(//(1 ,1 9,752P

TVT

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

f,( (567( *(=,(/7 ,1 '(5 m(,0%$+1 087,(57( o$86 817(5 '(5 x(5:(1'81* +202/2* 5(.20%,1,(57(5 guO|(//(1 :85'( S[Z[ %(6&+5,(%(1P f(5 (567( u&+5,77 %(, ',(6(5 v(&+1,. ,67 ',( g/(.75275$16)(.7,21 Jg/(.752325$7,21K (;2*(1(5 fpc ,1 guO|(//(1P f,( (;2*(1( fpc (17+>/7 ',( %($%6,&+7,*7( o87$7,21 81' -(:(,/6 %(1$&+%$57( +202/2*( J*(120,6&+(K u(48(1=(1 =80 5(/(9$17(1 i(1O /2&86 J7$5*(7,1* x(.725K Jc%%P VPVUKP f85&+ '(1 r52=(66 '(5 +202/2*(1 t(.20%,O 1$7,21 :,5' ',( 087,(57( (;2*(1( u(48(1= $1 '(5 %($%6,&+7,*7(1 u7(//( ,0 i(1/2&86 *(*(1 ',( *(120,6&+( u(48(1= $86*(7$86&+7P f,( h>+,*.(,7 =85 +202/2*(1 t(.20O %,1$7,21 ,67 +,(5%(, (,1( 1$7@5/,&+( g,*(16&+$)7 $8&+ 921 guO|(//(1N ',( '85&+ g1O =<0( '(6 fpcOt(3$5$7856<67(06 9(50,77(/7 :,5'P v<3,6&+(5:(,6( :,5' =85 i(1(O 5,(581* (,1(5 .12&.O287 o$86 (,1 :,&+7,*(5 d(67$1'7(,/ '(6 (1'2*(1(1 i(16 '85&+ (,1 c17,%,27,.$Ot(6,67(1=*(1 (56(7=7P f$'85&+ *(+7 ',( h81.7,21 '(6 (1'2*(1(1 i(16 9(5/25(1 81' ',( |(//( *(:,117 ',( c17,%,27,.$5(6,67(1=P m2007 (6 =8 (,1(5 8163(=,76&+(1N 1,&+7O+202/2*(1 k17(*5$7,21 '(5 (;2*(1(1 fpcN 62 :,5' $8&+ '(5 $8M(5+$/% '(5 j202/2*,($50( /,(*(1'( 1(*$7,9( u(/(.7,2160$5.(5 '(6 m216758.76 0,7@%(575$*(1 J7. ,1 c%%P VPVUKN 62 '$M ',(6( 81(5:@16&+7(1 m/21( *581'6>7=/,&+ 921 '(1(1 0,7 (,1(0 +202/2*(1 t(.20%,1$7,216(5(,*1,6 *(:211(1(1 817(56&+,(O '(1 :(5'(1 .?11(1P o,7 ',(6(0 v5,&. *(/,1*7 (6 $/62N ',( 5(/$7,9 6(/7(1(1 +202/2*(1 k17(*5$7,216(5(,*1,66( $86 '(5 o$66( '(5 81*(5,&+7(7(1 k17(*5$7,21(1 +(5$86=87O 6&+(1P c/6 326,7,9( u(/(.7,2160$5.(5*(1( 9(5:(1'(7 0$1 62/&+(N '(5(1 c1:(6(1+(,7 817(5 %(67,007(1 m8/785%(',1*81*(1 (66(17,(// )@5 '$6 %(5/(%(1 '(5 |(//( ,67 J=P dP '$6 1(2 i(1N '$6 )@5 (,1 g1=<0 .2',(57N :(/&+(6 '$6 %(5/(%(1 '(5 |(//(1 ,1 c1O :(6(1+(,7 (,1(6 c17,%,27,.806 '(5 p(20<&,1Om/$66( (50?*/,&+7KP h@5 ',( *(=,(/7( g,1)@+581* 921 o87$7,21(1 6,1' 9(56&+,('(1( u75$7(*,(1 0?*/,&+\ g,1(1 .203/(77(1 h81.7,2169(5/867 (,1(6 i(1(6 %(=(,&+1(7 0$1 $/6 .12&.O287 2'(5 p8//$//(/P j,(5%(, :,5' 0(,67(16 '$6 g;21N '$6 '$6 u7$576,*1$/ )@5 ',( v5$16/$7,21 (17+>/7 '85&+ (,1 u(/(.7,2160$5.(5*(1 (56(7=7 J5(3/$&(0(17 7<3( x(.725N c%%P VPVUKP „targeting“ Vektor

Wildtypallel

neo

2

3

4

1

2

3

4

neo

2

3

4

tk

homologe Rekombination „targeted“ Allel

c%%P VPVU i(1( v$5*(7,1*P i(=,(/7( i(1,1$.7,9,(581* '85&+ (,1( NN5(3/$&(0(17DD u75$7(*,(P f(5 r5202725 81' '$6 (567( g;21 ,0 *(120,6&+(1 n2&86 :(5'(1 1$&+ +202/2*(5 t(.20O %,1$7,21 '85&+ '$6 326,7,9( u(/(.7,2160$5.(5*(1 J1(2K '(6 7$5*(7,1*Ox(.7256 (56(7=7P f85&+O *(+(1'( n,1,(1 5(35>6(17,(5(1 +202/2*( u(48(1=(1 ,0 x(.725N y,/'7<3$//(/ 81' 5(.20%,O 1,(57(0 c//(/P g;216 6,1' $/6 +2+( 25(1( t(&+7(&.( '$5*(67(//7 81' 180(5,(57N ',( u(/(.7,216O 0$5.(5*(1( $/6 9$&+( t(&+7(&.( 0,7 (,1(5 c%.@5=81* )@5 '$6 %(75(5(1'( i(1 J1(2 3 p(206(17,(5(1 ',( k16(57,21667(//(1 '(6 u(/(.O 7,2160$5.(5*(16 81' $1'(5(5 +(7(52/2*(5 u(48(1=(1P

VP[ v,(502'(//( neo

„targeting“ Vektor

Wildtypallel

1

2*

3

4

2

3

4

2*

3

4

TVU

tk

homologe Rekombination „targeted“ Allel

1

neo

c%%P VPVV |,(/*(5,&+7(7(6 g,1)@+5(1 (,1(5 r81.7087$7,21P o,7 9(5*/(,&+%$5(5 u75$7(*,( :,( ,1 c%%,/'81* VPVU :,5' +,(5 '$6 1(2Oi(1 ,0 k17521 ,16(5,(57 81' $8) (,1( e2Om219(56,21 (,1(5 r81.7087$7,21 ,1 g;21 T 6(/(.7,21,(57P f,( r81.7087$7,21 :,5' 0,7 (,1(0 u7(51 1(%(1 '(5 p800(5 '(6 g;216 $1*('(87(7P f,( $1'(5(1 u<0%2/( 6,1' ,'(17,6&+ 0,7 '(1(1 ,1 c%O %,/'81* VPVUP j,(5 ,67 '$6 1(2Oi(1 921 /2;rOg/(0(17(1 J'81.(/%/$8( f5(,(&.(K 9$1.,(57N :$6 (,1( 63>7(5( g17)(5181* '(6 1(2Oi(16 0,7 j,/)( '(5 e5( t(.20%,1$6( (5/$8%7P f$6 g17)(51(1 '(6 1(2Oi(16 ,67 ,00(5 '$11 6,1192//N :(11 0$1 ',( g;35(66,21 (,1(6 087,(57(1 c//(/6 %(O $%6,&+7,*7N 80 1(*$7,9( k17(5)(5(1= =8 9(50(,'(1P

o87$7,21(1N %(, '(1(1 (,1 v(,/ '(5 i(1)81.7,21(1 (5+$/7(1 %/(,%7N =P dP :(11 (,1( r81.7087$7,21 '(1 c867$86&+ (,1(5 (,1=(/1(1 c0,126>85( ,0 i(1352'8.7 %(:,5.7N :(5'(1 $/6 NN3$57,$/ /266 2) )81&7,21DD 2'(5 +<320253+( c//(/( %(=(,&+1(7 Jc%%P VPVVKP d,6:(,/(1 .?11(1 o87$7,21(1 $8&+ i(1352'8.7( 0,7 1(8(1 h81.7,21(1 $8667$77(1N =P dP :(11 ',( d,1'81* 5(*8/$725,6&+(5 h$.725(1 9(5>1'(57 :,5'P u2/&+( o87$7,21(1 :(5'(1 '$11 $/6 NN*$,1 2) )81&7,21DD o87$7,21(1 %(=(,&+1(7P p$&+ '(5 v5$16)(.7,21 '(5 fpc ,1 ',( guO|(//(1 81' $17,%,27,6&+(5 u(/(.7,21 :(5'(1 ',( m/21( '(5 @%(5/(%(1'(1 |(//(1 0,7 02/(.8/$5%,2/2*,6&+(1 o(7+2'(1 Jret\ 6,(+( m$3P VPTPT] u287+(51 d/27Oc1$/<6(\ 6,(+( m$3P VPTPSK $8) ',( c1:(6(1O +(,7 '(5 o87$7,21 $0 *(:@16&+7(1 i(1257 +,1 817(568&+7P f$6 x(5+>/71,6 +202O /2*(5 =8 =8)>//,*(5 J1,&+7O+202/2*(5K t(.20%,1$7,21 /,(*7 %(, '(1 0(,67(1 g;3(5,O 0(17(1 ,0 d(5(,&+ 921 S\U %,6 S\WRR 5(6,67(17(5 m/21(P j$7 0$1 (,1(1 +202/2* 5(.20%,1,(57(1 guO|(//./21 ,'(17,7=,(57N :(5'(1 ',(6( |(//(1 ,1 m8/785 9(50(+57 81' ,1 g0%5<21(1 0,77(/6 o,.52,1-(.7,21 =85@&.9(539$1=7P j,(5%(, :>+/7 0$1 '$6 u7$',80 '(5 d/$672=<67(N $86 '(0 ',( guO|(//(1 85635@1*/,&+ 35(3$5,(57 :85'(1P SZ %,6 TW guO|(//(1 :(5'(1 0,7 j,/)( )(,1(5 i/$6.$3,//$5(1 817(5 1,&+7 81(5+(%/,&+(0 7(&+1,6&+(1 c8):$1' ,1 '(1 j2+/5$80 (,1(5 d/$672=<67(N '$6 d/$672=2(/N 0,.52O ,1-,=,(57 Jc%%P VPVWKP p$&+ '(5 k1-(.7,21 .2//$%,(57 ',( d/$672=<67( 81' ',( ,1-,=,(57(1 guO|(//(1 %,/'(1 0,7 '(1 |(//(1 '(5 ,11(5(1 |(//0$66( (,1( *(0(,16$0( u758.785P p$&+ .85=(5 k1.8%$7,21 5((;3$1',(57 '(5 g0%5<2 81' :,5' ,1 6&+(,16&+:$1*(5( g03)>1*(57,(5( @%(575$*(1P f,( %(575$*81* '(5 g0%5<21(1 (5)2/*7 ,1 '(1 w7(586N '$ d/$672=<67(1 $8&+ :>+5(1' '(5 1$7@5/,&+(1 g17:,&./81* ,0 w7(586 =8 71'(1 6,1'P g7:$ =:(, f5,77(/ '(5 u3(1'(57,(5( :(5'(1 6&+:$1*(5 81' 75$*(1 (,1(1 y85) $86P f,( g0%5<21(1 ,03/$17,(5(1 @%/,&+(5:(,6( 0,7 (,1(5 t$7( 921 WR@P y,( (5.(117 0$1 181 ',( &+,0>5(1 p$&+.200(1N '(5(1 i(:(%( 9,(/( |(//(1 0,7 '(0 75$16*(1(1 guO|(//Oi(127<3 (17+$/7(1a f,(6 :,5' (50?*/,&+7 '85&+ ',( x(5:(1'81* 921 guO|(//,1,(1 81' d/$672=<67(1 $86 9(56&+,('(1(1 o$8667>00(1N ',( 6,&+ ,1 ,+5(5 h(//)$5%( 817(56&+(,'(1P f,( p$&+.200(1N ',( (,1(1 *52M(1 c17(,/ 921 |(//(1 '(6 guO|(//Oi(127<36 ,0 h(// 81' ,1 '(5 j$87 75$*(1N +$%(1 -( 1$&+

TVV

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

In Vitro -Selektion für ES-Zellklone, die das gewünschte Integrationsereignis tragen

Einführung von DNA in ES-Zellen durch Elektroportation

Injektion von ES-Zellen in Blastozysten

Übertragung injizierter Blastozysten in scheinschwangere Empfängertiere

^

Züchtung männlicher Chimären

^

]

] potentiell heterozygote Maus für das beabsichtigte Integrationsereignis

c%%P VPVW u&+(0$7,6&+( f$567(//81* '(6 (;3(5,0(17(//(1 c%/$8)6 =85 j(567(//81* &+,0>5(5 o>86( '85&+ o,.52,1-(.7,21 921 *(=,(/7 9(5>1'(57(1 guO|(//(1 ,1 d/$672=<67(1P f,( fpc J*5$8( u<0%2/(K :,5' '85&+ v5$16)(.7,21 ,1 '(1 m(51 921 guO|(//(1 (,1*()@+57P |(//./21(N ',( '$6 u(/(.7,2160$5.(5*(1 1(2 75$*(1 81' ,1 '(5 $16&+/,(M(1'(1 02/(.8/$5%,2/2*,6&+(1 c1$/<6( '$6 *(:@16&+7( t(.20%,1$7,2160867(5 =(,*(1N :(5'(1 ,1 |(//.8/785 9(50(+57 81' ,1 d/$672=<67(1 ,1-,=,(57P f,( ,1-,=,(57(1 d/$672=<67(1 :(5'(1 ,1 '(1 w7(586 6&+(,16&+:$1*(5(5 g03)>1*(57,(5( @%(575$*(1 81' &+,0>5( o>86(N '(5(1 i(:(%( 6,&+ $86 |(//(1 '(5 d/$672=<67( 81' '(5 9(5>1'(57(1 guO|(//(1 =86$00(16(7=7N :(5'(1 *(%25(1P

c8635>*81* '(6 e+,0>5,6086 0(+5 2'(5 :(1,*(5 67$5. *(9(&.7(6 2'(5 *(675(,)7(6 h(//P p81 6&+/,(M7 0$1 921 '(5 d(7(,/,*81* '(5 guO|(//(1 $0 c8)%$8 921 j$87 81' h(// $8) '(5(1 d(7(,/,*81* $0 m(,0%$+1*(:(%(P m5(8=7 0$1 &+,0>5( 0>11/,&+( v,(5( 0,7 y,/'7<3:(,%&+(1 '(6 i(127<36 '(5 d/$672=<67(N 62 (5+>/7 0$1 ,1 '(5 1>&+O 67(1 i(1(5$7,21 (17:('(5 v,(5( 0,7 '(5 h(//)$5%( '(6 o877(57,(56 J.(,1( v5$160,66,21 '(6 guO|(//Oi(127<36K 2'(5 v,(5( 0,7 '(5 h(//)$5%( '(6 o$8667$00(6N 921 '(0 ',( guO|(//(1 67$00(1P k0 /(7=7(5(1 h$// 635,&+7 0$1 921 m(,0%$+175$160,66,21P

VP[ v,(502'(//(

TVW

j$7 0$1 817(5 ',(6(1 p$&+.200(1 0,7 j,/)( 02/(.8/$5%,2/2*,6&+(5 o(7+2'(1 JretK ',(-(1,*(1 v,(5( ,'(17,7=,(57N ',( ',( *(:@16&+7( o87$7,21 75$*(1N 62 :(5'(1 ',(6( j(7(52=<*27(1 =85 g5=(8*81* +202=<*27(5 o87$17(1 0,7(,1$1'(5 9(53$$57P i581'6>7=/,&+ .?11(1 ',( 62 (5=(8*7(1 .12&.O287 2'(5 .12&.O,1 o>86( 817(5O 6&+,('/,&+( r+>127<3(1 (17:,&.(/1P k0 *@167,*(1 h$// 63,(*(/7 ',( o$86 =P dP '$6 m5$1.+(,76%,/' '(6 o(16&+(1 :,'(5N )@5 '$6 (,1 v,(502'(// (17:,&.(/7 :(5'(1 62//7(P g6 .$11 6,&+ -('2&+ $8&+ (,1 *>1=/,&+ 819(5:$1'7(5 r+>127<3 (17:,&.(/1N 2'(5 +202=<*27 087$17( v,(5( 6,1' ,1 87(52 1,&+7 @%(5/(%(16)>+,* Jn(7$/087$17(KP c8&+ .?11(1 (5=(8*7( o87$7,21(1 3+>127<3,6&+ 67800 %/(,%(1N (7:$ :(,/ $1'(5( r52O =(66( '(1 (1767$1'(1(1 i(1'()(.7 .203(16,(5(1 Jt('81'$1=KP n(7=7/,&+ .$11 '(5 r+>127<3 087$17(5 v,(5( $8&+ '$921 $%+>1*(1N ,1 :(/&+(0 o$8667$00 6,( (5=(8*7 :85'(1P k1 ',(6(1 h>//(1 )@+5(1 ',(6(/%(1 o87$7,21(1 =8 817(56&+,('/,&+(1 r+>O 127<3(1P u2/&+( h>//( '(87(1 $8) ',( g;,67(1= 921 67$00$%+>1*,* 817(56&+,('/,&+ $86*(35>*7(1 h$.725(1 +,1N ',( (,1( c86:,5.81* $8) ',( 3+>127<3,6&+( c8635>*81* '(6 817(568&+7(1 i(16 +$%(1 .?11(1 JNN675$,1O63(&,7& 02',7(56DDKP

SMXMRMP a%)30)%,Y s)%2-/$%,,% &=2 b934)3#(% e)"2/3% f,( e<67,6&+( h,%526( JehKN $8&+ o8.29,6=,'26( *(1$117N ,67 (,1( '(5 +>87*67(1 /(7$/(1 +(5(',7>5(1 m5$1.+(,7(1 ,1 f(876&+/$1'P f$6 %(7525(1( i(1 :85'( S[Z[ ./21,(57P d(, '(0 i(1352'8.7 +$1'(/7 (6 6,&+ 80 (,1(1 e+/25,'Ok21(1.$1$/N '(1 NN&<67,& 7%526,6 75$160(0%5$1( &21'8&7$1&( 5(*8/$725DD JehvtK J6,(+( m$3P WPSPSKP f85&+ ',( g5=(8*81* (,1(6 (17635(&+(1'(1 o$8602'(//6 62// ',( r$7+2*(1(6( '(5 g5.5$1.81* %(66(5 $/6 %(,0 o(16&+(1 0?*/,&+ $1$/<6,(57 :(5'(1P c8M(5'(0 (5+257 0$1 6,&+ (,1 35>./,1,6&+(6 v(676<67(0 )@5 1(8( .219(17,21(//( v+(5$3,(675$7(*,(1 2'(5 )@5 ',( i(17+(5$3,( J6,(+( m$3P ZPTKP m12&.O287 o>86(N %(, '(1(1 '$6 ehvtOi(1 '85&+ +202/2*( t(.20%,1$7,21 ,1 guO|(//(1 ,1$.7,9,(57 :85'(N =(,*(1 ',( &+$5$.7(5,67,6&+(1 f()(.7( ,1 e+/25,'6(O .5(7,21 81' ,1 '(5 r$7+2/2*,( '(6 x(5'$881*675$.76N =P dP ',( (5+?+7( c..808/$7,21 =>+(1 u&+/(,06P f,(6( v,(5( 6,1' %(, '(5 g17:,&./81* *(17+(5$3(87,6&+(5 c16>7=( 921 *52M(0 p87=(1P u2 .2117( %(,63,(/6:(,6( *(=(,*7 :(5'(1N '$M 75$16*(1( o>86(N ',( '(1 .203/(77(1 ehvtOi(1/2&86 $/6 <($67 $57,7&,$/ &+5202620( J{ceK 75$*(1 J6,(+( m$3P VPSPSKN '(1 i(1'()(.7 921 ehvt .12&.O287 o>86(1 5(3$5,(5(1 .?11(1P f,(6( u78',(1 75$*(1 0,7 '$=8 %(,N ',( 5(*8/$725,6&+(1 g/(0(17( =8 ,'(17,7=,(5(1N ',( )@5 ',( 1250$/( g;35(66,21 '(6 ehvt 81' **)P )@5 ',( i(17+(5$3,( :,&+7,* 6,1'P c//(5',1*6 =(,*(1 ',( 0(,67(1 eh r$7,(17(1 .(,1( ehvt i(1'(/(7,21N 621'(51 0(,67 r81.7087$7,21(1N ',( =85 g;35(66,21 (,1(6 ,1 6(,1(5 u<17+(6( 2'(5 h81.7,21 *(67?57(1 m$1$/6 )@+5(1 J6,(+( m$3P WPSPSKP f,( f()(.7( 6,1' '$11 :(,7 :(1,*(5 '5$O 0$7,6&+ $/6 ,1 '(1 ehvt18// o>86(1N ',( =80 i52M7(,/ %(5(,76 :(1,*( v$*( 1$&+ '(5 i(%857 $1 x(56723)81*(1 '(6 x(5'$881*675$.76 67(5%(1P o,7 j,/)( '(5 ,1 c%O %,/'81* VPVV %(6&+5,(%(1(1 o(7+2'( :85'(1 1(8( x$5,$17(1 921 eh o>86(1 +(5O *(67(//7N ',( r81.7087$7,21(1 ,0 ehvtOi(1 75$*(1P f$'85&+ .2117(1 v,(502'(//( (17:,&.(/7 :(5'(1N '(5(1 m5$1.+(,769(5/$8) '(0 '(5 0(,67(1 eh r$7,(17(1 >+1/,&+(5 ,67P d(621'(56 ',( ,17(67,1$/(1 x(56723)81*(1 6,1' *(*(1@%(5 '(1 p8//087$17(1 '(87O /,&+ 9(50,1'(57 81' ',( %(5/(%(165$7( (5+?+7P f$'85&+ 67(//(1 6,( (;=(//(17( o2O '(//( '$5N %(, '(1(1 ',( eh r$7+2*(1(6( '(5 n81*(1 817(568&+7 :(5'(1 .$11P

TVX

V o2/(.8/$50(',=,1,6&+( o(7+2'(1

SMXMRMQ s)%2-/$%,,% &=(2%. :52 h$%.4)&):)%25.' -%.3#(,)#(%2 f%.$%&%+4% f,( ,1=:,6&+(1 :(,79(5%5(,7(7( p87=81* '(5 .12&.O287 v(&+1,. ,1 '(5 i581'/$*(1O )256&+81* +$7 =8 (,1(0 )@5 ',( o(',=,1 :,&+7,*(1 |86$7=$63(.7 *()@+57\ |8:(,/(1 (1767(+(1 0(+5 2'(5 :(1,*(5 =8)>//,* v,(5087$17(1N '(5(1 r+>127<3 c63(.7( 0(16&+/,&+(5 u<1'520( :,'(563,(*(/7N '(5(1 i(1'()(.7 %,6/$1* 81%(.$117 :$5P f,( fpc 62/&+(5 r$7,(17(1 .$11 '$11 $8) f()(.7( ,1 '(0 %(, '(5 o$86 817(568&+7(1 +202/2*(1 i(1/2&86 $1$/<6,(57 :(5'(1P f(5 .12&.O287 '(6 t(=(37256 JvtmcK '(6 p(59(1:$&+67806)$.7256 J1(59( *52:7+ )$&725N pihK )@+57 =80 x(5/867 63(=,76&+(5 p(8521(1N ',( (;2.5,1( f5@6(1 81' 6(1625,6&+( h81.7,21(1 :,( v(03(5$785O 81' u&+0(5=(0371'81* .21752//,(5(1 %=:P 9(50,77(/1P f,(6( u<03720( 6,1' $8&+ v(,/ (,1(5 0(16&+/,&+(1 g5%.5$1.+(,7N '(6 62*(1$117(1 ekrc u<1'5206 J&21*(1,7$/ ,1O 6(16,7,9,7< 72 3$,1 :,7+ $1+<'526,6KN $8&+ %(.$117 $/6 6(1625,6&+( 81' $872120( p(8523$7+,( v<3 kxP f,(6( $872620$/O5(=(66,9( g5%.5$1.+(,7 ,67 &+$5$.7(5,6,(57 '85&+ :,('(5.(+5(1'( h>//( 921 81(5./>5/,&+(0 h,(%(5N c1+<'526( Jx(5/867 '(5 u&+:(,M%,/'81*KN x(5/867 '(5 u&+0(5=(0371'81*N u(/%679(567@00(/81* 81' 0(1O 7$/(5 t(7$5',(581*P }+1/,&+ :,( %(, pih 81' vtmc .12&.O287 o>86(1 .2007 (6 %(, ekrc r$7,(17(1 =80 x(5/867 '(5 6<03$7+,6&+(1 p(8521(1N ',( =P dP (;2.5,1( u&+:(,M'5@6(1 ,11(59,(5(1 81' =80 x(5/867 62/&+(5 6(1625,6&+(5 p(8521(1 '(5 j,1O 7(5:85=(/*$1*/,(1N ',( )@5 ',( v(03(5$785O 81' u&+0(5=(0371'81* 9(5$17:257/,&+ 6,1'P f,( 02/(.8/$5*(1(7,6&+( c1$/<6( 921 81$%+>1*,*(1 ekrc h$0,/,(1 (5*$%N '$M ,1 $//(1 %,6+(5 817(568&+7(1 h>//(1 o87$7,21(1 ,0 75.c i(1 925/$*(1P u20,7 :$5 1,&+7 185 '(5 i(1'()(.7 '(6 ekrc u<1'5206 $8)*(./>57N 621'(51 $8&+ */(,&+O =(,7,* (,1 :,&+7,*(6 v,(502'(// (1767$1'(1P

SMXMS j/.$)4)/.!,% l54!'%.%3% f$6 r52%/(0 (0%5<21$/O/(7$/(5 o87$7,21(1 .$11 0$1 +(87( 0,7 (,1(5 1(8(1 u75$O 7(*,( =85 *(=,(/7(1 o87$*(1(6( 80*(+(1P f,(6( o(7+2'( 9(5:(1'(7 i(16&+$/7(5N ',( (6 (50?*/,&+(1N o87$7,21(1 *(:(%(O 2'(5 (17:,&./81*663(=,76&+ (,1=8)@+5(1 Jc%%P VPVWN c%%P VPVYK] 6,( %$6,(57 $8) '(5 m20%,1$7,21 '(5 6&+21 %(6&+5,(%(1(1 +202/2*(1 t(.20%,1$7,21 ,1 guO|(//(1 0,7 (,1(0 257663(=,76&+(1 t(.20%,1$7,21O 6(5(,*1,6P g,1 d(,63,(/ )@5 (,1(1 62/&+(1 i(16&+$/7(5N '$6 e5(O/2;r u<67(0N 62// +,(5 %(6&+5,(%(1 :(5'(1P f,(6(6 t(.20%,1$6(Ou<67(0 (1767$007 '(0 d$.7(5,23+$*(1 rSP n2&8663(=,76&+( t(.20%,1$6(1 6,1' g1=<0(N ',( 63(=,76&+( |,(/6(48(1=(1 (5O .(11(1N $1 '(1(1 6,( ',( fpc 6&+1(,'(1 81' 5(/,*,(5(1 81' 620,7 (,1( t(.20%,O 1$7,21 9(5856$&+(1P f$6 g1=<0 e5( J&$86(6 5(&20%,1$7,21K .$7$/<6,(57 ',( 25763(O =,76&+( t(.20%,1$7,21 =:,6&+(1 fpcO|,(/6(48(1=(1 921 -(:(,/6 UV %3N '(1 /2;rO g/(0(17(1 J/2&86 2) &5266,1* 29(5KP e5( $//(,1 5(,&+7 $86N 80 ',( t(.20%,1$7,21 =:,6&+(1 /2;rOg/(0(17(1 =8 .$7$/<6,(5(1N =86>7=/,&+( m2)$.725(1 :(5'(1 1,&+7 %(O 1?7,*7P f,(6( g,*(16&+$)7 (5/$8%7 ',( c1:(1'81* '(6 e5(O/2;r u<67(06 ,1 $1'(5(1 u3(=,(6P w0 (,1 |,(/*(1 0,7 j,/)( '(6 e5(O/2;r u<67(06 $86=86&+$/7(1N 0@66(1 =8O 1>&+67 /2;rOg/(0(17( '85&+ NN*(1( 7$5*(7,1*DD 62 ,1 '$6 |,(/*(1 (,1*(%5$&+7 :(5'(1N '$M (,1 (66(17,(//(6 g;21 921 =:(, /2;rOg/(0(17(1 9$1.,(57 :,5' JNN*(92;7(6DD c//(/K Jc%%P VPVXKP k1 c%:(6(1+(,7 921 e5( :,5' '$6 *(92;7( c//(/ 1250$/ (;35,0,(57 81' ',( 62 9(5>1'(57(1 o>86( J*(92;7( o$86K 62//7(1 .(,1( 3+>127<3,6&+(1 f()(.7(

VP[ v,(502'(//( „targeting“ Vektor

tk

Wildtyplocus

neo

1 1

TVY

2 2

3

homologe Rekombination „targeted“ Allel

neo

1

2

3

„site-specific“ Rekombination 2

1

Typ I: komplette Deletion

2

Typ II: „gefloxter“ Locus neo

2

Typ III: Exondeletion wird negativ selektioniert

c%%P VPVX NNh/2;DD 81' NN'(/(7(DD u75$7(*,(P f,( NN92;DD 81' NN'(/(7(DD u75$7(*,( =85 *(=,(/7(1 i(102',7.$7,21 (5/$8%7 ',( */(,&+=(,7,*( j(567(//81* (,1(6 0,7 /2;rOg/(0(17(1 9$1.,(57(1N -('2&+ )81.7,21$/ ,17$.7(1 c//(/6 Jv<3 kk NN*(92;7(6DD c//(/K 81' (,1(6 .203/(77(1 p8//$//(/6 Jv<3 kKP j,(5)@5 6,1' =:(, $8)(,1$1'(5)2/*(1'( t(.20%,1$7,2166&+5,77( 127:(1',*\ f,( +2O 02/2*( t(.20%,1$7,21 81' ',( NN6,7(O63(&,7&DD t(.20%,1$7,21 0,7 j,/)( '(5 t(.20%,1$6( e5( J=P dP ,1 (,1(5 75$16,(17(1 v5$16)(.7,21 0,7 (,1(0 e5(O.2',(5(1'(1 r/$60,'KP c//( /2;rO g/(0(17( +$%(1 %(, ',(6(5 u75$7(*,( ',( */(,&+( q5,(17,(581*P f,( u<0%2/( 6,1' ,'(17,6&+ 0,7 '(1(1 ,1 c%%,/'81* VPVUP

$8):(,6(1P f,( t(.20%,1$6( :,5' ,1 (,1(5 =:(,7(1 75$16*(1(1 o$86/,1,( (;35,0,(57 Je5(Oo$86KP |85 .21',7,21$/(1 c866&+$/781* '(6 NN*(92;7(1DD c//(/6 J257663(=,76&+( t(.20%,1$7,21K .2007 (6 '$11N :(11 ',( *(92;7( o$86 81' ',( e5(Oo$86 0,7O (,1$1'(5 *(.5(8=7 :(5'(1 Jc%%P VPVYKP f$%(, .$11 ',( g;35(66,21 921 e5( '85&+ (17635(&+(1'( 5(*8/$725,6&+( u(48(1=(1 62 *(67(8(57 :(5'(1N '$M (6 (17:('(5 =8 (,1(0 '(71,(57(1 g17:,&./81*667$',80N ,1 (,1(0 63(=,76&+(1 i(:(%( 2'(5 1$&+ (;2*(1(5 u7,08/$7,21 $.7,9 :,5'P m(117 0$1 '(1 i581' )@5 ',( )5@+( n(7$/,7>7 (,1(5 p8//087$17(N =P dP (,1(1 j(5=O '()(.7N .$11 0,7 ',(6(5 v(&+1,. '85&+ x(5:(1'81* 63(=,76&+(5 t(*8/$7,216(/(0(17( ',( t(.20%,1$7,21 ,0 j(5= 9(5+,1'(57 81' '$0,7 ',( n(7$/,7>7 '(5 o87$17( 80O *$1*(1 :(5'(1P u3>7(5( h81.7,21(1 (,1(6 |,(/*(16 ,1 $1'(5(1 i(:(%(1 .?11(1 620,7 $1$/<6,(57 :(5'(1P f,(6( o(7+2'( ,67 $8&+ ,1 62/&+(1 h>//(1 6(+5 1@7=/,&+N ,1 '(1(1 ',( g17:,&./81* =:(,(5 u758.785(1 (1* 0,7(,1$1'(5 *(.233(/7 ,67N :,( =P dP ',( g17:,&./81* 921 o86.(/1 81' ,+5( k11(59,(581* '85&+ o27251(8521(P q+1( o86.(/1 9(5.@00(51 ',( p(59(1N 81' 2+1( k11(59,(581* '(*(1(5,(5(1 ',( o86.(/1P k67 181 (,1 i(1352'8.7 )@5 ',( g17:,&./81* %(,'(5 u758.785(1 (66(17,(//N .$11 ',( i(1)81.7,21 ,1 (,1(5 u758.785 $86*(6&+$/7(7 :(5'(1 J=P dP o27251(8521(K 81' ,+5( c86:,5.81*(1 $8) ',( $1'(5( u758.785 Jo86.(/K 817(568&+7 :(5'(1P

TVZ

V o2/(.8/$50(',=,1,6&+( o(7+2'(1 Cre Maus

cre

X

gefloxte Maus

cre Ziel-Gen

cre

cre

Ziel-Gen

Ziel-Gen

Ziel-Gen

Induktion während der Ontognese gemäss den regulatorischen Elementen von Cre oder extern durch einen Indikator

cre

cre

Ziel-Gen

Ziel-Gen deletiert

c%%P VPVY |8&+76&+(0$ )@5 ',( .21',7,21$/( o87$*(1(6( ,1 o>86(1 '85&+ +202/2*( 81' NN6,7(O63(&,7&DD t(.20%,1$7,21P p85 (,1 c//(/ '(6 |,(/*(16 ,67 '$5*(67(//7P |:(, 81$%+>1*,*( o$8667>00( 6,1' +,(5)@5 1?7,*P g,1 u7$00 (;35,0,(57 ',( e5(Ot(.20%,1$6( ,1'8=,(5%$5 2'(5 ,1 *(:(%(63(=,76&+(5 h250P |(//(1 ',( e5( 1,&+7 (;35,0,(5(1 6,1' 0,7 6&+:$5=(0 t$1' '$5*(67(//7N ',(-(1,*(1N ',( (;35,0,(5(1 0,7 %/$8(0 t$1'P f(5 $1'(5( o$8667$00 75>*7 '(1 NN*(92;7(1DD n2&86 '(6 |,(/*(16N :(/&+(6 ,1 $//(1 |(//(1 (;35,0,(57 :,5'P p$&+ m5(8=81* (17O +>/7 -('( |(//( '$6 e5(Oi(1 81' '$6 NN*(92;7(DD i(1P |8 (,1(0 %(67,007(1 |(,7381.7 '(5 g17:,&./81* :,5' e5( *(:(%(63(=,76&+ (;35,0,(57 J%/$8 805$1'(7( |(//(K 2'(5 1$&+ |8*$%( (,1(6 k1'8.7256 921 $8M(1 $.7,9,(57 J1,&+7 *(=(,*7KP k1 '(1 5(/(9$17(1 i(:(%(1 71'(7 t(O .20%,1$7,21 67$77N ',( =85 g,1)@+581* '(5 %($%6,&+7,*7(1 o87$7,21 )@+57 J%/$8 805$1'(7( |(//( 0,7 +(//%/$8(0 j,17(5*581'KP

SMXMSMP f%7%"%30%:)&)3#(% l54!'%.%3% f,( 62*(1$117( NN92;O$1'O'(/(7(DD u75$7(*,( Jc%%P VPVXK :85'( =8(567 )@5 ',( ,1 9,92 c1$/<6( '(5 h81.7,21 (,1(6 $1 '(5 fpcOt(3$5$785 %(7(,/,*7(1 g1=<06 $1*(:(1'(7N '(5 fpcOr2/<0(5$6( tP f,( f(/(7,21 '(6 r52027256 81' (567(1 g;216 ,1 '(5 m(,0O

VP[ v,(502'(//(

TV[

%$+1 '(5 o$86 +$7 (,1(1 /(7$/(1 r+>127<3P k1 '(5 NN*(92;7(1DD o$86 :85'( '(5 r5202725 81' '$6 (567( g;21 '(6 i(16 '85&+ /2;r g/(0(17( 9$1.,(57P o>86(N ',( =:(, 62/&+( c//(/( 75$*(1N =(,*(1 .(,1(5/(, 3$7+2/2*,6&+(1 r+>127<3P i(.5(8=7 :85'( 0,7 (,1(5 75$16*(1(1 o$86N ',( e5( 817(5 m21752//( (,1(6 vO|(//O63(=,76&+(1 r52O 027256 J/&.K (;35,0,(57P c8) ',(6(0 y(* .2117( 817(568&+7 :(5'(1N 2% ',( fpcO r2/<0(5$6( %(, '(0 t($55$1*(0(17 '(5 vO|(//5(=(3725*(1( :>+5(1' '(5 g17:,&.O /81* 921 vOn<03+2=<7(1 (,1( t2//( 63,(/7P f,( g5*(%1,66( +$%(1 *(=(,*7N '$M '(5 fpcOr2/<0(5$6( t .(,1( (66(17,(//( d('(8781* )@5 ',( 1250$/( g17:,&./81* '(5 vO|(//(1 =8.2007N 6,( :2+/ $%(5 ,1 9,92 (,1( t2//( %(, '(0 x25*$1* '(6 NN%$6( (;&,6,21 5(3$,5DD 63,(/7 J6,(+( m$3P UPYPTPTKP

SMXMSMQ h.$5:)%2"!2% l54!'%.%3% d(, '(5 c1$/<6( '(6 r+>127<36 (,1(5 i(1087$7,21 .?11(1 :>+5(1' '(5 q172*(1(6( .203(16$725,6&+( g5(.7( '(6 q5*$1,6086 $8) ',( (,1*()@+57( o87$7,21 $8)75(7(1 81' '(1 r+>127<3 62 %((,19866(1P f$ =81(+0(1' .203/(;(5( x25*>1*( 817(568&+7 :(5'(1 62//(1N 0?&+7( 0$1 ,'($/(5:(,6( 0,7 u<67(0(1 $5%(,7(1N %(, '(1(1 0$1 =8 -('(0 |(,7381.7 '(5 g17:,&./81* (,1(6 q5*$1,6086 ',( o87$7,21 ,1'8=,(5(1 .$11] 62 (7:$ %(, c1$/<6(1 =85 *(1(7,6&+(1 i581'/$*( 921 n(51(1 81' i('>&+71,6N %(, '(0 '$6 x(5+$/7(1 (,1(5 ,1',9,'8(//(1 o$86 925 81' 1$&+ g,1)@+581* (,1(5 o87$7,21 $1$/<6,(57 :(5'(1 62//P |8 ',(6(0 |:(&. 0?&+7( 0$1 ',( t(.20%,1$6( ,1 '(5 e5(Oo$86 921 $8M(1 5(*8/,(5%$5 (;35,0,(5(1P g,1( m21752//( ,+5(5 c.7,9,7>7 :>5( $8) 75$16.5,37,21$/(5 81' 326775$16.5,37,21$/(5 g%(1( '(1.%$5P f,( c86:$+/ $1 %5$8&+%$5(1 ,1'8=,(5%$5(1 r5202725(1 %(, u>8*(7,(5(1 ,67 %,6+(5 12&+ 6(+5 %(6&+5>1.7P f$ e5( (,1( 6(+5 +2+( c.7,9,7>7 %(6,7=7N .2007 (6 '$5$8) $1N '$M ,0 1,&+7O,1'8=,(57(1 u7$786 '(5 e5(On2&86 .(,1(5/(, g;35(66,21 =(,*7P f,( 0(,67(1 r5202725(1 %(6,7=(1 (,1( =8 +2+( d$6,6$.7,9,7>7P f$5@%(5 +,1$86 %(6,7=7 -('(5 r5202725 (,1 %(6&+5>1.7(6 *(:(%(63(=,76&+(6 g;35(66,2160867(5N 62 '$M ',(O 6(5 c16$7= )@5 (,1( */2%$/( ,1 9,92 c1:(1'81* 1,&+7 %5$8&+%$5 ,67P c1'(5(56(,76 62// e5( (5,=,(17 ,1 $//(1 |(//(1 (,1(6 i(:(%(6 2'(5 ,1 (,1(0 %(67,007(1 |(//7<3 ,11(5+$/% (,1(6 i(:(%(6 (5,=,(17 6&+1(,'(1 81' 5(/,*,(5(1P f$+(5 =(,*7 (,1 ,'($/(6 u<67(0 (,1( +2+( k1'8=,(5%$5.(,7 %(, )(+/(1'(5 d$6,6$.7,9,7>7P g,1( c/7(51$7,9( =85 t(*8/$7,21 921 e5( $8) '(5 g%(1( '(5 v5$16.5,37,21 67(//7 ',( t(*8/$7,21 $8) '(5 g%(1( '(5 g1=<0$.7,9,7>7 '$5P d(, (,1(0 62/&+(1 c16$7= :,5' ',( t(.20%,1$6( $/6 h86,2163527(,1 0,7 (,1(5 n,*$1'(1%,1'81*667(//( (,1(6 j250215(=(37256 (;35,0,(57P k1 c%:(6(1+(,7 '(6 n,*$1'(1 ,67 '$6 h86,2163527(,1 ,1$.7,9P f(1.%$5 ,67 $8&+ (,1( m20%,1$7,21 '(5 m21752//( 921 e5( $8) 9(56&+,('(1(1 g%(1(1N 62/$1*( 0$1 ',( m20%,1$7,21 *(5,1*(5 d$6,6$.7,9,7>7 0,7 (,1(5 +2+(1 c.O 7,9,7>7 1$&+ k1'8.7,21 (55(,&+(1 .$11P p$&+7(,/,* ,67 +,(5%(, 185 '(5 (5+?+7( m5(8O =81*6$8):$1' %(, 81$%+>1*,* ,0 i(120 326,7,21,(57(1 5(*8/$725,6&+(1 g/(0(17(1P f(5=(,7 %(71'(1 6,&+ 62/&+( m21=(37( ,1 '(5 r+$6( '(5 7(&+1,6&+(1 g17:,&./81* 81' q37,0,(581*N (567( g;3(5,0(17( :85'(1 ,1 o>86(1 817(51200(1P c1:(1'81O *(1 ,0 %,20(',=,1,6&+(1 d(5(,&+ =85 g567(//81* 921 o$8602'(//(1 )@5 0(16&+/,&+( m5$1.+(,7(1 %$6,(5(1' $8) (,1(5 ,1'8=,(5%$5(1 g,1)@+581* '(5 o87$7,21 :(5'(1 9,(//(,&+7 %$/' 0?*/,&+ 6(,1P

This page intentionally blank

T g%2%$)4;2% d2+2!.+5.'%.

TMP j2!.+(%)4%. -)4 l%.$%,3#(%- u%2%2"5.'3-/$53 f$6 m21=(37 '(6 i(16 $/6 g,1+(,7 '(5 *(1(7,6&+(1 k1)250$7,21 *(+7 $8) ',( SZXX 9(5?5(17/,&+7(1 x(568&+( 921 i5(*25 o(1'(/ $1 g5%6(1 =85@&.P f,( d('(8781* ',(6(6 m21=(37(6 )@5 g5.5$1.81*(1 '(6 o(16&+(1 :85'( (567 6(+5 9,(/ 63>7(5 (5O .$117P |:(, *581'6>7=/,&+( x(5(5%81*602', .?11(1 817(56&+,('(1 :(5'(1 Jc%%P WPSKP d(,0 '20,1$17(1 g5%*$1* (5.5$1.(1 67$7,67,6&+ *(6(+(1 WR@ '(5 p$&+O .200(1 '(6 (5.5$1.7(1 o(5.0$/675>*(56P f,(6 .$11 '$5$1 /,(*(1N '$M JSK ',( c.O

autosomal rezessiv

autosomal dominant

X-chromosomal rezessiv

c%%P WPS u7$00%>80( o(1'(/6&+(5 x(5(5%81*60867(5P x2//67>1',* *()@//7( u<0%2/( (17O 635(&+(1 3+>127<3,6&+ $85>//,*(1 r(5621(1P j$/% *()@//7( u<0%2/( (17635(&+(1 3+>127<3,6&+ 81$85>//,*(1 r(5621(1N ',( *(127<3,6&+ -('2&+ %(575>*(5 '(5 -(:(,/,*(1 g5.5$1.81* 6,1' Jj(7(52=<*27(KP f,( +(//(1 u<0%2/( 67(+(1 )@5 3+>127<3,6&+ 81' *(127<3,6&+ 81$85>//,*( r(5621(1P d(,0 $872620$/ 5(=(66,9(1 g5%*$1* 75$*(1 ',( 3+>127<3,6&+ 81$85>//,*(1 g/7(51 $/6 %(5O 75>*(5 (,1 TW@,*(6 t,6,.2N (,1 3+>127<3,6&+ $85>//,*(6N *(127<3,6&+ +202=<*27(6 m,1' =8 %(.200(1P o,7 (,1(5 YW@,*(1 e+$1&( :(5'(1 ',( m,1'(5 -('2&+ 3+>127<3,6&+ 81$85>//,* 6(,1P d(,0 $872620$/ '20,1$17(1 g5%*$1* 6,1' %(, (,1(0 3+>127<3,6&+ %(7525(1(1N *(127<3,6&+ +(7(52=<*27(1 g/7(517(,/ 67$7,67,6&+ WR@ '(5 m,1'(5 3+>127<3,6&+ $85>//,* 81' *(127<3,6&+ :,('(580 +(7(52=<*27P f$6 i(6&+/(&+7 '(6 @%(575$*(1'(1 g/7(517(,/6 2'(5 '(5 m,1'(5 63,(/7 %(, ',(6(0 g5%*$1*N :,( $8&+ %(,0 $872620$/ 5(=(66,9(1 g5%*$1* .(,1( t2//( Jt$87(KP d(,0 zO&+5202620$/ 5(=(66,9(1 g5%*$1* @%(575>*7 ',( 3+>127<3,6&+ *(681'(N +(7(52=<*27( o877(5 '$6 %(7525(1( i(1 $1 WR@ ,+5(5 m,1'(5P u7$7,67,6&+ 6,1' WR@ ,+5(5 u?+1( *(127<3,6&+ +(0,=<*27 81' 3+>127<3,6&+ %(7525(1N :>+5(1' WR@ ,+5(5 v?&+7(5 :,('(580 +(7(52=<*27(N 3+>127<3,6&+ *(681'( m21'8.725,11(1 6,1'P

TWT

W j(5(',7>5( g5.5$1.81*(1

7,9,7>7 '(6 1250$/(1 c//(/6 48$17,7$7,9 1,&+7 $865(,&+7N '(1 c86)$// '(6 087,(57(1 c//(/6 =8 .203(16,(5(1 Jj$3/2,1685,=,(1=KN JTK '$6 087,(57( i(1352'8.7 ',( y,5O .81* '(6 1250$/(1N (7:$ '85&+ (,1( 3$7+2/2*,6&+( k17(5$.7,21N $8)+(%7 J'20,1$17 1(*$7,9(5 o(&+$1,6086K 2'(5 JUK '$6 9(5>1'(57( i(1 (,1( 1(8( 48$/,7$7,9( y,5.81* (17)$/7(7 J$.7,9,(5(1'( o87$7,21KP d(,0 5(=(66,9(1 x(5(5%81*602'86 6,1' ',( +(7(52=<*27(1 g/7(51 *(681'P f,( c.O 7,9,7>7 (,1(6 c//(/6 67(//7 620,7 ',( $865(,&+(1'( i(6$07$.7,9,7>7 '(6 n2&86 6,&+(5P y(11 -('2&+ %(,'( g/7(51 ,+5 087,(57(6 c//(/ $1 ',( p$&+.200(1 :(,7(5*(%(1N '85&+6&+1,77/,&+ %(, TW@ '(5 m,1'(5N 62 .2007 (6 =85 ./,1,6&+(1 o$1,)(67$7,21 '(6 n(,'(16P YW@ '(5 m,1'(5 6,1' 3+>127<3,6&+ 1,&+7 %(7525(1N :2%(, -('2&+ WR@ :,( ,+5( g/7(51 %(575>*(5 )@5 '$6 5(=(66,9( g5%/(,'(1 6,1'P l( 1$&+ &+5202620$/(5 n2.$/,6$7,21 817(56&+(,'(7 0$1 '$5@%(5 +,1$86 =:,6&+(1 $872620$/(1 81' zO&+5202620$/(1 x(5(5%81*60867(51P d(, '(1 zO&+5202620$/O 5(=(66,9 9(5(5%7(1 m5$1.+(,7(1 *(%(1 ',( +(7(52=<*27(1 m21'8.725,11(1 ',( 08O 7,(57( i(1.23,( $1 WR@ ,+5(5 p$&+.200(1 :(,7(5P f,( %(7525(1(1 o>'&+(1 6,1' '$11 :,( ',( o877(5 m21'8.725,11(1N :2+,1*(*(1 ',( m5$1.+(,7 6,&+ %(, '(1 %(O 7525(1(1 l81*(1 0$1,)(67,(57N '$ 6,( .(,1 :(,7(5(6 zOe+5202620 =85 m203(16$7,21 %(6,7=(1 Jj(0,=<*27,(KP x$5,$7,21(1 ,0 3+>127<3,6&+(1 c8635>*81*6*5$' 81' '(5 y$+56&+(,1/,&+.(,7 (,1(5 m5$1.+(,760$1,)(67$7,21 :(5'(1 817(5 '(1 d(*5,5(1 '(5 g;35(66,9,7>7 J*5$'8(// 817(56&+,('/,&+( c8635>*81* (,1(6 o(5.0$/6 2'(5 '(6 u&+:(5(*5$'(6 (,1(5 m5$1.+(,7K %=:P '(5 r(1(75$1= Jy$+56&+(,1/,&+.(,7 '(6 c8)O 75(7(16 0,1'(67(16 (,1(6 u<037206 ',(6(5 m5$1.+(,7K (5)$M7P k1 0$1&+(1 h>//(1 6,1' ',( 02/(.8/$5(1 o(&+$1,60(1 )@5 ',( 817(56&+,('/,&+(1 x(5(5%81*602', 81' )@5 ',( x$5,$7,21(1 ,0 ./,1,6&+(1 c8635>*81*6*5$' %(.$117P |80 (,1(1 .?11(1 817(56&+,('/,&+( o87$7,21(1 '(6 n2&86 6(/%67 2'(5 ',( c.7,9,7>7 921 :(,7(5(1 *(O 1(7,6&+(1 2'(5 (;2*(1(1 h$.725(1 '(1 m5$1.+(,769(5/$8) 02',7=,(5(1 J02',)<,1* )$&7256KP g,1,*( 02'(//+$)7( d(,63,(/( 62//(1 +,(5 (5/>87(57 :(5'(1P k1 '(5 :2+/ 92//67>1',*67(1 u$00/81* +(5(',7>5(5 m5$1.+(,7(1 '(6 o(16&+(1N '(0 921 o&m86,&. +(5$86*(*(%(1(1 m$7$/2* o(1'(/,$1 k1+(5,7$1&( ,1 o$1 6,1' ',( (7:$ UPRRR %(.$117(1 0212*21(1 g5.5$1.81*(1 =86$00(1*()$M7 81' )$67 SRPRRR i(1/2&, 0,7 0(+5 $/6 XRR $662=,,(57(1 0212*(1(1 m5$1.+(,7(1 5(*,675,(57P p(%(1 '(1 :(/7:(,7 6(+5 9(5%5(,7(7(1 j>02*/2%,123$7+,(1 6,1' ,1 p25':(67Og852O 3$ 817(5 '(1 0212*(1(1 g5%.5$1.+(,7(1 ',( h$0,/,>5( j<3(5&+2/(67(5,1>0,(N ',( j>02&+520$726( 81' ',( o8.29,6=,'26( %(621'(56 +>87*P o212*(1( g5%/(,'(1 0$&+(1 ,16*(6$07 $%(5 :(1,*(5 $/6 W@ $//(5 m5$1.+(,7(1 $86P h@5 '(1 c5=7 63,(/(1 ',(6( m5$1.+(,7(1 0(,67 $/6 6(/7(1( f,5(5(17,$/',$*126(1 +>87*(5 u<03720( (,1( t2//(P r5$.7,6&+ :,&+7,* 6,1' 925 $//(0 ',( %(+$1'(/%$5(1 m5$1.+(,7(1 ',(6(5 i583O 3(N ,16%(621'(5( :(11 %(, 9(563>7(7(5 f,$*126( 81' v+(5$3,( ,55(9(56,%/( u&+>'(1 =8 %()@5&+7(1 6,1'P f$5@%(5 +,1$86 ,67 '$6 x(567>1'1,6 '(5 0212*(1(1 g5.5$1.81O *(1 1$7@5/,&+ (,1 (567(5 u&+5,77 )@5 ',( g5)$6681* '(5 9,(/6&+,&+7,*(5(1 |86$00(1O +>1*( %(, '(1 +>87*(1 32/<*(1(1 %=:P .203/(;(1 m5$1.+(,76%,/'(51 $8) '(5 d$6,6 921 w0:(/7)$.725(1 81' 0(+5(5(1 i(1'()(.7(1P

WPS m5$1.+(,7(1 0,7 o(1'(/6&+(0 x(5(5%81*602'86

TWU

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Na+ Na-Kanäle Zellkern Transkription

Translation

mR

m oso Rib

A

AA

AA

Protein Transport an die Zellmembran

Cl –

PkA + cAMP

NA

P P PP

Golgi Apparat · Ausbildung der sekundär/Tertiärstruktur · Bindung an Chaperone

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Chromosom 11 5´

Â

GÁ

AÁ

„‚

Chromosom 16 ‰

‚

5´

˙

„˙ „· ·2 ·1 ı

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·2Â2

˙ 2Á 2

·2Á2

·2‰2

Hb Gower I

Hb Gower II

Hb Portland

HbF

HbA2

·2‚2 HbA

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· ‚

50 40 30 20 Â+˙

10

Á ‰ 4

8 12 16 20 24 28 32 36 4 pränatal (Wochen) Geburt

8 12 16 20 24 28 32 36 postnatal (Wochen)

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· ·2Á2 HbF F-Zell Selektion

‚ Präzipitation Dyserythropoiese Anämie

EPO

Transfusionen

Knochenmarkhyperplasie

Fe-Überladung

- Skelettdeformitäten - Folatmangel - erhöhter metabolischer Umsatz

- Cardiomyopathie - Leberzirrhose - endokrine Ausfälle

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TXR

W j(5(',7>5( g5.5$1.81*(1

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5kb LCR 4 5´

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WPS m5$1.+(,7(1 0,7 o(1'(/6&+(0 x(5(5%81*602'86

TXS

v$%P WPU x(56&+,('(1( o87$7,21(1 %(',1*(1 (,1(1 817(56&+,('/,&+(1 i5$' '(5 i(1,1$.7,9,(581* 81' (,1(1 817(56&+,('/,&+(1 r+>127<3 t(67$.7,9,7>7

o87$7,2167<3 Jd(,63,(/(K

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r+>127<3 %(, +202=<*27(0 i(127<3

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v+$/$66$(0,$ 0$-25

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v+$/$66$(0,$ ,17(50(',$

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HMG CoA Reduktase LDL Rezeptor Lysosom Cholesterin

LDL H+

Coated Pit Endosom

ACAT Cholesterin Ester-Tröpfchen

Aminosäuren

Protein CholesterinEster

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5´– 3´– 3´–

Rekombination während der Meiose – 5´

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Rekombinationsprodukt 1 mit Trinukleotidexpansion n = 35

– 5´

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cf g;3$16,21 %(, 0$7(5O 1$/(5 v5$16O 0,66,21

evi ,1 '(5 UAOwvt

R

cf eci ,1 W^O -89(1,/(5 .2',(5(1'(5 v<3 81' u(48(1= g;3$16,21 1$&+ 3$7(5O 1$/(5v5$16O 0,66,21 %(, 3$7(5O 1$/(5v5$16O 0,66,21 0(,67 m2175$.7,21

R

R

R

R

h81.7,21 '(5 o87$17(

SUA VV %(, i(681'(1 XWAZV %(, g5O .5$1.7(1

NN*$,1 2) )81&7,21DD 2+1( %(.$117(1 o(&+$1,6O 086

SV ASX %(, i(681'(1 TSATY %(, g5O .5$1.7(1

NN*$,1 2) )81&7,21DD 2+1( %(.$117(1 o(&+$1,6O 086

YASY %(, i(681'(1 UZASUR %(, g5O .5$1.7(1

NN*$,1 2) )81&7,21DD 2+1( %(.$117(1 o(&+$1,6O 086

. [S %(, i(681'(1 SRY A/WRR %(, g5O .5$1.7(1 WAUW %(, i(681'(1 V[ AZW %(, g5O .5$1.7(1

%(6&+/(81,*O 7( c323726(

WPU f<1$0,6&+( o87$7,21(1

T[S

)@5 ',( c0,126>85( i/87$0,1 Ji/1KN 62 '$M ,0 r527(,1 (,1 r2/87*.(,7 921 (7:$ S \ SRPRRR 925.2007P f(5 ./,1,6&+( x(5/$8) ,67 '85&+ (,1( d(:(*81*68158+( JNNx(,767$1=DDKN '(1 x(5/867 ,17(//(.78(//(5 h>+,*.(,7(1 62:,( 9,(/)>/7,*( $1'(5( 1(852/2*,6&+( 81' 36<&+,$75,6&+( c85>//,*.(,7(1 &+$5$.7(O 5,6,(57N ',( 6,&+ 7<3,6&+(5:(,6( ,0 0,77/(5(1 n(%(16$/7(5 =8 0$1,)(67,(5(1 %(*,11(1 81' %(, /$1*6$0 352*5(',(17(0 x(5/$8) 1$&+ (7:$ SRATR l$+5(1 =80 v2'( )@+5(1P k1 6(/7(1(1 h>//(1 .$11 '(5 o$1,)(67$7,216=(,7381.7 -('2&+ %(5(,76 ,0 m,1'(6O 2'(5 (567 ,0 i5(,6(1$/7(5 /,(*(1P r$7+2+,672/2*,6&+ 71'(7 6,&+ (,1 /2.$/,6,(57(5 x(5/867 921 p(8521(1 ,0 i(+,51N 925 $//(0 ,1 '(1 d$6$/*$1*/,(1 81' ,0 u75,$780P f$6 %(7525(1( i(1 :85'( S[[U ,'(17,7=,(57N ,67 (7:$ SZR %,6 TRR .% *52M 81' %(67(+7 $86 XY g;216P f$6 UVZ .f r527(,1 :85'( j817,1*7,1 *(1$117 81' .2007 +$8376>&+/,&+ ,0 i(+,51 $%(5 $8&+ ,1 $1'(5(1 i(:(%(1 925P f,( h81.7,21 '(6 j817,1*7,16 ,67 1,&+7 %(.$117P f,( |(//=(567?581* :,5' %(, '(5 jf -('2&+ $8) (,1( c323726( 921 p(8521(1 ,0 pP &$8'$786 81' ,0 r87$0(1 =85@&.*()@+57P k0 W^O.2',(5(1'(1 d(5(,&+ '(6 j817,1*7,1*(16 71'(7 6,&+ (,1 eciOo,.526$7(//,7N '(5 %(, p250$/3(5621(1 $86 SR %,6 UW o2'8/(1 %(67(+7P d(, [Z@ $//(5 p250$/O 3(5621(1 %(75>*7 ',( o2'8/=$+/ . URP d(, r$7,(17(1 0,7 jf ,67 '(5 eciOo,.52O 6$7(//,7 0,7 (,1(5 o2'8/=$+/ 921 VR %,6 TWR (;3$1',(57 Jc%%P WPSVKP d(, '(1 6(/7(1(1 o2'8/=$+/(1 921 UXAU[ />M7 6,&+ :(*(1 '(5 8192//67>1',*(1 r(1(75$1= .(,1( 6,&+(5( c866$*( =85 m5$1.+(,760$1,)(67$7,21 0$&+(1 JNNi5$8=21(DDKP c% (,1(5 o2'8/=$+/

Expansionswahrscheinlichkeit

pathologische Funktion

Poly (A)

minimal

–

Poly (A)

hoch

+ (späte Manifestation und langsame Progredienz)

Poly (A)

hoch

++ (frühe Manifestation und rasche Progredienz)

(CAG)10-35

CAP

5´– UTR

kodierende Sequenz (CAG)\40

CAP

kodierende Sequenz (CAG)\100

CAP

kodierende Sequenz

c%%P WPSV u758.785 '(6 j817,1*7,1*(16 0,7 (,1(0 $86 JeciK1 v5,18./(27,'02'8/(1 %(67(O +(1'(1 o,.526$7(//,7(1 ,1 '(5 .2',(5(1'(1 t(*,21N '(5 )@5 (,1(1 817(56&+,('/,&+ /$1*(1 r2/127<3 Jo,77( 96P 817(1KP

T[T

W j(5(',7>5( g5.5$1.81*(1

921 VT 0$1,)(67,(57 6,&+ ',( g5.5$1.81* 0,7 SRR@,*(5 r(1(75$1= ,11(5+$/% '(5 1250$/(1 n(%(1663$11( Jc%%P WPSVKP f,( n>1*( ',(6(6 o,.526$7(//,7(1 .$11 ,0 t$+O 0(1 '(5 o(,26( 62:2+/ (;3$1',(5(1 $/6 $8&+ .2175$+,(5(1N :2%(, g;3$16,21(1 %(, '(5 y(,7(5*$%( '85&+ '(1 x$7(5 (5+(%/,&+ +>87*(5 $/6 %(, '(5 '85&+ ',( o877(5 6,1'P p(8087$7,21(1 (1767(+(1 $866&+/,(M/,&+ @%(5 ',( 9>7(5/,&+( n,1,(N :$6 ',( %(O 621'(5( k167$%,/,7>7 ',(6(6 fpcOu(*0(176 %(,0 o$11 %(/(*7P f,( w56$&+( )@5 ',(6( d(2%$&+781* ,67 81%(.$117N .255(/,(57 -('2&+ 0,7 '(5 0(,67 3$7(51$/(1 x(5(5%81* '(5 jf %(, -89(1,/(1 r$7,(17(1P f$5@%(5 +,1$86 %(67(+7 (,1( 67$5.( m255(/$7,21 =:,6&+(1 '(0 o$1,)(67$7,216$/7(5 %=:P '(5 i(6&+:,1',*.(,7 '(5 m5$1.+(,76352O *5(',(1= 81' '(5 n>1*( '(6 o,.526$7(//,7(1P o?*/,&+( r$7+2*(1(6( g6 ,67 1,&+7 6,&+(5 %(.$117 :,( '(5 9(5/>1*(57( r2/<*/87$0,175$.7 ,0 pO7(50,1$/(1 d(5(,&+ '(6 j817,1*7,16 =85 3$7+2/2*,6&+(1 h81.7,21 )@+57P g;3(5,0(17(//( j,1O :(,6( *,%7 (6 )@5 (,1( d(6&+/(81,*81* '(5 c323726( 1(8521$/(5 |(//(1N (,1( x(50,1O '(581* '(6 g1(5*,(6725:(&+6(/6 '85&+ d((,175>&+7,*81* '(5 h81.7,21 921 g1=<0(1 '(5 i/<.2/<6( 81' )@5 ',( d,/'81* 921 c0',.7,9( f,$*1267,. c/6 810,77(/%$5( 35$.7,6&+( h2/*( '(5 k'(17,7.$7,21 '(6 j817,1*7,1*(16 81' 6(,1(5 o87$7,21(1 %(, '(5 jf (5*$% 6,&+ ',( %,6 '$+,1 1,&+7 9(5)@*%$5( o?*/,&+.(,7 (,1(5 35>6<03720$7,6&+(1 f,$*1267,.P c86 ',(6(0 7(&+1,6&+(1 h2576&+5,77 (5*$% 6,&+ 02O '(//+$)7 (,1 =:$5 )@5 ',( o2/(.8/$50(',=,1 1,&+7 63(=,76&+(6N $%(5 $.87(5 $/6 %(, .219(17,21(//(1 o(7+2'(1 :$+5*(1200(1(6 ',$*1267,6&+(6 f,/(00$P d(, (17635(O &+(1'(5 t,6,.26,78$7,21 +$7 '(5 r52%$1' $ 35,25, (,1 WR@,*(6 t,6,.2N ,0 0,77/(5(1 n(%(16$/7(5 $1 '(5 jf =8 (5.5$1.(1P f85&+ ',( 02/(.8/$5*(1(7,6&+( f,$*1267,. .$11 (5 (,1( 62 *87 :,( SRR@,*( u,&+(5+(,7 ,1 ',( (,1( 2'(5 $1'(5( t,&+781* (5/$1*(1P p85 (5*,%7 6,&+ $8&+ %(, (,1(5 35>',.7,9(1 f,$*1267,. '(5=(,7 .(,1( 7+(5$3(87,6&+( q37,21P f,( f,$*1267,. :85'( '$+(5 921 c1)$1* $1 ,1 (,1 ,17(5',6=,3/,1>5(6 m21=(37 0,7 (,1*(+(1'(5 +80$1*(1(7,6&+(5N 1(852/2*,6&+(5 81' 36<&+27+(5$3(87,6&+(5 d(O 5$781* '85&+ 63(=,(// *(6&+8/7( }5=7( (,1*(%81'(1 81' (567 1$&+ g,1:,//,*81* '(6 80)$66(1' ,1)250,(57(1 r52%$1'(1 '85&+*()@+57P f,( 36<&+2/2*,6&+(1 h2/*(1 (,1(5 35>',.7,9(1 f,$*1267,. 6,1' ,0 g,1=(//)$// '(112&+ 6&+:(5 925+(5=86(+(1P c8&+ 1$&+ c866&+/8M (,1(5 f,6326,7,21 =85 jf .?11(1 %(,63,(/6:(,6( 3$5$'2; (56&+(,O 1(1'( f(35(66,21(1 %(2%$&+7(7 :(5'(1N ',( (,1(5 7+(5$3(87,6&+(1 k17(59(17,21 %(O '@5)(1P

TMRMQMQ e2!'),%3LwLGe2!LwH r9.$2/- !,3 a%)30)%, &=2 %).% KK,/33 /& &5.#4)/.AA l54!4)/. g6 *,%7 1(852'(*(1(5$7,9( 81' 1(852086.8/>5( g5.5$1.81*(1N %(, '(1(1 (;3$1O ',(57( v5,18./(27,'0,.526$7(//,7(1 ,1 '(1 1,&+7O.2',(5(1'(1 u(48(1=(1 '(5 %(752)O )(1(1 i(1( 925.200(1 81' '(1 %(7525(1(1 i(1/2.86 ,1$.7,9,(5(1 Jc%%P WPSW 81'

WPU f<1$0,6&+( o87$7,21(1 Expansionswahrscheinlichkeit

(CGG) 5-59

CAP

5´– UTR

Methylierung

T[U Funktion

kodierende Sequenz

Poly (A)

minimal

–

+

kodierende Sequenz

Poly (A)

hoch

–

+

kodierende Sequenz

Poly (A)

hoch

+

–

(CGG) 43-200

CAP

5´– UTR (CGG) > 200 MMMMMMMMM

CAP

5´– UTR

c%%P WPSW u758.785 '(6 )05SOi(16 0,7 (,1(0 $86 JeiiK1 v5,18./(27,'02'8/(1 %(67(+(1'(1 o,.526$7(//,7(1 ,1 '(5 W^O1,&+7O.2',(5(1'(1 t(*,21 JW^OwvtKP d(, (,1(5 o2'8/=$+/ 921 WAW[ ,67 ',( g;3$16,216:$+56&+(,1/,&+.(,7 0,1,0$/N ',( eeiOv5,18./(27,'( 6,1' 1,&+7 0(7+087$7,21P f$6 o(7+
v$%P WPSTKP v<3,6&+(5:(,6( +$1'(/7 (6 6,&+ +,(5 80 eiO5(,&+( v5,18./(27,'( :,( eii 2'(5 ieeP f$6 h5$Oz u<1'520 ,67 (,1 d(,63,(/ )@5 ',(6(1 o87$7,2167<3 g6 .2007 0,7 (,1(5 j>87*.(,7 921 81*()>+5 S \ TPRRR 0>11/,&+(1 81' 81*()>+5 S \ VPRRR :(,%O /,&+(1 k1',9,'8(1 925P e<72*(1(7,6&+ ,67 ',(6( g5.5$1.81* 0,7 (,1(5 d5@&+,*.(,7 '(6 e+52026206 ,1 '(5 t(*,21 z4TYPU $662=,,(57P f,( u<03720( %(, m1$%(1 81' o>11(51 %(67(+(1 $86 (,1(5 9$5,$%/(1 c8635>*81* 0(17$/(5 t(7$5',(581*N 9(56&+,(O '(1(1 f<60253+,(1 81' ,1 (,1(5 x(5*5?M(581* '(5 v(67(6 1$&+ '(5 r8%(57>7P g,1 c17(,/ :(,%/,&+(5 i(175>*(5 =(,*7 (,1( ./,1,6&+( v(,/0$1,)(67$7,21P f$6 h5$Oz u<1O '520 ,67 1$&+ '(5 v5,620,( TS ',( +>87*67( w56$&+( )@5 (,1( *(1(7,6&+ %(',1*7( *(,67,*( t(7$5',(581*P d(, c1$/<6(1 921 u7$00%>80(1 )>//7 (,1( p(,*81* ',(6(5 g5.5$1.81* =85 c17,O =,3$7,21 ,162)(51 $8)N $/6 '$M ',( y$+56&+(,1/,&+.(,7 '(5 c8635>*81* '(6 r+>127<36 921 i(1(5$7,21 =8 i(1(5$7,21 =81,007P c8M(5'(0 .2007 (6 =85 $86*(35>*7(1 o$1,)(67$7,21 185 %(, %(575$*81* '85&+ ',( o877(5P f$6 S[[S (5670$/6 %(6&+5,(O %(1( )05SOi(1 JNN)5$*,/(OzO0(17$/O5(7$5'$7,21DDK (17+>/7 ,1 6(,1(5 1,&+7 75$16/$7,(57(1 t(*,21 $0 W^Og1'( '(6 v5$16.5,37(6 JW^OwvtK (,1(1 eiiOv5,18./(27,'0,.526$7(/O /,7(1N '(5 %(, i(681'(1 $86 W %,6 W[ o2'8/(1 %(67(+7 Jc%%P WPSWKP c% (,1(5 o2O '8/=$+/ 921 VU %,6 WV :,5' '(5 o,.526$7(//,7 ,167$%,/N 62 '$M 925 $//(0 %(, '(5 y(,O 7(5*$%( @%(5 ',( 0@77(5/,&+( n,1,( (,1( (5+(%/,&+( g;3$16,21 '(5 v5,18./(27,'02'8/( (5)2/*(1 .$11P r+>127<3,6&+ 81$85>//,*( %(575>*(5 '(6 h5$Oz u<1'5206 :(,6(1

T[V

W j(5(',7>5( g5.5$1.81*(1

(,1( eiiOo2'8/=$+/ 921 VUATRR $8)P o$1 635,&+7 '$%(, 921 (,1(5 r5>087$7,21P k1 '(5 1>&+67(1 i(1(5$7,21 .$11 (6 =8 (,1(5 (;3/26,216$57,*(1 g;3$16,21 '(6 o,O .526$7(//,7(1 %,6 =8 0(+5(5(1 7$86(1' o2'8/(1 .200(1P k17(5(66$17 ,67N '$M ',( n>1*( '(6 o,.526$7(//,7(1N :,( %(, $//(1 $1'(5(1 g5.5$1.81*(1 0,7 f<1$0,6&+(1 o87$7,21(1N 6(+5 *87 0,7 '(0 ./,1,6&+(1 u&+:(5(*5$' .255(/,(57P f(5 ,1 c%%,/'81* WPSX *(=(,*7(1 02/(.8/$5(1 f,$*1267,. .2007 '(6+$/% (,1( (176&+(,'(1'( d('(8O 781* =8N '$ ',( &<72*(1(7,6&+( f,$*1267,. 1,&+7 $865(,&+(1' =89(5/>66,* ,67 81' ./,O 1,6&+ (,1( t(,+( 921 f,5(5(17,$/',$*126(1 =8 %(5@&.6,&+7,*(1 6,1'P f(5 o(&+$1,6086 '(5 k1$.7,9,(581* '(6 )05SOi(16 %(67(+7 ,1 '(5 j<3(50(7+127<3 .$11 ,1 g,1O =(/)>//(1 $8&+ '85&+ r81.7087$7,21(1 '(6 )05SOi(16 =867$1'( .200(1N ',( =8 .(,1(5 d5@&+,*.(,7 '(6 zOe+52026206 )@+5(1P f,(6 %(/(*7 (,1'(87,*N '$M ',( k1O $.7,9,(581* '(6 )05SOi(16 6(/%67 81' 1,&+7 ',( d5@&+,*.(,7 ,0 d(5(,&+ z4TYPU ',( (176&+(,'(1'( 3$7+2*(1(7,6&+( t2//( 63,(/7P f,(6 63,(*(/7 6,&+ $8&+ ,1 '(5 c57 '(5 c17,=,3$7,21 ,0 u7$00%$80 :,('(5P f,( g;35(66,9,7>7 '(5 g5.5$1.81* 817(56&+(,O '(7 6,&+ ,1 '(1 i(1(5$7,21(1 1,&+7N '$ ',( k1$.7,9,(581* '(6 )05SOi(16 (,1 NNc//(6O 2'(5Op,&+76DD g5(.7 =8 6(,1 6&+(,17P y2+/ $%(5 67(,*7 0,7 '(5 i(1(5$7,216=$+/ ',( y$+56&+(,1/,&+.(,7 '(5 k1$.7,9,(581* 81' '$0,7 ',( r(1(75$1=P f,(6 817(56&+(,'(7 ',( NN/266 2) )81&7,21DD 921 '(1 NN*$,1 2) )81&7,21DD o87$7,21(1N %(, '(1(1 0,7 '(5 i(1(5$7,216=$+/ ',( g;35(66,9,7>7N 'P +P '(5 u&+:(5(*5$' '(5 g5.5$1.81*N =81,007P }+1/,&+ :,( %(, '(5 e+25($ j817,1*721 63,(/7 (6 %(,0 h5$Oz u<1'520 (,1( *52M( t2//(N 2% ',( o87$7,21 921 '(5 o877(5 2'(5 920 x$7(5 :(,7(5*(*(%(1 :,5'P d(, '(5 y(,7(5*$%( '85&+ ',( o877(5 .$11 (,1( r5>087$7,21 '(6 )05SOi(16 %(, '(5 o(,26( (;3/26,216$57,* (;3$1',(5(1N 62 '$M 6,&+ ',( g5.5$1.81* %(, '(1 m,1'(51 81' ,16%(621'(5( %(, '(1 u?+1(1 0$1,)(67,(57P d(, '(5 y(,7(5*$%( (,1(5 r5>087$7,21 '85&+ '(1 x$7(5 $1 6(,1( v?&+7(5 (;3$1',(57 '(5 eiiO o,.526$7(//,7 ,1 '(5 t(*(/ 1,&+7 :(,7(5 J62*(1$117( NN121O75$160,77,1* 0$/(6DDN pvoKP k67 '(5 x$7(5 ./,1,6&+

c%% WPSX o2/(.8/$5*(1(7,6&+( f,$*1267,. '(6 h5$Oz u<1'5206P f$6 u&+(0$ =(,*7 ',( 7 i581'/$*( (,1(5 u287+(51 d/27Oc1$/<6( 0,77(/6 0(7+1*,*(5 g$*k fpcOu3$/O 781* 81' j<%5,',6,(581* 0,7 '(5 )05SOu21'( 3rTP p250$/(5:(,6( 71'(7 6,&+ %(, (,1(0 o$11 (,1 TNZ .% *52M(6 g$*kOj,1'kkk h5$*0(17P d(, v5>*(51 (,1(5 r5>087$7,21 JroK '(5 eii o,.526$7(//,7(1 ,67 ',(6(6 h5$*0(17 80 WRAWRR d$6(13$$5( 9(5*5?M(57P d(, h5$8(1 71'(7 6,&+ ,1)2/*( '(5 zOk1$.7,9,(581* (,1( S \ S x(57(,/81* 0(7+M7 6,&+ @%(5 U i(1(5$7,21(1 (,1( |8O 1$+0( '(5 h5$*0(17*5?M(1 $8)*581' '(5 eii v5,18./(27,'(;3$16,21 (5.(11(1P f,( i52MO 0877(5 JSK =(,*7 ',( %(,'(1 p250$/)5$*0(17(N :>+5(1' 6,&+ %(,0 i52M9$7(5 JTK (,1 u&+0,(5 /(,&+7 9(5*5?M(57(5 h5$*0(17( ,0 r5>087$7,216%(5(,&+ JroK 1$&+:(,6(1 />M7P d(, '(5 v2&+7(5 JUK +$7 '(5 w0)$1* '(5 r5>087$7,21 12&+ /(,&+7 =8*(1200(1N 2+1( '$M ',(6 c86:,5.81*(1 $8) '(1 r+>127<3 +>77(P f(5 g1.(/62+1 JWK =(,*7 (,1( x2//087$7,21 0,7 0(+5(5(1 @%(5 WNW .% 9(5*5?M(57(1 h5$*0(17(1 81' ,67 ./,1,6&+ %(7525(1P c8&+ 6(,1( u&+:(67(5 JVK =(,*7 h5$*0(17( ,0 x2//087$7,216%(5(,&+P c%+>1*,* 920 zOk1$.7,9,(581*6%(5(,&+ .$11 ',(6 $8&+ %(, (,1(0 o>'&+(1 3+>127<3,6&+( m216(48(1=(1 =(,*(1] ,1 ',(6(0 h$// :$5 ',( u&+:(67(5 (,1( ./,1,6&+ *(681'( %(575>*(5,1 '(6 h5$Oz u<1'5206P h$67 $//( r$7,(17(1 0,7 h5$Oz u<1'520 2'(5 %(575>*(5 ,0 x2//087$7,216%(5(,&+ =(,*(1 (,1 620$7,6&+(6 o26$,. %(67(+(1' $86 |(//(1 0,7 817(56&+,('/,&+ (;3$1',(57(1 v5,18./(27,'5(3($76 JVN WKP

WPU f<1$0,6&+( o87$7,21(1 fmr 1:

Hindlll

Eagl

T[W

Hindlll

CGGCCG

CGGn

männlich (normal)

pP2 CGGCCG

CGGn pP2

CMet.GGCCMet.G

weiblich (normal)

CGGn pP2

CMet.GGCCMet.G

CGG(n>200) pP2

Vollmutation

Vollmutation PM 5,2 Kb. (normal; methyliert)

PM

PM

2,8 Kb. (normal; unmethyliert) 1

2

3

4

5

T[X

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inaktiv

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Angelman-Syndrom \ 75% \ 20% \ 3%

Deletion der AS-Region paternale UPD Imprinting Zentrum I Aktivitätsverlust UBE 3 A Mutationen unbekannter Pathomechanismus

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2

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UMSMQ n.+/'%.% e53)/.302/4%).% UMSMQMP c)% "#2L!", q%+/-").!4)/. c/6 r52727<3 '(5 3$7+2/2*,6&+(1 c.7,9,(581* (,1(6 q1.2*(16 @%(5 (,1( i(1)86,21 *,/7 ',( %&5O$%/ t(.20%,1$7,21N ',( 1$&+)2/*(1' $86)@+5/,&+(5 '$5*(67(//7 :,5'P f,( &+521,6&+ 0<(/2,6&+( n(8.>0,( JeonK :$5 ',( (567( 0$/,*1( g5.5$1.81* '(6 o(1O 6&+(1N %(, '(5 (,1 63(=,76&+(5 e+5202620(1'()(.7 1$&+*(:,(6(1 :(5'(1 .2117(P w17(5 '(0 o,.526.23 (5.(117 0$1N '$M (,1 v(,/ '(6 /$1*(1 c506 921 e+5202620 TT =80 e+5202620 [ @%(5*(:(&+6(/7 ,67] ',(6( t(.20%,1$7,21 1(117 0$1 1$&+ ,+5(0 g17'(&.81*6257 r+,/$'(/3+,$ Jr+KOv5$16/2.$7,21P o2/(.8/$5*(1(7,6&+( c1$O /<6(1 =(,*7(1N '$M (6 6,&+ 80 (,1( 5(=,352.( v5$16/2.$7,21 +$1'(/7N '$ ,0 i(*(1=8* (,1 v(,/ 921 e+5202620 [ =80 9(5.@5=7(1 e+5202620 TTN '(0 r+Oe+5202620N 75$16)(5,(57 :,5'P f,( r+Ov5$16/2.$7,21 (17635,&+7 $8) 02/(.8/$5(0 p,9($8 (,1(5 t(.20%,1$7,21 '(6 $%/ i(16 921 e+5202620 [4UV 0,7 '(0 %&5 i(1 921 e+52O 02620 TT4SSN :2%(, ',( 5(/(9$17( %&5O$%/ h86,21 $8) '(0 r+Oe+5202620 67$77O 71'(7N :>+5(1' ',( 5(=,352.( $%/O%&5 t(.20%,1$7,21 $8) e+5202620 [41 .(,1( )81.7,21(//( d('(8781* %(6,7=7 Jc%%P XPUKP g,1( r+Ov5$16/2.$7,21 71'(7 6,&+ %(, [W@ $//(5 r$7,(17(1 0,7 eonN 0(,67(16 $/6 7<3,6&+( 7J[]TTKP w1*()>+5 SR@ '(5 r$7,(17(1 :(,6(1 &<72*(1(7,6&+( u21'(5)250(1 $8)N :2%(, :(,7(5( e+5202620(1 $0 t(.20O %,1$7,216352=(M %(7(,/,*7 6(,1 .?11(1 J.203/(;( v5$16/2.$7,21K 2'(5 $0 e+5202O 620 [ %=:P e+5202620 TT .(,1( 0,.526.23,6&+ 6,&+7%$5(1 x(5>1'(581*(1 $85$//(1 J9$5,$17( 2'(5 0$6.,(57( v5$16/2.$7,21KP c//( h250(1 '(5 r+Ov5$16/2.$7,21 6,1'

9q+

Chromosom 9

9q34

abl

Ph-Translokation

22q11

bcr abl

bcr Chromosom 22

22q–

(Ph)

c%%P XPU k0 t$+0(1 '(5 5(=,352.(1 r+Ov5$16/2.$7,21N 7J[]TTKJ4UV]4SSKN (1767(+7 '$6 %&5O$%/ q1.2*(1 $8) '(0 r+Oe+5202620P

USV

X q1.2/2*,6&+( m5$1.+(,7(1

$%(5 '85&+ ',( %&5O$%/ t(.20%,1$7,21 &+$5$.7(5,6,(57 81' 817(56&+(,'(1 6,&+ 1,&+7 ,0 m5$1.+(,769(5/$8)P g7:$ W@ '(5 eon r$7,(17(1 :(,6(1 .(,1( r+Ov5$16/2.$7,21 $8)P f,( r+O1(*$7,9( eon 80)$M7 (,1( +(7(52*(1( m5$1.+(,76*5833(] %(, (7:$ VR@ '(5 r$7,(17(1 71'(7 6,&+ 02/(.8/$5*(1(7,6&+ (,1( %&5O$%/ t(.20%,1$7,21N 81' ',(6( h>//( 817(56&+(,'(1 6,&+ ./,1,6&+ 1,&+7 921 (,1(5 r+O326,7,9(1 eonP f,( @%5,*(1 h>//( 5(35>6(17,(5(1 9(56&+,('(1( h250(1 0<(/2352/,)(5$7,9(5 g5.5$1.81*(1 0,7 (,1(5 ,16*(6$07 6&+/(&+7(5(1 r52*126(P f,( r+Ov5$16/2.$7,21 %=:P %&5O$%/ t(.20%,1$7,21 71'(7 6,&+ 1,&+7 185 %(, '(5 eonN 621'(51 $8&+ %(, UW@ '(5 $.87(1 /<03+$7,6&+(1 n(8.>0,(1 JcnnK ,0 g5O :$&+6(1(1$/7(5P g6 %(67(+7 (,1( %(,1$+( /,1($5( c/7(56$%+>1*,*.(,7P m,1'(5 0,7 cnn =(,*(1 185 =8 V@ ',(6(1 *(1(7,6&+(1 f()(.7N :>+5(1' %(, 0(+5 $/6 '(5 j>/)7( '(5 @%(5 XR->+5,*(1 cnn r$7,(17(1 (,1( %&5O$%/ t(.20%,1$7,21 925/,(*7P f(5 p$&+:(,6 (,1(5 %&5O$%/ h86,21 ,67 921 *52M(5 ./,1,6&+(5 d('(8781*N :(,/ (6 6,&+ 80 ',( %?6O $57,*67( cnnOh250 +$1'(/7N ',( 7527= ,17(16,9(5 e+(027+(5$3,( 81' g,16$7= '(5 m12&+(10$5.675$163/$17$7,21 (,1( 6(+5 6&+/(&+7( r52*126( $8):(,67P f,( 817(5O 6&+,('/,&+( h5(48(1= '(5 r+O326,7,9(1 cnn ,1 9(56&+,('(1(1 c/7(56678)(1 (5./>57 620,7 $8&+ =8 (,1(0 v(,/ ',( %(66(5(1 j(,/81*6&+$1&(1 921 m,1'(51 0,7 cnn JYRA ZR@K ,0 x(5*/(,&+ =8 g5:$&+6(1(1 JURAVR@KP f,( (;$.7( n$*( '(5 d58&+381.7( 9$5,,(57 921 r$7,(17 =8 r$7,(17 Jc%%P XPVKP k0 $%/Oi(1 675(8(1 ',( d5@&+( @%(5 (,1( *52M( f,67$1= 921 TRR .% ,0 (567(1 k17521P f$*(*(1 .21=(175,(5(1 6,&+ ',( d58&+(5(,*1,66( ,0 %&5Oi(1 ,1 T t(*,21(1N ',( $/6 oO%&5 J0$-25O%5($.32,17 &/867(5 5(*,21K 81' 0O%&5 J0,125O%&5K %(=(,&+1(7 :(5'(1P

e1

e2

e12 e16 b1 23 4 5

bcr 25kb

5,8kb M-bcr: CML, ALL

m-bcr: ALL

a1b

a1a

e23

a2 a3

a11

abl 200kb CML, ALL bcr-abl Transkripte b2 a2 8,5 kb

b3 a2

Fusionsproteine

P210 BCR-ABL

e1 a2 7 kb

P190 BCR-ABL

c%%P XPV f$6 t($55$1*(0(17 =:,6&+(1 %&5 81' $%/ )@+57 ,1 c%+>1*,*.(,7 921 '(5 d58&+O 381.7/$*( =8 817(56&+,('/,&+ *52M(1 h86,216352'8.7(1 %(, r$7,(17(1 0,7 eon 81' cnnP

XPV c.7,9,(581* 921 q1.2*(1(1

USW

j,(5 %(67(+7 (,1 w17(56&+,(' =:,6&+(1 eon 81' cnnP d(, 1$+(=8 $//(1 eon r$O 7,(17(1 75(7(1 ',( d5@&+( ,1 '(5 WNZ .% *52M(1 oO%&5 $8)N ',( W ./(,1( g;216 80)$M7N :>+5(1' %(, (7:$ YR@ '(5 r$7,(17(1 0,7 r+O326,7,9(5 cnn ',( d5@&+( ,0 UAOd(5(,&+ '(6 (567(1 %&5 k175216 /,(*(1N '(5 0O%&5P c%+>1*,* 921 '(5 d58&+381.7/2.$/,6$7,21 ,0 %&5Oi(1 (1767(+(1 %&5O$%/ v5$16.5,37( 921 ZNW .% 2'(5 Y .% 81' h86,2163527(,1( 921 TSR .f$ 2'(5 S[R .f$P c8&+ $/7(51$7,9( u3/(,M352'8.7( :(5'(1 %(2%$&+7(7P u2 .$11 (,1 fpcOt($55$1*(0(17 ,0 k17521%(5(,&+ =:,6&+(1 oO%&5 g;21 %U 81' %V $8) tpcOg%(1( =8 (,1(5 x(5.1@3)81* 921 %U 0,7 $%/ g;21 $T )@+5(1N $%(5 $/7(51$7,9 .?11(1 ',( %&5 g;216 %T 2'(5 62*$5 (S $8&+ ',5(.7 $1 g;21 $T *(63/(,M7 :(5'(1P g,1( ./,1,6&+( t(/(9$1= '(5 817(56&+,('/,&+(1 %&5O$%/ t(.20%,1$7,21(1 81' ,+5( u3/(,M9$5,$17(1 .2117( %,6+(5 1,&+7 @%(5=(8*(1' %(/(*7 :(5'(1P c0 d(,63,(/ '(5 %&5O$%/ t(.20%,1$7,21 />M7 6,&+ *87 '$6 c860$M '(5 '85&+ (,1( q1.2*(1$.7,9,(581* ,1'8=,(57(1 u7?581*(1 '(5 u,*1$/75$16'8.7,21 ,//8675,(5(1P w1O 7(56&+,('/,&+( t(*,21(1 %(,'(5 h86,2163$571(5 75$*(1 =85 0$/,*1(1 v5$16)250$7,21 %(, Jc%%P XPWKP g,1( :(6(17/,&+( m20321(17( %,/'(1 $0,127(50,1$/( detOf20>O 1(1P g,1( 921 ,+1(1 ,1'8=,(57 ',( d,/'81* 921 detOcdn v(75$0(5(1P j,(5%(, .2007 (6 =85 d,1'81* 921 detOu(48(1=(1 $1 ',( 62*(1$117( ujT JuteO+202O /2*1( 921 cdnN *()2/*7 921 (,1(5 '5$67,6&+(1 u7(,*(581* '(5 v<526,1.,O 1$6($.7,9,7>7 921 cdnP f,( ujTBujUOf20>1(1 63,(/(1 $8&+ (,1( :,&+7,*( t2//( %(, '(5 g5.(1181* 81' t(.587,(581* '(5 *52M(1 |$+/ 921 =(//8/>5(1 u8%675$7(1 '(5 detOcdn r527(,1.,1$6(P c8M(5'(0 $.7,9,(57 (,1( pO7(50,1$/( detOt(*,21 (,1( eO7(50,1$/( cdnOf20>1(N :(/&+( )@5 (,1( d,1'81* $1 hOc.7,1 625*7] ',( m21O 6(48(1= +,(5$86 ,67 (,1( m233/81* $1 '$6 e<726.(/(77N 62 '$M '(5 %(575,77 921 detOcdn ,1 '(1 |(//.(51 %/2&.,(57 :,5'N :>+5(1' cdn 1250$/(5:(,6( (,1( t2//( %(, '(5 |(//=<./86.21752//( 63,(/7P f,( $0,127(50,1$/( detOt(*,21 (50?*/,&+7 $%(5 1,&+7 185 (,1( d,1'81* $1 cdn 621'(51 $8&+ ',( k17(5$.7,21 0,7 (,1(5 *$1=(1 t(,+( :(,7(5(5 r527(,1( ',( (,1( ujTOf20>1( %(6,7=(1P x21 %(621'(5(0 k17(5(66( ,67 +,(5 '$6 c'$37(53527(,1 itdTN :(/&+(6 detOcdn @%(5 uqu 0,7 '(5 tcuOtchS 9(50,77(/7(1 u,*1$/.(77( 9(5.1@3)7 81' '$0,7 (,1(1 '(5 3520,1(17(67(1 u,*1$/75$16O '8.7,216:(*( '(5(*8/,(57 J6,(+( UP[PTK] (,1( x(5%,1'81* =85 tcuOtchS m$6.$'( :,5' =8'(0 @%(5 ',( cdnOujT f20>1( 81' ',( det u(5,1Ov+5(21,1.,1$6( +(5O *(67(//7P f$5@%(5+,1$86 :(5'(1 '85&+ detOcdn =:(, (66(17,(//( t(*8/$725(1 '(6 |(//=<./86N e<&/,1 fS 81' o{eN 3$7+2/2*,6&+ $.7,9,(57 J6,(+( m$3P UPXKN :>+5(1' ',( (%(1)$//6 =8 9(5=(,&+1(1'( k1'8.7,21 921 denT (,1( c323726( '(5 %(75(5(1'(1 n(8.>0,(=(//(1 9(5+,1'(57 J6,(+( m$3P UPZKP k16*(6$07 $.7,9,(57 ',( %&5O$%/ t(.20O %,1$7,21 $/62 i(1(N :(/&+( ',( |(//352/,)(5$7,21 67,08/,(5(1 81' '(1 |(//72' ,1+,%O ,(5(1P p2&+ *,/7 (6 $%(5N ',( 9,(/(1 g,1=(/%()81'( =8 (,1(0 (,1+(,7/,&+(1 d,/' =86$0O 0(1=86(7=(1 81' ',( u&+/@66(/'()(.7( =8 ,'(17,7=,(5(1N ',( '$11 $8&+ |,(/ 1(8(5 7+(5$3(87,6&+(5 u75$7(*,(1 6(,1 .?117(1P g;3(5,0(17(//( d(+$1'/81*6$16>7=( 80)$6O 6(1 '(5=(,7 c17,6(16(Oq/,*218./(27,'( %=:P t,%2=<0( *(*(1 %&5O$%/ u(48(1=(1 2'(5 $8&+ 1$&+*(6&+$/7(7( g5(.725(1 :,( 0<& J6,(+( m$3P ZPTKP c8&+ $1 '(5 g17:,&./81* (,1(5 *(*(1 '$6 detOcdn h86,2163527(,1 *(5,&+7(7(1 k00817+(5$3,( :,5' *($5O %(,7(7P g%(162 :,5' ',( y,5.6$0.(,7 921 6(/(.7,9(1 k1+,%,725(1 '(5 detOcdnOv1( @%(535@)7P

USX

X q1.2/2*,6&+( m5$1.+(,7(1 P145 ABL N

P160 BCR N

SH3 SH2

Oligomerisation Serin-Threoninkinase SH2-Bindung

m-bcr

Tyrosinkinase

Kernlokalisation

M-bcr

DNA-Bindung Aktin-Bindung C

C Fusion RAS-RAF1 Signalweg

Substratbindung Aktivierung weiterer Signalkaskaden

Bindung an das Cytoskelett

c%%P XPW f,( 1250$/(1 cdn 81' det r527(,1( (17+$/7(1 9(56&+,('(1( h81.7,216'20>1(1N ',( $1 '(5 f(5(*8/$7,21 921 u,*1$/75$16'8.7,216:(*(1 '85&+ '$6 %&5O$%/ q1.2*(1 %(7(,/,*7 6,1'P f,( pO7(50,1$/( t(*,21 921 det 80)$M7 (,1 q/,*20(5,6$7,216027,9N (,1( u(5,1Ov+5(2O 1,1.,1$6( 62:,( (,1( ujTOd,1'81*6'20>1(P p250$/( cdnOh81.7,21(1 ,0 |(//.(51 :(5'(1 '85&+ (,1 18./(>5(6 n2.$/,6$7,2166,*1$/ 81' (,1( fpcOd,1'81*6'20>1( 9(50,77(/7P k1)2/*( '(5 detOcdn t(.20%,1$7,21 .2007 (6 =85 d,/'81* 921 detOcdn v(75$0(5(1] det u(O 48(1=(1 $.7,9,(5(1 ',( hOc.7,1 d,1'81*6'20>1( 62:,( ',( v<526,1.,1$6( 921 cdn 81' )@+5(1 62 =8 (,1(5 h,;,(581* 921 detOcdn $0 e<726.(/(77 81' =85 k1'8.7,21 (,1(5 x,(/=$+/ 921 u,*1$/.$6.$'(1P y(,7(5( detOf20>1(1N '(5(1 d('(8781* )@5 ',( n(8.>0,((1767(+81* 81O %(.$117 ,67N :85'(1 ,0 u&+(0$ 1,&+7 $8)*()@+57P f,( r)(,/( 0$5.,(5(1 ',( n$*( '(5 d58&+O 381.75(*,21(1P

XPV c.7,9,(581* 921 q1.2*(1(1 1

2

3

4

5

6

USY

C

– 5 kb

c%%P XPX u287+(51 d/27Oc1$/<6( 921 6(&+6 r$7,(17(1 0,7 eon 81' (,1(0 *(681'(1 r52O %$1'(1 JeKP d(, '(1 r$7,(17(1 W 81' X :$5 &<72*(1(7,6&+ .(,1 r+Oe+5202620 1$&+:(,6%$5P f,( $86 '(1 n(8.>0,(=(//(1 ,62/,(57( fpc :85'( 0,7 '(0 g1=<0 d*/kk 9(5'$87 81' 0,7 (,1(5 u21'( $86 '(5 oO%&5 t(*,21 +<%5,',6,(57P p(%(1 '(0 m(,0%$+1)5$*0(17 921 W .% '(6 1250$/(1 e+52026206 TT 71'(7 6,&+ ,1 $//(1 r$7,(17(1 (,1 ,1',9,'8(//(6 o867(5 '(6 5($5O 5$1*,(57(1 %&5Oc//(/6P

f,$*1267,6&+( c63(.7( f,( %&5O$%/ t(.20%,1$7,21 .$11 '85&+ 9(56&+,('(1( v(&+1,.(1 $8) fpcON tpcO 81' r527(,1(%(1( 1$&+*(:,(6(1 :(5'(1P j,(5=8 *(+?5(1 ,16%(621'(5( ',( hkuj f,$O *1267,. $1 k17(53+$6(.(51(1 81' ',( u287+(51 d/27Oc1$/<6( Jc%%P XPXKP d(, '(5 +(87( +>87* %(187=7(1 tvOret f,$*1267,. $03/,7=,(57 0$1 1$&+ u<17+(6( (,1(5 &fpc ',( -(:(,/,*(1 h86,21675$16.5,37(N '$ $8) *(120,6&+(5 g%(1( ',( d58&+381.7( =8 :(,7 675(8(1 Jc%%P XPYKP f,(6( o(7+2'( ,67 =8'(0 6(+5 6(16,7,9 81' (,*1(7 6,&+ =85 %(535@)81* '(6 g5)2/*(6 (,1(5 e+(027+(5$3,(N m12&+(10$5.675$163/$17$7,21 2'(5 k17(5)(521%(+$1'/81*] 6,( 6(7=7 $//(5',1*6 $8&+ 675,.7( s8$/,7>7667$1'$5'6 =85 x(50(,'81* .217$0,1$7,216%(',1*7(5 )$/6&+O326,7,9(5 g5*(%1,66( 925$86 Jm$3P XPSRKP

UMSMQMQ !,,PLs2!.3,/+!4)/.%. "%) $%2 r;5',).'3,%5+;-)% c8) (,1,*( :(,7(5( c63(.7( 921 q1.2*(1)86,21(1 6(, 12&+ 0,7 '5(, d(,63,(/(1 +,1O *(:,(6(1P k0 i(*(16$7= =85 (;./86,9(1 t(.20%,1$7,21 921 %&5 0,7 $%/ (5*,%7 6,&+ )@5 '$6 $//SO i(1 J$8&+ 0// *(1$117K $8) e+5202620 SS4TU (,1( x,(/=$+/ 921 h8O 6,2163$571(51P $//S .2',(57 (,1 m(513527(,1N '$6 $1 fpc %,1'(7N ,+5( u758.785 02O '8/,(57 81' '$6 ,0 |86$00(163,(/ 0,7 $1'(5(1 18./(>5(1 h$.725(1 $/6 v5$16.5,3O 7,2165(*8/$725 )81*,(57P %(5 UR $//SOv5$16/2.$7,21(1 6,1' %(.$117 81' ',( +>87*O 67(1 :85'(1 %(5(,76 ./21,(57P f,( 0(,67(1 h86,2163$571(5 6,1' 817(5(,1$1'(5 1,&+7 9(5:$1'7P $//SOt($55$1*(0(176 71'(1 6,&+ %(, r$7,(17(1 0,7 $.87(5 /<03+$7,6&+(5 81' $.87(5 0<(/2,6&+(5 n(8.>0,( JconK 81' 6,1' 0,7 (,1(5 6&+/(&+7(1 r52*126(

USZ

X q1.2/2*,6&+( m5$1.+(,7(1 cDNA e1

– 271

a2

a3

271bp m-bcr

b1 – 395 – 320

b2

b3

a2

395/320bp M-bcr

a2 – 173

a3

a3 173bp abl

ALL

1

2

3

W

4

5

6

C

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UTR

X q1.2/2*,6&+( m5$1.+(,7(1 normal CoRK

RA

RAR RXR

CoRK

Transkription reprimiert

ATRA

ATRA

PLZF

PLZF

RAR RXR

PLZF-RAR· Fusion

PML

PML

RAR RXR

PML-RAR· Fusion

Transkription aktiviert

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UTT

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n-myc

Amplifikation

HSR

2

8

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DNA

RNA

1

2

3

4

1

2

3

4

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UTV

X q1.2/2*,6&+( m5$1.+(,7(1

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DNA-Bindung/Dimerisierung

Box 2

bHLH-LZ

N N

CACGTG

C MYC C MAX

Zielgen

Signalübertragung durch Regulatorproteine

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XPW h(+/5(*8/$7,21 '(5 c323726(

UTW

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UTX

X q1.2/2*,6&+( m5$1.+(,7(1 p 1 1 q

p 1

2 3

q 1 2

14

IgH CJDV

1 2

1 2 3

bcl-2 18

t(14; 18)(q32; q21)

IgH CJ/bcl -2 14q+

IgH DV 18q--

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XPX u7?581*(1

UTY

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UMWMR d2",)#(% +/,/2%+4!,% j!2:)./-% f$6 .2/25(.7$/( m$5=,120 ,67 (,1( '(5 +>87*67(1 m5(%6)250(1 ,1 f(876&+/$1'P l>+5/,&+ (5.5$1.(1 (7:$ WR RRR r(5621(1 $1 ',(6(0 v8025N 'P +P (7:$ W@ 816(5(5 d(9?/.(581* 6,1' ,0 n$8)( '(6 n(%(16 +,(5921 %(7525(1P o$1 *(+7 '$921 $86N '$M SRASW@ '(5 g5.5$1.81*(1 $8) (,1(5 *(1(7,6&+(1 f,6326,7,21 %(58+(1P f,( )$0,/,>5( $'(120$7?6( r2/<326,6 JhcrK 75,77 0,7 (,1(5 h5(48(1= 921 S $8) SRPRRR g,1:2+1(5 5(/$7,9 6(/7(1 $8) 81' :,5' )@5 (7:$ S@ $//(5 .2/25(.7$/(1 m$5O =,120( 9(5$17:257/,&+ *(0$&+7P f,(6( g5.5$1.81* ,67 '85&+ '$6 c8)75(7(1 7$86(1O '(5 r2/<3(1 ,0 *(6$07(1 f,&.'$50%(5(,&+ *(.(11=(,&+1(7 81' )@+57 2+1( &+,585O *,6&+( k17(59(17,21 ,1 1$+(=8 SRR@ '(5 h>//( 0(,67 ,0 9,(57(1 n(%(16-$+5=(+17 =8 (,1(0 m2/21.$5=,120P f,( hcr %(58+7 $8) (,1(0 f()(.7 '(6 $3&Oi(16 $8) e+52O 02620 W4TSP cre 625*7 ,1 m223(5$7,21 0,7 '(5 r527(,1.,1$6( i/<.2*(16<17+$O 6(.,1$6( Ut ,1 9(56&+,('(1(1 i(:(%(1 )@5 '(1 c%%$8 921 tOe$7(1,1P $3&O o87$7,21(1 9(5+,1'(51 ',( d,1'81* $1 tOe$7(1,1 81' 5(68/7,(5(1 62 ,1 '(5 tOe$O 7(1,1O9(50,77(/7(1 c.7,9,(581* '(5 v5$16.5,37,216)$.725(1 vehOnghN ',( @%(5 |,(/O *(1( :,( 0<& 81' &<& fS ',( |(//352/,)(5$7,21 67,08/,(5(1P c%+>1*,* 921 '(5 63(O =,76&+(1 $3&Oo87$7,21 %,/'(1 6,&+ 185 :(1,*( 2'(5 0(+5(5( 7$86(1' r2/<3(1N :2%(, '$6 t,6,.2 =85 0$/,*1(1 g17$5781* ',5(.7 0,7 '(5 r2/<3(1=$+/ .255(/,(57P g,1 5(/$7,9 0,/'(5 m5$1.+(,769(5/$8) (5*,%7 6,&+ )@5 o87$7,21(1 ,0 >8M(567(1 WAOd(5(,&+ 921 $3& J. e2'21 SWYK 81' %(, :(1,*(1 UA 921 e2'21 SW[R %(2%$&+7(7(1 o87$7,21(1P j,1*(*(1 :(5'(1 %(621'(56 6&+:(5( m5$1.+(,76%,/'(5 %(, r$7,(17(1 0,7 o87$7,21(1 ,1 e2'21 STWRASVXV J,16%(621'(5( e2'21 SUR[K %(2%$&+7(7 Jc%%P XPSYKP g7:$ UW@ '(5 hcr r$7,(17(1 =(,*(1 m(,0%$+1087$7,21(1 ,1 e2'21 SRXS 2'(5 e2'21 SUR[P k0 i(*(16$7= =8 '(1 i(1(1 %5&$S 81' %5&$TN ',( $866&+/,(M/,&+ %(, +(5(',7>5(1 o$00$.$5=,120(1 087,(57 6,1'N 63,(/(1 $3&Oo87$7,21(1 $8&+ (,1( :(6(17/,&+( t2//( %(, '(5 g17:,&./81* 6325$',6&+(5 m2/21.$5=,120(] 1(%(1 o87$7,21(1 ,1 e2O '21 SUR[ 75(7(1 +,(5 *(+>8)7 n>6,21(1 ,1 e2'21 SVWR $8)P g,1( %(, c6&+.(1$6,0 +>87*( JX@ ',(6(5 r238/$7,21K v B c v5$169(56,21 ,1 e2'21 SURYN JcKUvJcKV B JcKZ *(1(5,(57 (,1( o,.526$7(//,7(16(48(1= 921 Z c'(1,1(1N ',( $1)>//,* )@5 n(6(O )(+/(5 '(5 tpcOr2/<0(5$6( :>+5(1' '(5 v5$16.5,37,21 ,67P f,( '85&+ ',(6( o212O

UVR

X q1.2/2*,6&+( m5$1.+(,7(1 Desmoide CHRPE 1061

1309 1450

typische Polyposis attenuierte FAP

N

1

500

1000

1500

2000

2500

C 2843 AA

APC

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XPZ h$0,/,>5( v8025(5.5$1.81*(1

UVS

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T GTGT CACA

G T

MSH2 MSH6

MSH2 MSH3

MLH1

MLH1

PMS2

PMS2

G C

GTGT CACA

GCTG CGAC

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UVT

X q1.2/2*,6&+( m5$1.+(,7(1

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CACACACACACA(CA)nCACACA

Allel 2

CACACACA(CAn)CA

Elektrophoretische Auftrennung der PCR Produkte N

T

Allel 1 Allel 2

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XPZ h$0,/,>5( v8025(5.5$1.81*(1

UVU

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Keimbahnmutation

msh2/mlh1 apc

normales Kolonepithel somatische Mutation

apc

Hyperproliferation ‚-catenin

Adenom-Formen

k-ras

smad4 dcc

Karzinom

p53 smad2

Metastase

src

?

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UVV

X q1.2/2*,6&+( m5$1.+(,7(1

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XP[ m/21$/( t($55$1*(0(176 '(5 k0081*/2%8/,1 81' vO|(//Ot(=(3725 i(1(

UVW

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pluripotente Stammzelle

CD34

myeloische Stammzelle

lymphatische Stammzelle

TdT HLA-DR CD34

L AU

Prä-B All

B-ALL Burkitt L.

CLL B-NHL

Myeloblast

Monoblast

unreifer Thymocyt

Prä-PräB-Zelle

Megakaryoblast

PräB-Zelle

reife B-Zelle

Immunocyt

reife Thymocyten

Thrombocyten

Erythrocyten

Granulocyten

Makrophagen

frühe B-Zelle

Plasmazellen (Ig)

(HLA-DR) cytopl. IgH/L

Multiples Myelom

T-Zellen (TCRÁ /‰)

Cytotoxische T-Zellen (TCR· /‚

Helfer T-Zellen (TCR· /‚

Immunozytom (M. Waldenström)

HLA-DR HLA-DR HLA-DR TdT TdT CD19, CD22 CD19, CD22 CD19, CD22 HLA-DR HLA-DR (CD10) Oberfl. IgH/L cytopl. IgH/L CD19, CD22 CD19, CD22 Oberfl. Ig CD10 CD10 cytopl. Ì lgH

cALL

Pro-Erythroblast

ProThymocyt

ProB-Zelle

TdT HLA-DR CD34 CD19, CD22

Pro-B All

UVX X q1.2/2*,6&+( m5$1.+(,7(1

XP[ m/21$/( t($55$1*(0(176 '(5 k0081*/2%8/,1 81' vO|(//Ot(=(3725 i(1( BamHI

KeimbahnKonfiguration

c

BamHI d

Vκ e

f

12,0 kb

Jκ 12345

g

UVY BamHI

Cκ

Cκ-Sonde BamHI

BamHI 7,0 kb

Rearrangement (Vd J5) Vc

BamHI

Vd J5

BamHI

14,5 kb Rearrangement (Vf J2) Vc

Vd

Ve

Vf J2 J3 J4 J5

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10 5 10 4 103 10 2 10 1 10 0

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XPSR p$&+:(,6 6(+5 ./(,1(5 o(1*(1 0$/,*1(5 |(//(1

UWU

1 klinische Manifestation

10 –1 10 –2

CR

10 –3

M R D

10 –4 10 –5 10 –6 10 –7 10 –8

Heilung 0 RI KR

1

2 E

3

4 Jahre

Therapie

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=(//(1 12&+ 0(+5(5( o21$7( %,6 6,( '$11 *$1= 9(56&+:,1'(1P u&+/,(M/,&+ (;,67,(57 (,1( j2&+5,6,.2*5833( 921 (7:$ SW@ '(5 m,1'(5 0,7 cnnN %(, '(1(1 ',( n(8.>0,(O =(//(1=$+/ 185 .1$33 817(5 ',( p$&+:(,6*5(1=( 921 u7$1'$5'9(5)$+5(1 $%*(6(1.7 :,5' 81' $8) +2+(0 p,9($8 3(56,67,(57 2'(5 @%(5 0(+5(5( o21$7( (,1(1 67(7,*(1 y,('(5$167,(* =(,*7] ,1 ',(6(1 h>//(1 .2007 (6 )$67 ,00(5 =80 ./,1,6&+(1 t(=,',9P f,(6( 1(8(1 g5.(1171,66( :(5'(1 '(5=(,7 )@5 '(1 g17:85) ,1',9,'8$/,6,(57(5 v+(5$O 3,(.21=(37( 187=%$5 *(0$&+7P g,1 :(,7(5(6 o$5.(56<67(0 %,/'(1 ',( q1.2*(15(.20%,1$7,21(1 ,0 t$+0(1 &+5202620$/(5 f()(.7(] v$%P XPZ =(,*7 +>87*( t(.20%,1$7,21(1N :(/&+( %(, (7:$ VR@ '(5 r$7,(17(1 0,7 cnnN UR@ 0,7 con 81' [W@ 0,7 eon 1$&+:(,6%$5 6,1'P f$ 6,&+ ',(6(6 o$5.(56<67(0 $8) %,2/2*,6&+O*(1(7,6&+ '(71,(57( n(8.>0,(68%)25O 0(1 %(=,(+7N :,5' $8&+ 9(567>1'/,&+N '$M 6,&+ +,(5 ',( f$7(1 =80 t(0,66,21667$786 $8) retOp,9($8 -( 1$&+ m5$1.+(,76%,/' '(87/,&+ 817(56&+(,'(1P d(, r$7,(17(1 0,7 r+O326,7,9(5 cnn 71'(1 6,&+ 6(/%67 1$&+ g55(,&+(1 (,1(5 .203/(77(1 +>0$72/2*,O 6&+(1 t(0,66,21 (17635(&+(1' '(5 6(+5 +2+(1 t(=,',95$7( 0(,67 12&+ n(8.>0,(O =(//(1N :>+5(1' ',( ,17(16,9,(57(1 v+(5$3,(675$7(*,(1 %(, r$7,(17(1 0,7 $)VO$//S t(O .20%,1$7,21 j(,/81*(1 (5=,(/(1 .?11(1N ',( '$11 0,7 (,1(0 1(*$7,9(1 retOd()81' (,1+(5*(+(1P c8&+ %(, '(5 con =(,&+1(7 6,&+ (,1 ',5(5(1=,(57(6 d,/' $%P u2 .2007

Verknüpfungsregion

J‰1

Sonde

CTTGGGG · TG T T T T C AGGCCTTCCGGTGGGGGATA AAC T T GGG · ATAAC NNNNNNN PPP D‰2 NN NNNNNNNN J‰1 V‰1 D‰3

Sonde

3

2

1

10-1 10-2 10-3 10-4 10-5 10-6

Sonde: GTGTTTTCAGGCCTTCC

Sonde: CTACAGGAAGGTGGGTACTG

Sonde: ACTAGGACAACTTCCTACACTGG

D

C

Monate 1 3 6

681'(1 r52%$1'(1 JeK %(67,007 :,5'P k1 ',(6(0 h$// /,(*7 ',( g03O 71'/,&+.(,7 '(5 '5(, u21'(1 %(, -(:(,/6 (,1(5 n(8.>0,(=(//( 817(5 SRR RRR 1250$/(1 n<03+2&<7(1 JSR2WKP o$1 (5.(117 ',( 817(56&+,('O /,&+(1 o(1*(1 5(6,'8$/(5 d/$67(1 ,0 m12&+(10$5. '(5 '5(, r$7,(1O 7(1 ,1 '(1 o21$7(1 1$&+ g,1/(,781* '(5 e+(027+(5$3,(\ y>+5(1' 6,&+ %(, r$7,(17 S 6&+21 1$&+ 9,(5 y2&+(1 .(,1( n(8.>0,(=(//(1 0(+5 1$&+:(,6(1 /$66(1N 71'(7 6,&+ %(, r$7,(17 U =8 $//(1 w17(568&+81*6O =(,7381.7(1 12&+ (,1( %(75>&+7/,&+( o(1*( 5(6,'8$/(5 d/$67(1] %(, ',(6(0 r$7,(17(1 .$0 (6 =:(, o21$7( 63>7(5 =8 (,1(0 ./,1,6&+(1 t(=,',9P

CTTG · T GCC T C T TCCTTCCTAC AGGAAGG T GGGTACTGGGGGGT · ACACCGATAAC NNNNNNNNNNPP V‰1 NNNNNNNN D‰2 D‰3 PP J51

Sonde

CTTGGGGAACT · AGG AC AACTTCCTACACTGGGGG · ACACCGATAAAC PP NNNNN D‰2 V‰1 D‰3 J‰1

V‰1

3´

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3

2

1

5´

UWV X q1.2/2*,6&+( m5$1.+(,7(1

XPSR p$&+:(,6 6(+5 ./(,1(5 o(1*(1 0$/,*1(5 |(//(1

UWW

v$%P XPZ q1.2*(15(.20%,1$7,21 =80 p$&+:(,6 5(6,'8$/(5 n(8.>0,(=(//(1 n(8.>0,(

q1.2*(1(

e+5202620$/( c%(55$7,21

j>87*.(,7 J,16*(6$07 %(, cnnBconK

cnn

%&5O$%/

7J[]TTK

7(/O$0/S

7JST]TSK

3%;SO(T$ $)VO$//S

7JS]S[K 7JV]SSK

6,/O7$/S

'(/JS3UTK

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(72O$0/S 30/O5$5l 0<+SO&%)%

7JZ]TSK 7JSW]SYK ,19JSXK

$)[O$//S

7J[]SSK

TR @ oT [W @ oU SR @ oV SRR @ oVgq SW @ oVBoW

%&5O$%/

7J[]TTK

[W @

con

eon

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UWX

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v$%P XP[ c1*,2*(1(7,6&+( 81' $17,$1*,2*(1(7,6&+( h$.725(1 c1*,2*(1(6()$.725(1

c17,Oc1*,2*(1(6()$.725(1

c1*,2*(1,1 c1*,232(7,1 g3,'(50$/ *52:7+ )$&725 JgihKsBt h,%52%/$67 *52:7+ )$&725 JhihKsBt j(3$72&<7( *52:7+ )$&725 JjihK k1+,%,725 2) ',5(5(17,$7,21 Jl'K SBU k17(5/(8.,1 Z r/$7(/(7O'(5,9(' (1'27+(/,$/ &(// *52:7+ )$&725 v5$16)250,1* *52:7+ )$&725 JvihKsBt v8025 1(&526,6 )$&725 JvphKs x$6&8/$5 (1'27+(/,$/ *52:7+ )$&725

c1*,267$7,1 g1'267$7,1 h80$*,//,1 i(1,67(,1 k17(5)(521 sBt r/$7(/(7 )$&725 V v+$/,'20,' v+520%26321',1

UMPQ s%,/-%2!3%!+4)6)4;4 ). s5-/2:%,,%. v(/20(59(5.@5=81*(1 &+$5$.7(5,6,(5(1 (,1( :,&+7,*( m20321(17( '(6 c/7(581*6O 352=(66(6 921 |(//(1 81' k1',9,'8(1P m(,0=(//(1 2'(5 $8&+ u7$00=(//(1 '(5 j>O 0$7232(6( '@5)(1 ,1 ,+5(0 d(67$1' $%(5 1,&+7 925=(,7,* *()>+5'(7 :(5'(1P k1 ',(6(1 |(//3238/$7,21(1 :,5.7 '$6 g1=<0 v(/20(5$6( '(0 x(5/867 7(50,1$/(5 fpcOu(O 48(1=(1 %(, '(5 fpc t(3/,.$7,21 (17*(*(1N ,1 '(0 (6 $1 '$6 UAOg1'( '(6 g/7(51O 675$1*(6 =86>7=/,&+( vvciiiOo27,9( $1.233(/7N 62 '$M ',( 1$&+)2/*(1'(1 fpcO x(5/867( ,0 v2&+7(5675$1* 1,&+7 ',( r5,0>5%(67$1'7(,/( '(5 e+5202620(1(1'(1 (5O )$66(1 Jm$3P UPXPSKP u20$7,6&+( |(//(1 %(6,7=(1 ,0 i(*(16$7= =8 m(,0=(//(1 1250$O /(5:(,6( .(,1( v(/20(5$6($.7,9,7>7] ,+5( v(,/81*6.$3$=,7>7 ,67 '(01$&+ %(*5(1=7P g,1( *(:,66( g;35(66,21N ',( '(1 c/7(581*6352=(M 352/21*,(57N 71'(7 6,&+ $%(5 ,1 63(=,76&+(1 |(//3238/$7,21(1 0,7 u7$00=(//&+$5$.7(5 :,( (7:$ +>0$7232(7,6&+(1 x25/>8)(5=(//(1N d$6$/=(//(1 '(5 g3,'(50,6 2'(5 |(//(1 '(5 352/,)(5$7,9(1 |21( ,1 ,17(67,1$/(1 m5<37(1 Jc%%P XPTYKP v8025=(//(1N ',( $/6 6(+5 5$6&+ 352/,)(5,(1'(6 i(:(%( -$ ,1 %(621'(5(0 o$M( 921 v(/20(59(5.@5=81*(1 81' '(0 '$5$86 5(68/7,(5(1'(1 |(//72' %('52+7 :>5(1N =(,*(1 (%(1)$//6 (,1( +2+( v(/20(5$6($.7,9,7>7P f,(6(5 r$7+20(&+$1,6086 63,(/7 ,1 '(5 m5(%6(17:,&./81* (,1( :(6(17/,&+( t2//( 81' :,5' ,1 ZW@ $//(5 o$/,*120( $1*(7525(1P o(,67 :(,6(1 v8025=(//(1 ,1 '(5 k1,7,$/3+$6( (,1( *(:,66( x(5.@5=81* '(5 v(/20(5( $8)N %,6 ',( v(/20(5$6( 92//( c.7,9,7>7 (17)$/7(7 81' ',( g1'(1 $85@//7 Jc%%P XPTYKP |8 '(1 k1'8.725(1 '(5 v(/20(5$6( =>+/7 (7:$ '$6 q1.2*(1 0<&P d(, W@ '(5 v8025( +$7 0$1 (,1( .2167$17( v(/20(5/>1*( 2+1( %(*/(,7(1'( v(/20(5$O 6($.7,9,7>7 %(2%$&+7(7] ',(6 :(,67 $8) (,1(1 v(/20(5$6(O81$%+>1*,*(1 o(&+$1,6086 '(5 v(/20(59(5/>1*(581* +,1P f,(6( g5.(1171,66( .?117(1 @%(5 ',( g17:,&./81* 921 v(/20(5$6(Ok1+,%,725(1 $8&+ 7+(5$3(87,6&+( k03/,.$7,21(1 +$%(1P f,( 6<67(0,6&+( i$%( '(5$57,*(5 r+$5O 0$.$ :@5'( $%(5 (9(178(// @%(5 ',( g/,0,1$7,21 v(/20(5$6(O326,7,9(5 u7$00=(//(1 $8&+ =8 '5$67,6&+(1 p(%(1:,5.81*(1 )@+5(1P k1 ',(6(0 |86$00(1+$1* 6,1' (567(

UWZ

X q1.2/2*,6&+( m5$1.+(,7(1 Telomer

somatische Zelle

Centromer Zelltod Telomer Keimzelle Telomerase

Telomerase

Krebszelle Telomerase

c%%P XPTY k1 620$7,6&+(1 |(//(1 )@+57 '(5 67(7,*( x(5/867 921 v(/20(56(48(1=(1 :>+5(1' '(5 fpcOt(3/,.$7,21 =85 i(120,167$%,/,7>7 81' =80 |(//72'P k1 m(,0=(//(1 625*7 ',( v(O /20(5$6( )@5 (,1( .2167$17( n>1*( '(6 v(/20(5%(5(,&+(6P k1 '(1 0(,67(1 v8025=(//(1 .2007 (6 @%(5 (,1( 3$7+2/2*,6&+( c.7,9,(581* '(5 v(/20(5$6( =85 v(/20(59(5/>1*(581*P

d(2%$&+781*(1 $1 o>86(1 ,17(5(66$17N '(5(1 .$7$/<7,6&+( v(/20(5$6('20>1( '85&+ .12&.O287 '(6 7(57Oi(16 *(=,(/7 $86*(6&+$/7(7 :85'(P f,(6( o>86( 6,1' =81>&+67 /(%(16)>+,* 81' )(57,/P c8&+ v8025( .?11(1 (1767(+(1] ',(6 =(,*7N '$M ',( v(/20(O 5$6($.7,9,7>7 .(,1( &21',7,2 6,1( 48$ 121 '(5 m5(%6(17:,&./81* '$567(//7P g567 63>7(5( p$&+.200(1 JXP i(1(5$7,21K ',(6(5 o>86( =(,*(1 '$11 f()(.7( ,1 '(5 u3(50$72O *(1(6( 62:,( j>0$7232(6( 81' (17:,&.(/1 =81(+0(1' e+5202620(1$120$/,(1N 62 '$M 6,&+ '(5 ,00(5 67>5.(5( v(/20(59(5/867 ,1 :(,7(5(1 i(1(5$7,21(1 $/6 n(7$/O )$.725 (5:(,6(1 '@5)7(P f(112&+ /$66(1 6,&+ ',(6( f$7(1 1,&+7 810,77(/%$5 $8) '(1 o(16&+(1 @%(575$*(1P u2 %(6,7=(1 o>86( (7:$ =(+10$/ />1*(5( v(/20(5( $/6 o(1O 6&+(1N ,+5( 3+<6,2/2*,6&+( r85(5.$3$=,7>7 %,6 =80 c8)75(7(1 921 h81.7,2169(5/8O 67(1 ,67 $/62 *5?M(5P c8&+ .?117( ',( 6(+5 9,(/ />1*(5( n(%(16=(,7 '(6 o(16&+(1 0,7 ./,1,6&+(1 o$1,)(67$7,21(1 9(5%81'(1 6(,1N ',( %(, o>86(1 1,&+7 %(2%$&+7(7 :(5'(1P g6 .2007 +,1=8N '$M '(5 c86)$// '(5 v(/20(5$6( ,1 '(1 .12&.O287Oo>86(1 '85&+ 12&+ 81=85(,&+(1' &+$5$.7(5,6,(57(N $/7(51$7,9( u&+87=0(&+$1,60(1 *(*(1 v(/20(59(5.@5=81*(1 .203(16,(57 :(5'(1 .?117(P c1'(5(56(,76 :>5( (6 92567(//%$5N '$M '(5 g,16$7= 921 v(/20(5$6(Ok1+,%,725(1 (,1 %5(,7(5(6 p(%(1:,5.81*663(.7580 =(,*7 $/6 ',( *(=,(/7( c866&+$/781* '(6 g1=<06P f(5 u7(//(1:(57 ',(6(5 1(8(1 i5833( 921 e+(027+(5$3(87,.$ %/(,%7 620,7 12&+ $%=8./>5(1P

V h.&%+4)/.3+2!.+(%)4%.

VMP l/,%+5,!2% a!+4%2)/,/')% VMPMP f%.%4)+ 6/. a!+4%2)%. c/6 d$.7(5,(1 %(=(,&+1(7 0$1 (,1=(//,*( o,.5225*$1,60(1N ',( 6,&+ ,1 0(+5)$&+(5 j,16,&+7 921 '(1 |(//(1 +?+(5(5 q5*$1,60(1 817(56&+(,'(1 Jv$%P YPSKN %(,63,(/6:(,6( '85&+ (,1( .203/(; $8)*(%$87( |(//:$1'N '$6 h(+/(1 921 |(//25*$1(//(1N 81' ',( x(50(+581* '85&+ |:(,7(,/81*P v$%P YPS g,*(16&+$)7(1 921 g8.$5<217(1 81' r52.$5<217(1 Jd$.7(5,(1K g,*(16&+$)7

r52.$5<217

g8.$5<217

m(510(0%5$1 e<723/$60$0(0%5$1 |(//:$1' 0,7 r(37,'2*/<.$1 |(//25*$1(//(1 x(50(+581* r/$60,'( |(//*5?M( i(120*5?M(

2 1 1 2 '85&+ |:(,7(,/81* 1 SA W ~0 S4SRNASRO %3

1 1 2 1 *(6&+/(&+7/,&+ 2 TRASRR ~0 S4SRQASRIH %3

VMPMPMP f%./-L 5.$ f%.2%'5,!4)/. "%) a!+4%2)%. f$6 i(120 921 d$.7(5,(1 Jr52.$5<217(1K ,67 1,&+7N :,( %(, '(5 (8.$5<217(1 |(//(N ,1 h250 (,1(6 0(0%5$1806&+/266(1(1 |(//.(516 25*$1,6,(57N 621'(51 /,(*7 )5(, ,0 |(//3/$60$ 925P f$6 i(120 '(5 d$.7(5,(1 :,5' $/6 m(51>48,9$/(17 %(=(,&+1(7P |8O 6>7=/,&+ =80 m(51>48,9$/(17 75$*(1 9,(/( d$.7(5,(1 (;75$&+5202620$/( fpc ,1 h250 5,1*)?50,*(5N '233(/675>1*,*(5 fpcOo2/(.@/(N ',( $/6 r/$60,'( %(=(,&+1(7 :(5'(1P g,1 i52M7(,/ '(6 %$.7(5,(//(1 i(1206 %(67(+7 $86 .2',(5(1'(1 u(48(1=(1P f,( 02/(.8/$5(1 o(&+$1,60(1 '(5 i(15(*8/$7,21 %(, d$.7(5,(1 .?11(1 )2/*(1'(5O 0$M(1 =86$00(1*()$M7 :(5'(1\ A u758.785*(1(N ',( )@5 ',( u<17+(6( 921 g1=<0(1 (,1(6 %(67,007(1 u725:(&+6(/O 6&+5,77(6 .2',(5(1N 6,1' +,17(5(,1$1'(5 $1*(25'1(7P d(*,11 81' g1'( (,1(6 '(5O

UXR

Y k1)(.7,216.5$1.+(,7(1 Operon

Repressor

Promotor (Transkriptionsstart) Operator RNA Polymerase

Gen 1

Gen 2

Terminator (TranskriptionsGen 3 stop)

Repressorprotein

+ Induktor

RNA Polymerase

c%%P YPS f$567(//81* '(5 i(15(*8/$7,21 $0 d(,63,(/ (,1(6 '85&+ (,1 t(35(66253527(,1 .21O 752//,(57(1 q3(5216P

$57,*(1 fpcOc%6&+1,77(6 :(5'(1 '85&+ &,6O5(*8/$725,6&+( m21752//6(48(1=(1 %(O *5(1=7N ',( ',( v5$16.5,37,21 .21752//,(5(1P f,(6( :(5'(1 $/6 q3(5$725 81' v(5O 0,1$725 %(=(,&+1(7P f,( *(6$07( h81.7,216(,1+(,7 :,5' q3(521 *(1$117 Jc%%P YPSKP A f,( c.7,9,7>7 (,1(6 q3(5216 :,5' 921 (,1(0 t(*8/$725*(1 *(67(8(57P f,(6(6 .2O ',(57 )@5 (,1 c.7,9$725O 2'(5 t(35(66253527(,1P t(35(6625 %=:P c.7,9$725 6,1' ,1 '(5 n$*(N 6,&+ $1 '(1 q3(5$725 $1=8+()7(1P f$'85&+ :,5' ',( tpcOr2/<0(5$6( %/2&.,(57 %=:P $.7,9,(57P A c86*$1*6352'8.7( (,1(6 u725:(&+6(/:(*(6 $.7,9,(5(1 '(1 c.7,9$725 %=:P ,1$.O 7,9,(5(1 '$6 t(35(66253527(,1P d(,63,(/6:(,6( 817(5/,(*7 '$6 n$.726(23(521 '(5 m21752//( '85&+ (,1 t(35(66253527(,1P f$6 u8%675$7 ,1$.7,9,(57 '(1 t(35(6625N :2'85&+ '$6 n$.726(23(521N :(/&+(6 )@5 68%675$7$%%$8(1'( g1=<0( .2',(57N $1O *(6&+$/7(7 :,5'P g1=<068%675$7(N ',( (,1 t(35(66253527(,1 ,1$.7,9,(5(1N :(5'(1 k1'8.725(1 *(1$117P g1'352'8.7( (,1(6 u725:(&+6(/:(*(6 $.7,9,(5(1 '(1 t(35(6O 625 %=:P ,1$.7,9,(5(1 '$6 c.7,9$7253527(,1P

VMPMPMQ t.4%23#()%$% :7)3#(%. d5+!29/.4%. 5.$ o2/+!29/.4%. j,16,&+7/,&+ '(5 w06(7=81* *(1(7,6&+(5 k1)250$7,21 (5*(%(1 6,&+ :(6(17/,&+( w1O 7(56&+,('( =:,6&+(1 g8.$5<217(1 81' r52.$5<217(1\ SP c8)*581' )(+/(1'(5 m203$57,0(17$/,6,(581* .?11(1 %(, d$.7(5,(1 v5$16.5,37,21 81' v5$16/$7,21 (,1(6 i(16 */(,&+=(,7,* $%/$8)(1] ',( 0tpcOu<17+(6( %(*,117 $0 W^Og1'(N '$6 k1,7,$7,216&2'21 %(71'(7 6,&+ (%(1)$//6 $0 W^Og1'(] v5$16.5,3O 7,21 81' v5$16/$7,21 9(5/$8)(1 ,1 ',( */(,&+( t,&+781*P

YPS o2/(.8/$5( d$.7(5,2/2*,( Transkriptionsstartpunkt

Ribosomenbindungsstelle

Ribosomenbindungsstelle

Ribosomenbindungsstelle

UXS

Transkriptionsterminationspunkt

Gen Gen 1

mRNA

Gen 2

Gen 3

AUG

UAA

GUG

UAG

AUG

UAG

AUG

UAA

GUG

UAG

AUG

UAG

UAA

GUG

UAG

AUG

UAG

5´

polygenische 3´ mRNA

Ribosomen AUG 5´

3´

polygenische mRNA

c%%P YPT c8)%$8 (,1(5 352.$5<27,6&+(1 0tpcP cwi 2'(5 iwi 5(3>6(17,(5(1 (,1(6 '(5 %(,'(1 k1,7,$7,216.2'216N wciN wic 81' wcc ',( 0?*/,&+(1 v5$16/$7,2166723.2'216P

TP r52.$5<217( 0tpc6 +$%(1 )$67 ,00(5 0(+5(5( m2',(581*65(*,21(1 J32/<*(1,O 6&+( 2'(5 32/<&,67521,6&+( 0tpcKP u,( 75$*(1 $/62 0(,67(16 ',( k1)250$7,21 =85 j(567(//81* 0(+5(5(5 r527(,1(P l('( (,1=(/1( m2',(581*65(*,21 ,67 $8) '(5 W^Ou(,7( (,1*(5$+07 921 (,1(5 t,%2620(1%,1'81*667(//( 62:,( '(0 v5$16/$7,216,1,7,$O 7,216&2'21N $8) '(5 U^Ou(,7( 921 (,1(0 v5$16/$7,2167(50,1$7,216&2'21 Jc%%P YPTKP f,( 32/<&,67521,6&+( p$785 %(',1*7 (,1( d(621'(5+(,7 %$.7(5,(//(5 o2/(.8/$5*(O 1(7,.N 62*(1$117( 32/$5( g5(.7(P f$5817(5 9(567(+7 0$1 ',( c86:,5.81* (,1(5 o87$7,21 ,0 r52027(5O1$+(1 v(,/ '(6 q3(5216 $8) ',( g;35(66,21 '(5 i(1( ,0 r52027(5O)(51(1 v(,/ '(6 q3(5216P f(5$57,*( o87$7,21(1 +$%(1 2)7 1,&+7 185 '(1 h81.7,2169(5/867 '(6 %(7525(1(1 i(16 =85 h2/*(N 621'(51 $8&+ '(1 '(5 1$&+O )2/*(1'N $8) '(0 q3(521 $1*(25'1(7(1 i(1(P g6 ,67 /(,&+7 9(567>1'/,&+N '$M o87$7,21(1 ,0 r52027(5 ',( g;35(66,21 '(6 *(6$07(1 q3(5216 %(75(5(1N :>+O 5(1' o87$7,21(1 ,1 u758.785*(1(1 .$80 32/$5( g5(.7( =(,*(1P UP tpcOu3/(,M352=(66( :(5'(1 %(, d$.7(5,(1 1,&+7 %(2%$&+7(7P

VMPMPMR o,!3-)$%K h.3%24)/.3%,%-%.4% 5.$ s2!.30/3/.3 r/$60,'( 6,1' =,5.8/>5(N 6,&+ $872120 9(50(+5(1'(N (;75$&+5202620$/(N '233(/O 675>1*,*( fpcOo2/(.@/(N '(5(1 i5?M( 81' c1=$+/ 6(+5 817(56&+,('/,&+ 6(,1 .$11 JS4SRK %,6 T4SRN d$6(13$$5(N T %,6 SRR m23,(1 352 d$.7(5,(1=(//(KP f,( *5?M(5(1 r/$60,'( 75$*(1 i(1(N ',( ,+5( %(575$*81* $8) $1'(5( d$.7(5,(1 (50?*/,&+(1P g,1 :(,7(5(6 e+$5$.7(5,67,.80 ,67 '$6 y,57663(.7580\ o$1&+( r/$60,'( .?11(1 185 =:,6&+(1 d$.7(5,(1 '(56(/%(1 2'(5 (,1(5 1$+( 9(5:$1'7(1 c57 @%(575$*(1 :(5'(1N $1'(5( .?11(1 =:,6&+(1 62 817(56&+,('/,&+(1 c57(1 :,( u7$3+
UXT

Y k1)(.7,216.5$1.+(,7(1

81$%+>1*,* 921 '(5 '(5 &+5202620$/(1 fpc] %(, '(5 |(//7(,/81* :(5'(1 ',( 925O +$1'(1(1 r/$60,'( 0(+5 2'(5 :(1,*(5 =8)>//,* $8) ',( v2&+7(5=(//(1 9(57(,/7P g,1( :(,7(5( i5833( 921 %(:(*/,&+(1 *(1(7,6&+(1 g/(0(17(1 :,5' $/6 k16(57,216O (/(0(17( %=:P v5$16326216 %(=(,&+1(7 Jc%%P YPUKP k16(57,216(/(0(17( 6,1' 02%,/( *(1(7,6&+( g/(0(17(N ',( ,+5(1 r/$7= ,0 i(120 >1'(51 .?11(1P k0 t$+0(1 '(5 v5$16326,7,21 :,5' (17:('(5 (,1( m23,( '(6 k16(57,216(/(0(17(6 $1 (,1(5 1(8(1 u7(//( ,1 ',( &+5202620$/( 2'(5 r/$60,'Ofpc ,16(5,(57N :2%(, '$6 85635@1*/,&+( k16(5O 7,216(/(0(17 $1 6(,1(0 r/$7= %/(,%7N 2'(5 '$6 k16(57,216(/(0(17 6(/%67 :(&+6(/7 '(1 r/$7= 81' +,17(5/>M7 (,1( f(/(7,21 $1 '(5 $/7(1 u7(//(P k16(57,216(/(0(17( :(5'(1 $1 '(1 g1'(1 +>87* '85&+ ,'(17,6&+(N ,1 '(5 u(48(1= *(*(1/>87*( p8./(27,')2/*(1 %(*5(1=7N ',( 62*(1$117(1 NN,19(57(' 5(3($76DDP f,(6( 5$+0(1 u(48(1=(1 (,1N ',( )@5 r527(,1( .2',(5(1N ',( )@5 '(1 r52=(M '(5 v5$16326,7,21 (5)25'(5/,&+ 6,1' Jv5$16O 326$6(N t(62/9$6(KP d(, '(5 v5$16326,7,21 +$1'(/7 (6 6,&+ 80 (,1( 1,&+7O+202/2*( t(.20%,1$7,21N 62 '$M ,'(17,6&+( k16(57,216(/(0(17( $1 9?//,* 817(56&+,('/,&+(1 u7(//(1 '(6 %$.7(5,(//(1 i(1206 ,17(*5,(5(1 .?11(1P v5$16326216 6,1' 35,1=,3,(// */(,&+$57,* $8)*(%$87 :,( k16(57,216(/(0(17(] =86>7=/,&+ =8 '(1 i(1(1 )@5 v5$16O 326,7,216)81.7,21(1 75$*(1 v5$16326216 -('2&+ 12&+ $1'(5( i(1(N %(,63,(/6:(,6(

IR

Pathogenitätsgen (Antibiotikaresistenz, Virulenzfaktor)

Mobilisationsgene (Resolvase, Transposase)

IR

ATTAT TAATA versetzter Schnitt im Wirtschromosom

TAATA

ATTAT

Transposon IR

IR

IR

IR

ATTAT TAATA IR

IR

TAATA

ATTAT

ATTAT TAATA

c%%P YPU u&+(0$7,6&+(5 c8)%$8 (,1(6 v5$16326216 81' o2'(// )@5 ',( k16(57,21 (,1(6 v5$16O 326216P i(:?+1/,&+ 6,1' ',( '$6 v5$1632621 9$1.,(5(1(1 u(48(1=(1 ,1 '(0 y,576&+5202620 ,'(17,6&+P ktN ,19(57(' 5(3($7P

YPS o2/(.8/$5( d$.7(5,2/2*,(

UXU

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Transformation +

freie DNA

DNA-Aufnahme

Bakterienzelle

rekombinierte Bakterienzelle nach Transformation

Transduktion

+

Aufnahme der Phagen-DNA

Bakteriophagen Bakterienzelle

Donorzelle (Plasmidhaltig)

c%%P YPV

Akzeptorzelle

Rekombination

rekombinierte Bakterienzelle nach Transduktion

Konjugation +

Rekombination

Kontakt über F+ Pili

konjugative Plasmid-Übertragung

Bakterienzelle nach Konjugation

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YPS o2/(.8/$5( d$.7(5,2/2*,( Extrazellularsubstanzen

UX[

Beispiele: • Kollagenasen • Hyaluronidasen • Steptokinasen • Fibrinolysin • Enterotoxine

S. pyogenes

Hyaluronidase Auflösung der extrazellulären Matrix Ausbreitung im Gewebe

Beispiele: • S. aureus ·-Toxin • C. perfringens ·-Toxin • Hämolysine • Leukozidine • Steptolysine

Zellmembran C. perfringens S. aureus ·-Toxin Phospholipase C Hydrolyse des Phosphorylcholins der Zellmembran

·-Toxin

Zellzerstörung Zellmembran

Bildung von Poren

Lyse

Beispiele: • Tetanustoxin • Botulismustoxin • Choleratoxin • Diphterietoxin • Enterotoxine

Intrazellulär wirkende Toxine

C. diphtheriae

C. botulinum C. diphtheriae Toxin Zellmembran

Zelluntergang

Inaktivierung des Elongationsfaktors 2

c%%P YPW

Zelluntergang

Acetylcholin enthaltende Vesikel motorische Endplatte

Toxin

Muskelfaser

Blockade der Proteinsynthese

u&+(0$7,6&+( y,5.0(&+$1,60(1 921 v2;,1(1P

Toxin blockiert die Freisetzung von Acetylcholin

Muskellähmung

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Kultur

Extraktion von Nukleinsäuren

Amplifikation eines 16S rRNA Genfragments

Sequenzanalyse

Computergestützte Analyse; Abgleich der Sequenz mit der Datenbank

Identifizierung

c%%P YPX u&+(0$ '(5 u(48(1=,(581* retO$03/,7=,(57(5 SXu 5tpc i(1)5$*0(17( =85 k'(1O 7,7=,(581* 921 o,.5225*$1,60(1P

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Transpeptidase-Domäne Penicillin bindendes Protein 2B Tschechoslowakei

(1987)

Südafrika

(1978)

Vereinigte Staaten

(1983)

Spanien

(1984)

Kenia

(1992)

Papua Neu-Guinea

(1970)

= Streptococcus pneumoniae

= unbekannte Streptokokkenart

= unbekannte Streptokokkenart

= Streptococcus mitis

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Bindung an den zellulären Rezeptor Eintritt in die Zelle Freisetzung des viralen Genoms Replikation des Genoms

Synthese der viralen Proteine (nicht umhüllte Viren) Freisetzung durch Lyse

Zusammenbau von Viruspartikeln (umhüllte Viren)

Freisetzung durch Knospung

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f,( p27:(1',*.(,7 =85 j(567(//81* 921 0tpc6N ',( '(5 =(//8/>5( r527(,16<17+(O 6($33$5$7 75$16/$7,(5(1 .$11N %(',1*7 63(=,76&+( g5)25'(51,66( )@5 '$6 x,586P f$ ',( =(//8/>5( 0tpcOu<17+(6( '85&+ v5$16.5,37,21 81' $16&+/,(M(1'( o2',7.$7,21 ,0 |(//.(51 67$7771'(7N +$7 ',( |(//( .(,1( g1=<0( =85 v5$16.5,37,21 921 9,5$/(1 tpcO 2'(5 fpcOi(120(1 ,0 |<723/$60$P f(0(17635(&+(1' .?11(1 185 fpcO x,5(1N ',( ,0 |(//.(51 5(3/,=,(5(1 81' *((,*1(7( v5$16.5,37,2166,*1$/( 75$*(1N '(1 =(//8/>5(1 v5$16.5,37,216$33$5$7 $86187=(1] $//( $1'(5(1 x,5(1 08M7(1 (,*(1( g1O =<0( =85 j(567(//81* 921 0tpc (17:,&.(/1P c8M(5'(0 ,67 ',( (8.$5<217( r527(O ,16<17+(6( $8) ',( v5$16/$7,21 0212&,67521,6&+(5 tpc %(6&+5>1.7N :$6 $1*(6,&+76 '(5 *(5,1*(1 i(120*5?M( %(, */(,&+=(,7,*(0 d('$5) )@5 =$+/5(,&+( 817(56&+,('/,&+( 9,5$/( r527(,1( (,1 r52%/(0 )@5 ',( x,5865(3/,.$7,21 '$567(//7P x,5(1 +$%(1 '(6+$/% %(621'(5( u75$7(*,(1 (17:,&.(/7N 80 817(56&+,('/,&+( 0tpc6 921 (,1(0 i(120 =8 6<17+(7,6,(5(1N 2'(5 '85&+ ',5(5(17,(//(6 81' 7(,/:(,6( ,1(5,=,(17(6 u3/(,M(1 %=:P '85&+ g',7,(5(1 (,1(6 r5,0>575$16.5,37(6 817(56&+,('/,&+( 0tpc6 +(5=867(//(1P o$1&+( 0tpc6 .?11(1 '85&+ y(&+6(/ '(6 75$16/$7,21$/(1 n(6(5$+0(16 2'(5 '85&+ ,17(51( k1,7,$7,21 2'(5 t(,1,7,$7,21 '(5 v5$16/$7,21 817(56&+,('/,&+ *(187=7 :(5'(1P c8M(5'(0 :,5' (,1( x,(/=$+/ 9,5$/(5 r527(,1( 921 (,1(5 0tpc $/6 62*(O 1$117(6 r2/<3527(,1 6<17+(7,6,(57 81' 63>7(5 '85&+ 9,5$/( 81' =(//8/>5( r527($6(1 ,1 ',( )81.7,21(//(1 d(67$1'7(,/( *(63$/7(1P f,( d('(8781* '(5 j(567(//81* )81.O 7,21(// 0212&,67521,6&+(5 0tpc6 0,7 (5:(,7(57(5 .2',(5(1'(5 m$3$=,7>7 .$11 /(,&+7 $1 '(5 v$76$&+( $%*(/(6(1 :(5'(1N '$M $//( x,5(1 0,7 ./(,1(5 i(120*5?M( (,1( 2'(5 0(+5(5( '(5 *(1$117(1 u75$7(*,(1 )@5 ,+5( i(1(;35(66,21 187=(1P g5,=,(17( x,5869(50(+581* (5)25'(57 ',( 5$6&+( r52'8.7,21 *52M(5 o(1*(1 '(5 9,5$/(1 r527(,1(P f$+(5 +$%(1 9,(/( x,5(1 u75$7(*,(1 (17:,&.(/7N ',( ',( %(925=8*7( v5$16/$7,21 9,5$/(5 0tpc 2'(5 '$6 .203/(77( 2'(5 7(,/:(,6( c%6&+$/7(1 '(5 v5$16O /$7,21 2'(5 r52'8.7,21 =(//8/>5(5 0tpc %(:,5.(1P f,( %((,1'58&.(1'( x,(/)$/7 '(5 *(:>+/7(1 u75$7(*,(1 +$7 9,(/( :,&+7,*( d(,75>*( =80 x(567>1'1,6 '(5 =(//8/>5(1 o(&+$1,60(1 921 0tpcOv5$16.5,37,21N r52=(66,(581*N v5$163257 81' v5$16/$7,21 *(/,()(57P c8) i581' ,+5(5 g5,=,(1= %,/'(1 9,5$/( g/(0(17( ',( i581'/$*( 81' x25O $866(7=81* $//(5 ,1 '(5 d,27(&+12/2*,( 9(5:(1'(7(1 g;35(66,2166<67(0(N 81' (6 %(O 67(+7 .(,1 |:(,)(/N '$M ',( c'$37$7,21 9(56&+,('(1(5 x,586$57(1 $1 ,+5( 3$5$6,7>5( %(5/(%(16)250 81' '(5 g5)2/* '(5 '$%(, (92/9,(57(1 u75$7(*,(1 '$6 h81'$0(17 '(5 %,27(&+12/2*,6&+(1 g17:,&./81* '$567(//7P p$&+ ',(6(5 g,1)@+581* ,1 $//*(0(,1( c63(.7( '(5 02/(.8/$5(1 x,52/2*,( 62// ,0 )2/*(1'(1 ',( 0(',=,1,6&+ 81' %,27(&+12/2*,6&+ %(621'(56 :,&+7,*( h$0,/,( '(5 t(O 7529,5(1 81' '$%(, ,16%(621'(5( '$6 +80$1( k0081'(7=,(1=9,586N '(5 g55(*(5 921 ckfuN $86)@+5/,&+(5 %(6&+5,(%(1 :(5'(1P c1 ',(6(0 d(,63,(/ 62// (5./>57 :(5'(1N :,( o(7+2'(1 '(5 02/(.8/$5(1 o(',=,1 =80 x(567>1'1,6 '(6 k1)(.7,216$%/$8)6N =85 f,$*126(67(//81* 81' =85 g17:,&./81* 921 v+(5$3(87,.$ %(,*(75$*(1 +$%(1 81' :(/&+( c16>7=( 81' r52%/(0( )@5 ',( k03)6725(17:,&./81* 6,&+ '$5$86 (5*(%(1P

VMQMQ q%42/6)2%. f,( h$0,/,( '(5 t(7529,5(1 80)$M7 (,1( *52M( i5833( 80+@//7(5 tpcOx,5(1P f(5 )81'$0(17$/( w17(56&+,(' =:,6&+(1 t(7529,5(1 81' $1'(5(1 x,586)$0,/,(1 81' '$6 '(71,(5(1'( e+$5$.7(5,67,.80 ',(6(5 h$0,/,( %(67(+7 ,1 '(5 t(3/,.$7,216:(,6( ,+5(6

YPT o2/(.8/$5( x,52/2*,(

UZ[

i(1206\ f,(6( (5)2/*7 @%(5 5(9(56( v5$16.5,37,21 '(6 tpcOi(1206 ,1 (,1( /,1($5( '233(/675>1*,*( fpcN :(/&+( $16&+/,(M(1' ,1 '$6 =(//8/>5( i(120 ,17(*5,(57 :,5'P f$0,7 ,67 %(, '(1 t(7529,5(1 '(5 85635@1*/,&+ $/6 =(175$/(6 f2*0$ '(5 i(1(;35(6O 6,21 $1*(6(+(1( k1)250$7,21698M 921 fpc =8 tpc =8 r527(,1 3$57,(// 80*(.(+57P f,( g17'(&.81* ',(6(5 w0.(+581* 81' '(6 )@5 ',(6(1 u&+5,77 9(5$17:257/,&+(1 g1O =<06N '(5 t(9(56(1 v5$16.5,37$6( %('(87(7( (,1( t(92/87,21 '(5 02/(.8/$5%,2/2O *,6&+(1 x2567(//81*(1P t(9(56( v5$16.5,37,21 .2007 $8&+ %(, (,1(5 t(,+( $1'(5(5 x,5(1 81' 1,&+7 9,5$/(5 g/(0(17( 925P p(%(1 ,+5(5 d('(8781* )@5 ',( x,52/2*,( ,67 ',( 5(9(56( v5$16.5,37$6( $8&+ (,1 :,&+7,*(6 y(5.=(8* '(5 02/(.8/$5%,2/2*,6&+(1 h256&+81* 81' '(5 %,27(&+12/2*,6&+(1 c1:(1'81*N '$ 6,( ',( j(567(//81* 921 &fpc $86 =(//8/>5(5 0tpc (50?*/,&+7 J6,(+( m$3,7(/ VPUPTKP t(7529,5(1 $/6 g55(*(5 921 v8025(1 81' n(8.>0,(1 %(, 9(56&+,('(1(1 v,(563(=,(6 :85'(1 %(5(,76 =8 d(*,11 '(6 TRP l$+5+81'(576 %(6&+5,(%(1N 81' '$6 920 t286 u$5O .20 x,586 '(6 j8+1(6 @%(575$*(1( q1.2*(1 J65&K 63,(/7( (,1( *581'/(*(1'( t2//( %(, '(5 g17:,&./81* '(6 q1.2*(1Om21=(37(6 J6,(+( m$3,7(/ XPTPSKP t(7529,5(1 :85O '(1 $8&+ %(, 9,(/(1 $1'(5(1 v,(5$57(1 $/6 g55(*(5 921 n(8.>0,(1 81' v8025(1 *()81'(1N -('2&+ 7527= ,17(16,9(5 u8&+( =81>&+67 1,&+7 %(,0 o(16&+(1P g567 g1'( '(5 YR(5 l$+5( :85'( '$6 (567( 0(16&+/,&+( n(8.>0,(9,586N '$6 +80$1( vO|(//O n(8.>0,(9,586 v<3 S JjvnxOkKN %(6&+5,(%(1N '$6 (,1( ,1 %(67,007(1 t(*,21(1 l$O 3$16 (1'(0,6&+( n(8.>0,()250 81' $8M(5'(0 (,1( 1(852/2*,6&+( m5$1.+(,7N ',( 7523,6&+( 63$67,6&+( r$5$3$5(6(N 9(5856$&+7P k0 i(*(16$7= =8 9(56&+,('(1(1 v,(5O $57(1 6,1' n(8.>0,(9,5(1 %(,0 o(16&+(1 -('2&+ $16&+(,1(1' 6(/7(1 81' )@5 ',( g1767(+81* 81' x(5%5(,781* 921 n(8.>0,(1 921 *(5,1*(5(5 d('(8781*P o,7 '(0 c8)75(7(1 (,1(5 1(8(1 h250 (,1(5 (5:25%(1(1 k00816&+:>&+(.5$1.+(,7N '(0 c&O 48,5(' k00812'(7&,(1&< u<1'520( JckfuKN c1)$1* '(5 ZR(5 l$+5( 81' '(5 d(O 6&+5(,%81* '(6 9(5856$&+(1'(1 g55(*(56N '(6 t(7529,586 jkx ,0 l$+5 S[ZUN %(.$0 '$6 u78',80 '(5 t(7529,5(1 $8&+ )@5 ',( j80$10(',=,1 (,1( *52M( d('(8781*P k1 '(1 SW l$+5(1 6(,7 6(,1(5 g17'(&.81* ,67 jkx =8 (,1(0 '(5 $0 %(67(1 817(568&+7(1 x,5(1 @%(5+$837 *(:25'(1P

VMQMR q%0,)+!4)/.3:9+,53 6/. q%42/6)2%. f(5 t(3/,.$7,216=<./86 921 t(7529,5(1 )2/*7 '(0 *(1(5(//(1 o867(5 (,1(5 k1)(.7,21 0,7 80+@//7(1 x,5(1N (17+>/7 -('2&+ (,1( t(,+( 81*(:?+1/,&+(5 c63(.7( Jc%%P YPSS $KP k1)(.7,?6( 5(7529,5$/( r$57,.(/ +$%(1 (,1(1 f85&+0(66(5 921 *87 SRR 10 81' (17+$/7(1 (,1( ,11(5( e$36,'6758.785N ',( '$6 9,5$/( i(120 J=:(, m23,(1 (,1(5 r/86Ou75$1* tpc 921 YAST .%K 806&+/,(M7N 62:,( (,1( o(0%5$1+@//(N ,1 ',( 9,5$/( i/<.23527(,1( (,1*(/$*(57 6,1'P

U[R

Y k1)(.7,216.5$1.+(,7(1

Bindung an zellulären Rezeptor

Membranfusion

Proteolytische Reifung

Freisetzung des Virusgenoms Reverse Transkription

Transport zum Genom der Wirtszelle

Integration GAG GAG-POL Transkription Translation

Freisetzung durch Knospung

Zusammenbau von Partikeln

ENV

-f. Einfaches Retrovirus (Mason-Pfizer Monkey Virus) provirale DNA

LTR

LTR

U3 R U5

U3 R U5

offene Leserahmen

pro

gag

env pol

Komplexes Retrovirus (HIV-1) provirale DNA

offene Leserahmen

-g.

LTR

LTR RRE

U3 R U5

gag

pro

pol

tat vpr vif

vpu rev

rev env tat

U3 R U5 nef

YPT o2/(.8/$5( x,52/2*,(

U[S

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U[T

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HIV-2 / SIVsm

SIVcpz B

D J A

C

F E G H

HIV-1 Gruppe M

HIV-1 Gruppe 0

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TAT (Trans-Aktivator der Transkription)

Transkription

Spleißen

Provirus

Spleißen

NEF

Reifung

REV (Post-transkriptionaler Regulator der Genexpression) Transport Genomische GAG RNA Kernexport GAG-POL

Freisetzung

Zusammenbau ENV

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VSX

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YPU r5,21(1

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Prion-Gen im Genom des Wirtes (DNA) kontinuierliche Transkription + Translation Infektion

neue Prionen können mit weiteren PRPc-Molekülen interagieren

PRPc Interaktion von Prionen und PRPc

Spontane oder erblich bedingte Konversion von PRPc in PRPsc

Prionen – infektiöses PRPsc ohne Nukleinsäure

bewirkt Konversion von PRPc in infektiöses PRPsc

sporadische oder familiäre TSE

erworbene TSE neue Prionen

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VSZ

Y k1)(.7,216.5$1.+(,7(1 PRPc schnell

PRPc

(a)

PRPsc Keimwachstum, Keimfragmentierung und weitere Konversion

langsam PRPsc

Nukleationskeim aus aggregiertem PRPsc; de novo entstanden oder durch Infektion eingebracht

schnell

PRPc langsam PRPc

(b)

schnell PRPsc de novo entstanden oder durch Infektion eingebracht

Heterodimer

PRPsc

+

PRPsc

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7$7,21(1KN $%(5 $8&+ (,1( f(/(7,21 2'(5 k16(57,21 *5?M(5(5 d(5(,&+( J=P dP f20>1(1K 2'(5 (,1( p(89(5.1@3)81* 921 u(48(1=(1 Jh86,21(1K 80)$66(1P m21=(37,21(// %,(O 7(7 6,&+ '$'85&+ ',( o?*/,&+.(,7N g,*(16&+$)7(1 921 r527(,1(1 *(=,(/7 ,1 *(:@16&+7(5 y(,6( =8 9(5>1'(51P f,(6 .$11 (7:$ ',( u7$%,/,7>7N n?6/,&+.(,7N u3(=,77>7 %=:P t(O =(3725%,1'81* 2'(5 ',( r+$50$.2.,1(7,. 921 r527(,1(1 %(75(5(1P f85&+ *(=,(/7(6 f(6,*1 (5+$/7(1( 9(5>1'(57( r527(,1:,5.6725( +$7 0$1 $/6 NN=:(,7( i(1(5$7,21DD 7+(O 5$3(87,6&+(5 r527(,1( %(=(,&+1(7P f$6 *(*(1:>57,*( x(567>1'1,6 '(5 u758.785Oh81.7,216Od(=,(+81*(1 ,1 r527(,1(1 ,67 $//(5',1*6 12&+ )5$*0(17$5,6&+P f(6+$/% ,67 (6 %,6+(5 185 ,1 (,1,*(1 (,1)$&+(1 h>//(1 0?*/,&+ *(:(6(1N '(1 g5(.7 921 }1'(581*(1 '(5 1$7@5/,&+(1 c0,126>85(O 6(48(1= $8) %(2%$&+7%$5( g,*(16&+$)7(1 921 r527(,1(1 =875(5(1' 925+(5=86$*(1P k1 '(5 t(*(/ 0@66(1 -('2&+ ',( c11$+0(1N ',( =80 f(6,*1 921 o87(,1(1 )@+5(1N 12&+ ,00(5 (03,5,6&+ 9(5,7=,(57 :(5'(1P v527='(0 ,67 (6 %(5(,76 ,1 0(+5(5(1 h>//(1 *(/81*(1N 5(.20%,1$17( r527(,1( =80 g,16$7= $/6 3+$50$=(87,6&+( y,5.6725( *(O =,(/7 =8 237,0,(5(1P h2/*(1'( r5>3$5$7(N %(, '(1(1 3527(,1 (1*,1((5,1* 0,7 *$1= 817(56&+,('/,&+(5 |,(/6(7=81* 9(5:(1'(7 :85'(N 6,1' '(5=(,7 $/6 =8*(/$66(1( o(',O .$0(17( 9(5)@*%$5\ k168/,1 /,6352P u8%.87$1( k1-(.7,21 921 k168/,1 )@+57 1,&+7 =80 */(,&+(1 =(,7/,&+(1 y,5.81*63527/N :,( ',(6 )@5 ',( r/$60$.21=(175$7,21 921 k168/,1 %(, r(5621(1 2+1( f,$%(7(6 0(//,786 326735$1',$/ (55(,&+7 :,5' Jc%%P ZPUK\ p$&+ '(5 k1-(.7,21 '(6 k1O 68/,16 67(,*7 '(5 r/$60$63,(*(/ 185 9(5=?*(57 $1N 62 '$M ',( k1-(.7,21 0(+5 $/6 SW o,187(1 925 (,1(5 o$+/=(,7 (5)2/*(1 08MP y(*(1 '(6 /$1*6$0(5(1 c%)$//6 '(6 k1O 68/,163,(*(/6 %(67(+7 $1'(5(56(,76 63>7(5 ',( i()$+5 '(5 j<3(5,168/,1>0,(P f,( /$1*O 6$0( c167,(*63+$6( %(58+7 $8) '(5 )@5 ',( f,662=,$7,21 921 +(;$0(5(0 k168/,1 =8 f,0(5(1 81' o2120(5(1 %(1?7,*7(1 |(,7P w0 ',(6( =8 9(55,1*(51N :85'(1 =$+/O

Plasma-Insulinkonzentration (nmol/l)

0.50 0.40 0.30 0.20 0.10 0.00

0.0

1.5

3.0 4.5 Zeit (min)

6.0

7.5

subkutane Injektion bzw. Mahlzeit

c%%P ZPU k168/,1Om21=(175$7,21(1 ,0 r/$60$P r(5621(1 0,7 1250$/(5 i/8.26(72/(5$1= 1$&+ (,1(5 o$+/=(,7 J K %=:P 1$&+ 68%.87$1(5 k1-(.7,21 921 k168/,1 JA A A AKP Jx(5>1'(57 1$&+\ d$51(77N cPjP $1' q:(16N fPtP JS[[YK n$1&(7 UV[N VYAWS J@ v+( n$1&(7 n7'PN 0,7 i(1(+O 0,*81*KP

ZPS t(.20%,1$17( r527(,1(

VUS

5(,&+( k168/,1Oo87(,1( .216758,(57N %(, '(1(1 ',( %,2/2*,6&+( c.7,9,7>7 '(6 j250216 (5+$/7(1 %/(,%7N ',( f,662=,$7,2165$7( '(6 j(;$0(56 ,1 n?681* $%(5 (5+?+7 ,67P c/6 62/&+(6 k168/,1Oc1$/2* 67(+7 NNk168/,1 /,6352DD =85 x(5)@*81*N %(, '(0 A :,( ',(6 $8&+ %(,0 1$7@5/,&+(1 k168/,1Oj202/2*N NN,168/,1O/,.( *52:7+ )$&725OkDD JkihOkK *(O )81'(1 :85'( A ',( t(,+(1)2/*( '(5 c0,126>85(5(67( dTZ 81' dT[ *(7$86&+7 :85'( Jc%%P ZPTKP k168/,1 /,6352 .$11 $8) i581' 6(,1(6 6&+1(//(5(1 y,5.81*6(,175,776 81O 0,77(/%$5 925 '(5 o$+/=(,7 ,1-,=,(57 :(5'(1P f,( r81.7087$7,21 )@+57 +,(5 $/62 =8 (,1(5 3+$50$.2.,1(7,6&+ 5(/(9$17(1 }1'(581* '(5 c**5(*$7,216(,*(16&+$)7(1 '(6 r527(,16P t(7(3/$6(P u(,7 S[[X )@5 ',( d(+$1'/81* '(6 $.87(1 j(5=,1)$5.76 =8*(/$66(1 ,67 t(O 7(3/$6(N (,1 o87(,1 '(6 %(5(,76 S[ZY )@5 ',( */(,&+( k1',.$7,21 (,1*()@+57(1 r/$6O 0,12*(1Oc.7,9$7256 920 i(:(%67<3 J7,668( 3/$60,12*(1 $&7,9$725N 7OrcN c/7(3/$O 6(KP f,( y,5.81* '(5 r/$60,12*(1Oc.7,9$725(1 %(58+7 $8) '(5 c.7,9,(581* '(6 ,1O $.7,9 ,1 '(5 d/87%$+1 =,5.8/,(5(1'(1 r52(1=<06 r/$60,12*(1 =85 $.7,9(1 r527($6( r/$60,1P f,(6(6 ,67 ,1 '(5 n$*(N '$6 81/?6/,&+( h,%5,1 '(6 d/87*(5,116(/6 3527(2/<7,6&+ =8 /?6/,&+(1 r(37,'(1 =8 63$/7(1 81' '$'85&+ '(1 i()>M9(56&+/8M =8 %(6(,7,*(1 Jc%%P ZPVKP i(*(1@%(5 )5@+(5 9(5:(1'(7(1 h,%5,12/<7,&$ :,( '(5 %$.7(5,(//(1 u75(372.,1$6( 81' '(5 $86 w5,1 2'(5 |(//.8/785 *(:211(1(1 w52.,1$6( %(67(+7 (,1 :(6(17/,&+(5 x257(,/ 921 7Orc '$5,1N '$M (6 ,1 )5(,(5 h250 1$+(=8 ,1$.7,9 ,67 81' (567 ,0 7(51>5(1 m203/(; 0,7 h,%5,1 81' r/$60,12*(1 6(,1( 92//( c.7,9,7>7 (17)$/7(7P g6 :$5 '$+(5 =8 (5:$57(1N '$M $8)*581' ',(6(5 NNh,%5,1Ou3(=,77>7DD $.7,9(6 r/$60,1 185 /2.$/ $0 v+520%86 (1767(+7N :>+5(1' (,1( 6<67(0,6&+( c.7,9,(581* 921 r/$60,12*(1 81' '$'85&+ (,1( f(3/(7,(581* 921 h,%5,12*(1 ,1 '(5 d/87%$+1 0,7 '(5 h2/*( (5+?+7(5 d/8781*6*()$+5 :(,7*(+(1' 9(50,('(1 :(5'(1 .?11(P v$76>&+/,&+ .2117( ,1 ./,1,O 6&+(1 i52M678',(1 %(, d(+$1'/81* 921 j(5=,1)$5.7 r$7,(17(1 0,7 7Orc *(*(1@%(5 u75(372.,1$6( (,1( (5,=,(17(5( i()>M?5181*N 9(5%81'(1 0,7 185 *(5,1*)@*,* (5+?+O 7(5 d/8781*65$7(N 81' '$5$86 5(68/7,(5(1' (,1( *(5,1*(5( o257$/,7>7 %(/(*7 :(5'(1P Plasminogen-Aktivatoren Inhibitoren der Plasminogen-Aktivatoren Plasminogen

Plasmin ·2-Plasmininhibitor

Fibrinogen (löslich)

Fibrin (unlösliches Blutgerinnsel)

Fibrinogen-Spaltprodukte (löslich)

c%%P ZPV

c//*(0(,1(6 u&+(0$ '(5 h,%5,12/<6(P

Fibrin-Spaltprodukte (löslich)

VUT

Z v+(5$3(87,6&+( g17:,&./81*(1 200 S

E

A E C

G

A

V

F K A G K Y

T S W T G

100

R

Y

S

80 F G

A GK E

C

P

C

E

I

I

C

Y

F

L

S

–

W

P

S

S

K

A

L

A

E

120 Q

K1

160 S

S

G Q

D

E

E

F

Y

C T

C

S

T P A C

K

E

S

L

P Y S D G R R R D P P D A N I R R C 140 L Y G N H N G L

S

G A S C L

T L K N R R

S

S

C D T RA Q C C P F V N E F G D S G S C T 60 F S C Y K Q L Q V A R P V L P L R V S W S N H S 20 R CQ Q V A H E R 40 Q Y C G Q W C Y N S I M Q T K E D R C I VQ Y 1 S R V S P S Q E I H A R F R R G A F V A G C L L L R KMA DM NH2 V C C L G

E

T N W N

H T G

R Y

A

C

H

V

P W N

W

P

S

M

I

240

K

D

K2 L

S

T

W E

G N

G

180

F

Y

D

Y

C

G

C

D

R Y

N

L

I

G

K V Y T A Q N P S A Q A L G K G L

A

D P

N

V H P S 260 C S T C G L

C

220

280 F

A

D

I

A

S H P

W Q A A I F A K

L RQ G G Y S L C V K Q P I T Q F P P R R DA L H V Q R L V R P S S D 300 P S W G T E E G Y G K H E R S E A Q F L R G D I L I G G C L L C E A F P S S N TM P R L L 420 S C C H C V QE W P R F V H I G F H C L S L S L A A I Y P 480 S 380 T I S G D V 320 E S G I S R W L L G S K K L D E G E L A G 500 G K Q E R Q F Q H C C E E T L V V A G 340 Y G L R P E R D Q V V A L K 440 H L L K Y I H Y L I D P S S R C T S Q D N V N V N A R H P Q D T K 360 P G Y GG V E C T V S R A L MN D T D D D F G T D Y T 460 K V T N L DW I R D NMR P S

N

G

400

P

—COOH

520

(a)

E

G A S C L

S

T L

L K N R R

S H T G

R Y

A

C

H

V

P W N

W

P

S

M

K A D

K2 L

S

T

W E

G N

Y

C

G

D

C V F

R Y

N

D P

N

I

L

I

G

K V Y T A Q N P S A Q A L G K G L

H S H P A W I Q D A S T A C G F S A L L N RQ NH2 — S Y Q G G I G Y S C V F L K Q P Q T P P A F R I A R D K L H V Q R L V R P S S D P S W G T E E G Y G K H E R S E A Q F L L L I R G I G D G C L C E A F P S S N TM P R S L L C C H C V QE W P R F V H I G F H C L S L S L A A I Y P S T I S G D V E S G I S R W L L G S K K L D E G E L Q G A G K E R Q F Q H C C E E T L V V A G G Y L R P E D Q V V R A L K H L L K Y I H Y L I D P S S R C T S Q D N V N V N A R H P Q D T K P G Y GG V E T F V S R A C L MN T D D D D T D G Y T K V T N L DW I R D NMR P G

F

Y

D

C

S C

P

(b)

—COOH

ZPS t(.20%,1$17( r527(,1(

VUU

f,(6( 9257(,/+$)7(1 g,*(16&+$)7(1 921 c/7(3/$6( :(5'(1 '85&+ (,1( 6(+5 .85=( j$/%:(576=(,7 ,0 d/87 J&$P W 0,1PK %((,175>&+7,*7P f$ ',( f26,6 ,1)2/*( '$11 =81(+O 0(1'(5 p(%(1:,5.81*(1 1,&+7 %(/,(%,* *(67(,*(57 :(5'(1 .$11N ,67 '$6 r27(17,$/ '(6 c.7,9$7256 =8 6&+1(//(5 i()>M?5181* 1,&+7 92// 187=%$5P d(, t(7(3/$6( :85'(1 '$+(5 *(=,(/7 ',(-(1,*(1 d(5(,&+( '(6 7Orc (17)(517N ',( )@5 ',( +2&+$5,1( h,%5,1O %,1'81* 81' )@5 ',( 5(=(37259(50,77(/7( e/($5$1&( '(6 c.7,9$7256 $86 '(5 d/87%$+1 9(5$17:257/,&+ 6,1' JNNgihOf20>1(DDN NNh,1*(5Of20>1(DD 81' NNm5,1*(/ SOf20>O 1(DDK Jc%%P ZPWKP |8'(0 :,5' t(7(3/$6(N $1'(56 $/6 ',( $86 5(.20%,1$17(1 u>8*(5O =(//(1 *(:211(1( c/7(3/$6(N ,1 *(17(&+1,6&+ 9(5>1'(57(1 gP &2/,Od$.7(5,(1 +(5*(O 67(//7P f$6 '$'85&+ 9(5856$&+7( h(+/(1 '(5 1$7@5/,&+(1 i/<.261*(57( j$/%:(576=(,7 (5/$8%7 %(, t(7(3/$6( (,1( :(6(17/,&+( x(55,1*(581* '(5 =8 $33/,=,(5(1'(1 f26,6 '(6 c.7,9$7256P q%:2+/ ',( +2&+$5,1( h,%5,1%,1'81* )(+/7N %(6,7=7 t(7(3/$6( ,1 9,752 h,%5,1Ou3(=,77>7 J*(0(66(1 $/6 u7,08/$7,21 '(5 r/$60,12*(1Oc.7,9,(581* ,1 i(*(1:$57 921 h,%5,1KN :(11 $8&+ ,1 *(5,1*(5(0 o$M $/6 c/7(3/$6(P k1 9,92 $//(5',1*6 ,67 ',( h,%5,1Ou3(=,77>7 A *(0(66(1 $/6 h,%5,12*(1Oc%%$8 %(, 7+520%2/<7,6&+ >48,327(17(1 f26(1 A %(, %(,'(1 c.7,O 9$725(1 9(5*/(,&+%$5P k1 ./,1,6&+(1 u78',(1 :85'( $8)*581' '(5 />1*(5(1 %,2/2*,O 6&+(1 j$/%:(576=(,7 81' '(6 817(56&+,('/,&+(1 y,5.0(&+$1,6086 (,1( 6&+1(//(5( n<6( %(2%$&+7(7 $/6 0,7 7OrcP y(,7(5( r527(,1:,5.6725( NN=:(,7(5 i(1(5$7,21DDP h@5 ',( 1$+( |8.81)7 6,1' h257O 6&+5,77( ,16%(621'(5( $8) '(0 i(%,(7 '(5 5(.20%,1$17(1 k008172;,1( =8 (5:$57(1P j,(5 +$1'(/7 (6 6,&+ 80 m21-8*$7( 2'(5 h86,21(1 $86 (,1(0 =(//%,1'(1'(1 c17(,/ J0(,67 '(5 c17,*(1Od,1'81*65(*,21 (,1(6 c17,.?53(56K 81' $86 (,1(0 &<7272;,6&+(1 d(5(,&+N (7:$ (,1(0 %$.7(5,(//(1 v2;,1 :,( f,3+7+(5,(Ov2;,1 2'(5 r6(8'2021$6O g;272;,1 Jc%%P ZPXKP k008172;,1( 71'(1 ,1 '(5 (;3(5,0(17(//(1 m5(%67+(5$3,( c1O :(1'81*P u,( .?11(1 .219(17,21(// '85&+ &+(0,6&+( m233/81* +(5*(67(//7 :(5'(1] :(11 ',( 72;,6&+( m20321(17( 6(/%67 r527(,1&+$5$.7(5 +$7N %,(7(7 6,&+ -('2&+ '(5 y(* @%(5 (,1 5(.20%,1$17 +(5*(67(//7(6 h86,216.216758.7 $1P k1 ./,1,6&+(1 r+$6(OkB kkOu78',(1 :85'(1 %(5(,76 (5087,*(1'( t(68/7$7( 0,7 k008172;,1(1 (5+$/7(1N %(, '(1(1 ',( c17,.?53(5Ou3(=,77>7 *(*(1 63(=,76&+( q%(59>&+(1Oc17,*(1( 921 v8025O =(//(1 *(5,&+7(7 ,67P c/6 c17,*(1( *(187=7 :(5'(1 +,(5%(, 1$0(17/,&+ ',( v5$16)(55,1O 81' knOTOt(=(3725(1 62:,( ',( gtddTO 81' n(:,6O{Oc17,*(1(P

8 c%%P ZPW u&+(0$7,6&+( f$567(//81* '(5 u758.785(1 921 J$K c/7(3/$6( J7OrcK 81' J%K t(7(3/$6(P f,( (,1=(/1(1 r527(,1Of20>1(1 6,1'\ uBnN u,*1$/OBn($'(5Ou(48(1= J)(+/7 ,0 5(,)(1 7OrcK] hN h,1*(5Of20>1(] gN (3,'(50$/ *52:7+ )$&725O>+1/,&+( f20>1(] mSN m5,1*(/ S] mTN m5,1*(/ T] rN r527($6(Of20>1(P t(7(3/$6( (17+>/7 185 ',( mTO 81' rOf20>1(1P f,( ,1 c/7(3/$6( 925+$1'(1(N ,1 t(7(3/$6( )(+/(1'( i/<.26
VUV

Z v+(5$3(87,6&+( g17:,&./81*(1

VL

VH

VH

VL

C

C

C

C

VH L

H1 SS

H1 S S SS

C

H2

C

H3

VL VH

L

SS

C

C

L

SS

H2

H3

C

H1

C

VL

VH

SS

VL

Toxin

Toxin

Toxin

Toxin

IgG-TOXIN 200 kDa

Fab-TOXIN 90 kDa

scFv-TOXIN 66 kDa

dsFv-TOXIN 64 kDa

c%%P ZPX u&+(0$ '(5 u758.785(1 9(56&+,('(1(5 k008172;,1(P y>+5(1' k*iOv2;,1( 81' h$%O v2;,1( '85&+ &+(0,6&+( m21-8*$7,21 +(5*(67(//7 :(5'(1 .?11(1N 6,1' 6&h9Ov2;,1( 81' '6h9O v2;,1( 185 $/6 5(.20%,1$17( r527(,1( =8*>1*/,&+P Jx(5>1'(57 1$&+\ d5,1.0$11N wP $1' r$O 67$1N kP JS[[WK o(7+2'6 ZN SVUASWXN @ c&$'(0,& r5(66N k1&PN 0,7 i(1(+0,*81*KP

|8 (5:>+1(1 ,67N '$M o87(,1( A '$ 1,&+7 0(+5 0,7 .?53(5(,*(1(1 g,:(,M6725(1 ,'(17,6&+ A 327(17,(// ,00812*(1 6(,1 .?11(1P d(, '(1 %,6+(5 (,1*()@+57(1 7+(5$O 3(87,6&+(1 r527(,1(1 NN=:(,7(5 i(1(5$7,21DD +$7 6,&+ ',(6( d()@5&+781* 1,&+7 %(67>O 7,*7] 6,( ,67 -('2&+ )@5 k008172;,1( =8 %($&+7(1N ',( @%(5 %$.7(5,(//( J1,&+7O+80$1(K u(48(1=(1 9(5)@*(1P j80$1(N .?53(5(,*(1( r527(,1( 6,1' ,1 *5?M(5(1N 327(17,(// 81%(*5(1=7(1 o(1*(1 (567 '85&+ ',( i(17(&+1,. =8*>1*/,&+ *(:25'(1P p(%(1 '(1 5(.20%,1$17(1 r527(O ,1(1 NN(567(5 i(1(5$7,21DD 71'(1 =81(+0(1' *(=,(/7 ,1 ,+5(5 c0,126>85(6(48(1= 9(5O >1'(57( r527(,1Oo87$17(1 Jo87(,1(K $/6 =:(,7( i(1(5$7,21 921 r527(,1Oy,5.6725(1 c1:(1'81*P h@5 ',( |8.81)7 =(,&+1(7 6,&+ $%N '$M '(5 m?53(5 '(6 r$7,(17(1 6(/%67 ',( d,26<17+(6( :,5.6$0(5 r527(,1( $8) d$6,6 (,1*(6&+/(867(5 *(1(7,6&+(5 k1)250$O 7,21 @%(51(+0(1 :,5'\ f,( i(17+(5$3,( ,67 ,1 ',(6(0 u,11 $/6 NN'5,77( i(1(5$7,21DD '(5 02'(51(1 r527(,17+(5$3,( $1=8635(&+(1P

WMQ f%.4(%2!0)% w17(5 i(17+(5$3,( ,0 (1*(5(1 u,11( 9(567(+7 0$1 ',( *(=,(/7( x(5>1'(581* '(5 *(1(7,6&+(1 k1)250$7,21 =85 r5>9(17,21 2'(5 d(+$1'/81* 921 m5$1.+(,7(1P i581'O 6>7=/,&+ .200(1 m(,0=(//(1 2'(5 620$7,6&+( |(//(1 $/6 |,(/ (,1(5 62/&+(1 x(5>1O '(581* ,1 h5$*(P d(, m(,0=(//(1 .2007 (6 '$%(, =8 (,1(5 %/(,%(1'(1 81' :(,7(5O 9(5(5%%$5(1 x(5>1'(581* '(5 *(1(7,6&+(1 k1)250$7,21P f(5=(,7 :,5' $86*(6352&+(1 .217529(56 ',6.87,(57N 2% ',(6 (,1 (7+,6&+ 9(575(7%$5(6 g5*(%1,6 >5=7/,&+(1 j$1'(/16

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therapeutisches Gen in seinem Vektor

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kultivierte Zielzellen

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retroviraler Vektor LTR

Transduktion

therapeutisches Gen

LTR

Transfektion

virale RNA

a lasm top Zy

POL

gag

reverse Transkription

virale DNA

Nukleus pol

Zytopla sma

Integration

RNA

env

Nukle us

DNA der Zielzelle

Translation Transkription und Transport

ENV GAG POL Verpackungszelline

therapeutisches Genprodukt

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ZPT i(17+(5$3,(

VVS

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VVT

Z v+(5$3(87,6&+( g17:,&./81*(1

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Ziel mRNA 5´—

XXXXXU

G

— 3´

X X X X X G – 5´

Gruppe I Intron Ribozym

5´—

XXXXXU

— 3´

„reparierte” mRNA

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ZPT i(17+(5$3,(

VVU

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Ziel-mRNA Hammerhead Ribozym

5´– X X X X X X X X X X X X X X X X X U Y X X X X X X X X X X X X X X – 3´ 3´– X X X X X X X X X X X X X X X X X A X X X X X X X X X X X X X X – 5´ A CUG A A A GX G CG XX XX XX X X XX

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VVV

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SR i/266$5

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VYR

SR i/266$5

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SR i/266$5

VYS

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SR i/266$5

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SR i/266$5

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SR i/266$5

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SR i/266$5

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