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Thesis

Reference

Spontaneous rDNA copy number variation modulates Sir2 levels and epigenetic gene silencing

MICHEL, Agnès

Abstract

Chez la levure "S.cerevisiae", l'ADN ribosomal (ADNr) est constitué par environ 200 répétitions en tandem des séquences codant pour les ARN ribosomaux et dont le nombre est maintenu constant. Nous avons cependant mis en évidence l'existence de variants stables mitotiquement et meiotiquement, dont le nombre de copies d'ADNr est réduit de moitié. Cette réduction corrèle avec une augmentation de la répression transcriptionnelle aux télomères et aux loci "HM" et une diminution de moitié de l'expression du gène "SIR2". Ce résultat est surprenant puisque la protéine Sir2p, présente sur l'ADNr, aux télomères et aux loci HM, est limitante pour la répression transcriptionnelle. Nous résolvons ce paradoxe en proposant et testant un modèle selon lequel les protéines Sir2p libérées de l'ADNr lorsque celui-ci se réduit de taille, se lieraient aux télomères et aux loci "HM" pour en réprimer la transcription et auto-réguleraient de façon négative leur propre production.

MICHEL, Agnès. Spontaneous rDNA copy number variation modulates Sir2 levels and epigenetic gene silencing . Thèse de doctorat : Univ. Genève, 2005, no. Sc. 3650

URN : urn:nbn:ch:unige-4563

DOI : 10.13097/archive-ouverte/unige:456

Available at:

http://archive-ouverte.unige.ch/unige:456

Disclaimer: layout of this document may differ from the published version.

(2)

Département de biologie moléculaire Professeur David Shore

Spontaneous rDNA Copy Number Variation Modulates Sir2 Levels And Epigenetic Gene Silencing

THÈSE

présentée à la Faculté des sciences de l'Université de Genève pour obtenir le grade de Docteur ès sciences, mention biologique

par

Agnès H. MICHEL

de

Pont­à­Mousson (France)

Thèse N° 3650

GENÈVE

Atelier de reproduction de la Section de physique

2007

(3)

Table Of Content

Remerciements ………...…………..i

Résumé en français ………..………...…………ii

A­ General Introduction …...…...…………1

B­ Results ………..…………...………….67

Spontaneous   rDNA   copy   number   variation   modulates   Sir2 

levels and epigenetic gene silencing 

Michel et al., Genes & Development 19:1199­1210, 2005

C­ Discussion ……….………...……105

(4)

Mes remerciements

Vont à tous ceux qui, de près ou de loin, ont contribué à  l’aboutissement de cette thèse…

…en particulier

au Professeur   David  Shore, pour  m’avoir accueillie  dans  son laboratoire

aux   Professeurs   Rolf   Sternglanz   et   Claudio   De   Virgilio,  pour avoir accepté de juger ce travail

…plus largement à ma famille

à mes amis, scientifiques ou non

…et spécialement à Benoît

à mes parents

(5)

Résumé en français

_______________________________

I Introduction

Hétérochromatine et répression de la transcription

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II Présentation du projet et résultats

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Variations spontannées de la taille du rDNA : plus de silencing, moins de Sir2

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III Conclusion et perspectives

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Références

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(18)

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(19)

A- GENERAL INTRODUCTION

I Heterochromatin...2

II Silencing in S. cerevisiae...5

Yeast mating-type locus...5

Telomeres...8

Silencing at truncated telomeres ...9

o Natural versus truncated telomeres...12

Functions of TPE in yeast and other organisms...13

o Yeast ...13

o Trypanosoma brucei and Plasmodium falciparum...14

The nucleolus and the rDNA ...16

rDNA Silencing ...16

rDNA cluster size maintenance is related to rDNA replication and transcription. ...17

o Replication ...18

o Transcription ...20

More nucleolar functions ...22

o Mitotic exit...22

o TAR1: a protein coding sequence in the rDNA...22

III The multi-faces of Sir2... 23

The metabolism-aging connection...24

A role for O-Acetyl-ADP-Ribose (AAR) ...26

IV Checkpoints ... 27

Definition and general description...27

Checkpoint pathways ...29

Overview...29

The G1/S Checkpoint...31

The S-phase checkpoint ...32

o The sensors...32

o The mediators and the effectors...33

o The response. ...35

o The G2/M Chekpoint ...37

Checkpoints and chromatin...38

o Chromatin as a checkpoint trigger ...38

o Checkpoints can modify chromatin stucture...38

V Ribonucleotide Reductase ... 41

Introduction...41

Class Ia RNR...42

Reaction ...43

o Allosteric regulation...45

o Checkpoint and dNTP synthesis ...46

Bibliography... 47

(20)

A -GENERAL INTRODUCTION

_____________________________________________________________________

I Heterochromatin

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II Silencing in S. cerevisiae

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Silencing at truncated telomeres

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rDNA Silencing

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6 . . ' !

9 $ % & 8 9 "

& 8 9 " - ; 4 !#

% & 8 9 " 5 ' !

5 ! % 4( % 4(

- - " ( "

% " ? % % " '

" ) " ' - "

" 2 " % ' @ " " 2 @ * "

% - "

" ) $ 4( ) $ A " "

% " ) " ' % -

4( " % B

% % " %

" 4 % ) % & + + 5

(38)

6 $ % &

8 9 " 1 . . ' !

8 9 "

# - ; 4

" - ; 4 $

#

- ; 4 6 < F ! 4

6 $ % & # ∆

$ 8 9 " 1

. . ' / : . . A !# - ; 4 $ 1

/ 1 . . ' ! 4 # 1 #∆

8 9 " $ 8 ! : # ' ,& #

$ "

1 / 1 . . ' !

: 8 9 "

8 9 "

! 4 ! = 6 # 2 %

8 9 " 2

4 . . !

o Transcription

G 8 9 "

* 8 9 " , " 8 9 "

5 . . 3 !

0 2 0 22

# 4

. . 3 ! # 8 9 "

0 22 0 2 0

0 22 % 0 2!

(39)

J "5 6 # 8 9 "

& > &

G ! G & 0 22

8 9 " 0 2

; 9 " 4 # #$ -#

0 2# 8 9 " 2

#$ -

3 A 6 ; 9 "

0 22 8 9 " &

#$ - ' ,& #

' ,& # * , 8 9 " #

#$ - ∆ 1 / 1

. . ' ! 2 # #$ - ∆ 8 9 " > #

# 8 9 " &

#$ -* ' ,& # 1 ! ∆

8 9 " &

8 9 " 1 . . ' / : . . A ! 8 ' ,& #

8 9 " #

& 1 . . ' ! # ' ,& #

8 9 "

> 2 8 9 "

' ,& # # > 2 #

' ,& # & 8 9 "

5

(40)

More nucleolar functions

o Mitotic exit

& ; - 9 ;

9 6 ! & #

4 ' # 9 # 2

! 6 6 / < . . / . . ' ! 5

< # 4 ' %

9 " # 4 '

< 0 # & 6

!# 6 6 ! =

6 # 9 % 8 9 " #

; - 9 & # #

6 #

6 1 . . ! 9 9 &

1 . . !

9 0 2 ; 9 " 6

. . ! 9 0 2

6 . . !

o TAR1: a protein coding sequence in the rDNA

8 9 " ; 9 "

# "; " ; ; 9 "!#

A 6; 9 "

&

! ; 9 "

2 # & ∆ >

4 . . ! 2 ! # 0 2 0

22# &

(41)

III The multi-faces of Sir2

6 9 "8 P!$

2 . . . / = . . . /

6 . . . ! 6 $ ! 9 "8 P

# G $

$"8 0 $ ""; !# 9 " 9 ": # +3

! . . . / . . ' !

9 ": "";

# # 6 & "

. . 3 / < . . ' / = . . A ! 5 A !

. " ' ( 4 * ' %

4# 2 ' ! & ! & 2 ) " * % $

! ( 4C & >2 2 ' 2 4# 2 * % " " '

! & ! & 2 ) " - ( D % % $

0 & + + 5

(42)

6

2 % 8 9 "#

# & E

6 B6 ' & ; - 9 & ; - 9 &

6 # 9 # 4 ' 6 / . . ' !

8 9 " 6 B6 ' & 6

6 ' # 6 3 . . ' ! 2

2 "

# 4

8 9 " #

8 9 " 4

. . . !

The metabolism-aging connection

;

# G

#

8 # " 1 / < . . /

; . . ' ! 2 #

4 ; ! 4 ; $

# 2

# # # # # # #

> @ / = . . ! 2 # =

. . . !# ; . . / ; . . ' / >

. . ' !# 4 ; % " # 6

6

6 1 ! 6

- ; 4 5

(43)

8 9 " 6 < F / 1 ! 9 "8 P

9 "8

9 9 ": ! 6 $

2 9 "8 P 2 ) # 2 ! ##

9 "8 6 . . ! 4

# # ) 2 ## 9 "8 P

6 G # 2 ! # 9 "8 P

" E =

. . . !# 8 9 " # : ;

6 . . . ! 4 # 2 ) # & 8 9 "

" . . ! 9 ":

$ B 6 + . . ! 2 #

9 ": " #

# 8 9 "

9 ": 6 &

% 2 ) # " . . 3 !

2 # 9 6 8 9 "

# 6

; - 9 & 6 B6 ' & . . ' !

; - 9 & 9 ": 6 B6 ' &

9 "8

4 9 "8 P#

9 "8 2 # 4 ; &

& = . . !

9 "8 #

= . . ' !# 6

8 9 "8 2 ) ##

& #

9 "8 = . . ' !

(44)

6 9 "8 PB9 "8 #

5 @ !

E # - ' ' A F 3 ! " =

9 % ) ! & " " - ' " "

' G & + + 5

A role for O-Acetyl-ADP-Ribose (AAR)

> 6 #

,$" $"8 0 $; # # #

""; #

# 62; & /

# 6 3 6 B6 '

& = . . A ! 2

9 ": ; - 9

& # ""; 6 B6 ' &

6

5 # 6 # 2

! 6 $6

; ! $ &

0 . . ' !

(45)

IV Checkpoints

Definition and general description

: $

# & &

< & 8 9 " B #

! #

4

&

8 9 "

#

8 9 "

7 8 K" A !

- & #

4 2 #

Protein function Mammals S. pombe S. cerevisiae

Sensors

RFC-like Rad17 Rad17 Rad24

PCNA-like Rad9 Rad9 Ddc1

Rad1 Rad1 Rad17

Hus1 Hus1 Mec3

PI3-Kinases (PIKK) ATM Tel1 Tel1

ATR Rad3 Mec1

PIKK binding partner ATRIP Rad26 Ddc2/Lcd1/Pie1

(46)

Protein function Mammals S. pombe S. cerevisiae

Mediators

MDC1

53BP1

TopBP1 Cut5 Dpb11

Claspin Mrc1 Mrc1

BRCA1 Crb2/Rph9 Rad9

Transducers

Kinase Chk1 Chk1 Chk1

Chk2 Cds1 Rad53

4( % ) " " ' ' *

% ! & + + 5

4

& & #

$ 9 @ ! -

8 9 " % 5 & #

8 9 " .'

Q = 9 F ! J J 7 !

C #

8 9 "

9 - & ; 9 - ; !

= ! 2 2; ! ; G & 6 ; G 6!

& 8 9 " $ 8 6+ !

; ! $

$C 9 - D ! 5 D !

(47)

Checkpoint pathways

Overview

4 < B6

8 9 " 6 ";

8 6 # 8 9 "

8 9 "

< B:

# 8 9 "

:

+ #

' #

# #

2 # #

2 #

#

8 9 " 2 #

#

#

2 #

#

# "

8 9 "

; 0 " # 8 9 "#

2 # 8 9 " #

3 $ $

0 21 1 ! #

(48)

:

" & : " : ! " : $

" ; !

#

#

# % #

$

3 8 9 "

4

5 # & :

. . / 6 . . ' !

H % " 4( % ) " % %

' - %

* * "

' " " 0 /! ! 2" "

0 & / % ! & + + 5

(49)

#

# %

6$

#

The G1/S Checkpoint

< B6 6

8 9 " 2 8 9 "

6$ # #

$

J #

< 6 6 ";

/ ! 0 . . ! # 6$

8 9 " # 6 ";

<

6 . . ' !! 2 #

# ; A 3 $ #

6 ' B@ #

< # 6$ 6

+ F ! :

6 ' / > ' ! 5 & # J 7

< & #%

< #

6$ 9 !

#

& $

6 3 / 0 A / 9 /

< . . !

(50)

The S-phase checkpoint

8 9 "

: $ 2 &

8 9 " & < ! 0

A ! % $!6$

1 /

6 8 / 6 / 4 . . . /

8 . . / . . ! 5 =

. . 3 !

o The sensors

3 $

# : " ; " : !

$ $ :

# 2 # #

: # ; A 3

: J . . ! : 8 #

0 . . . /

; D . . . / > . . ! 8 8 6+

; 0 " ; 0 "! # 8 6+

8 9 " ? - . . 3 ! 5 : $8

% & ; F # : 3

8

0 4 9 "! * , 8 9 " / : C

+ . . 3 ! 2 # &

: ; ; 5 4 $ ! & ; '

0 / 1 / ? . . ! ; 5 4

$ C 0 4 9 " 8 9 "#

> 6 / : C

+ . . ' !! : # < 6 #

(51)

; 5 4 $ 0 4 9 "$ & 8 9 "

6 # % : $) $

; A . & 8 K" D . . / < . . !

o The mediators and the effectors

G 8 9 " # ; A 3

4 4 < # ; A 3 %

!# ; : : ;

4 !

; #

> . % < B:

> ! ;

% 8 9 " >

/ 6 3 / 0 A ! .

> / >

. / 6 3 / 0 A ! ;

7 !

8 9 " : B

% ; A 3 4

& ! - / 7

! 2 ;

; A 3 ; A 3

$ 6 . . ! 0

; A 3

$ # #

8 9 " !

(52)

8 I % % J * 4( 2 % ) "

) " 4( $ "

) " * % ! * % "

) " * % ! B4 & B & E

4 B ,B H : 2 2 % " F " * '

" ' 4( % ! " % ' % 2

" ! " B4 & 4 B H B ,

% " F % " ) " *

4 B H B , ' ? ' & 5 I& 5 J B % " F " )

9 % ? % " F -

' / - ) " " %

4( " A " " 4 B H B , % " F

" K : $ K " " ' '

% ? ' ) & + + &

(53)

; C :

" . . / ; . . !

2$ !# :

:

% #

& 1

. . 3 / G - . . 3 !

o The response.

" 6$

; 8 9 " #

9 0 & &

; ; !!

6$ E

6

. . / . . 3 !# #

" ' / > ' / 6

@ / 5 F / 8 / 6 8 / =

. . 3 ! 8 9 "

2 ; A 3 #

# #

= . . !

; A 3 ; 0 " 8 9 "

+ @ / = @ / = @ / :

F / + 1 . . . ! G 4 F B8 ' #

8 9 " D . . . / 1 . . 3 !#

; A A 6 + . . . / =

. . . !

"

9 0 2

% 9 0

2 # : ; A 3

(54)

9 0 0

! J # 9 0

9 0 # &

; 9 ; # ; ; ; 9 ; # $

9 0 # !# ## ; 9 ; #

# ; 9 ; 8

/ ? / 4 / ? . . . !

J 6$ #

< B6 J 6$

# ; A 3 8 # #

4 2 ! ! 6 ?

. . . / ? ; . . !# ; 9 ;

& - 8 . / - 3 !

:

4 # 8 8

: - 9 : - & 9 ! & $

0 F / < !

5 6$

(55)

: " ) " " - ' ' " ) 4(

% ! " " - ' *

. , " ) . , % % - % ) "

* % ' 6 ) * ' % ! " 6 )

- " ! " 4( % 4(

" 6 ) 4( % " "

6 ) 4( % % G ' $ - & + + +

o The G2/M Chekpoint

< B:

8 9 " $

#

( F / $1 : !

(56)

Checkpoints and chromatin

2

&

E

$ 6 &

# 1 . . ' !!

o Chromatin as a checkpoint trigger

: '

< B: ; : A !

%

% 8 9 " 6 # $ $

- ; $

4 ! : #

! ## 3 1 ' %

8 9 " 9 F / + . . / 1

. . !# ; ; A 3 ;

; 0 " ; 0 "!

6 . . ! 5 #

1 . . ' !

o Checkpoints can modify chromatin stucture

6 : 3 # < B6# $6

< B: : 3

0 - 4 !

; # ; A 3

(57)

: B &

< C 7 . . 3 !

4 "5 & %

8 9 " 6 @ / < @ !

8 # 4 "4 # : $

: $ 8 9 " !#

0 - 0 - :

G

2 #

" : # #

+ 1 . . 3 !

"

" # " 8 # ") !

4 $

3 4 :

8 6+ #

/ $

0 . . 3 ! 0 % :

" : B" ; $" : %

8 6+ # " ; ! 8 . . . / +

. . / > 4 . . ! 2 % " :

" ; " " 5

. . A ! 0 ") γ− ") # " !

8 6+ # : #

8 6+ J . . ' !

2 # γ ") H A . +! 8 6+#

$ 8 6+ #

: 8 9 " 6 . . ' !

(58)

5 # # 8 9 "

: : 6 : : 6# 3 $

# 8 6+ :

: F / 6 !! + 8 9 " 8 6+

8 9 " 0 @ !!

# 0 - : #

8 6+ ; # 1 . #

6 3 6 ' : / : " / : ! 6 3

6$ : " !

; % 6 : ! 6 3 # 6 '

1 . # 1 .

$ 3 . 6

: / : ! 6

8 9 "

: ! 6 #

8 9 " % ) # .

: / : " / : !

& $ 8 9 "

# 4 -$

4 / :

/ 4 0 . . . / = . . . ! : #

; A 3 : !

= . . . ! " #

8 9 " $

C

(59)

V Ribonucleotide Reductase

Introduction

; ; ; 9 ; ! $

# A I$ !$ O

# $ # $ # O # I$ &

# 8 9 "

; # 9 0

8 9 "

6$ 9 0 % 8 9 " 2 #

& # $

9 0 ; ;

# 8 9 "

; #

!

#

#

- F / 6 8 8 !

#

#

$ G $

; @ !

- ; F / 6C F !

2 # ; 9 ; &

# & 2

# 4 2 ; 9 ; 4 2 ; 9 ;

# 2 2 # %

D ' ! 4 2 & # # #

(60)

# 2 2 2 ; 9 ;

Class Ia RNR

4 2 ; 9 ; α β !

α

# ; β ; ! $

&

2 ; 9 ; # ααIββI #

; 9 ; # ; 9 ; 3 - 8 . !# ; 9 ; ; 9 ; '

> F ! ; 9 ; ; 9 ; 3 . L ; 9 ;

; 9 ; ; 9 ; 3 ; 9 ; ' ; 9 ; ; 9 ; 3

; ; # ; ; 3 ; 3 ; 3 ! # ; ;

8 . . ! 2 $

2 # - & ; 9 ; ; 9 ;

&

< $6 + 2 # 2 8 9 " ; 9 ; 3

# &

8 9 " - 8 . ! # 2 $

8 9 " #

2 # - / - 3 ! >

2 ; # 2 % ; $ ;

# >

F !

(61)

Reaction

E

9 8 0 P $ 6 ! → 9 0 P $ 6$6!

2 2 ; 9 ; #

;

! $

; $ &

& & 5 . !

2 ; 9 ; 5 !

;

; G A !

+ % ' ' &

% " L//% " " /# ! / ( & % M

(62)

4 ' 3 ; #

α Bβ$ ; 9 ; 5 !

" - * ' *

( % % ' *

" ' %

' ' " - ' $ & 2 * *

' % % " L ' '

' " - - % ' 2

% ( + 2 / 2 "

' " " ' ' - "

) % ! ) & + + & N G & + + 5

5 ! 9

3 A " R !Q 4 ' 3

(63)

& % % % O : : 8

o Allosteric regulation

G &

& - & %

!/ &

+ ; @ !

: # " 0 !

2 2 ! I 8

9 0 9 0

% + /

1 ' ! "

%

: 4 2 " 0 !

" 0 ! ; + ; @ !

; %

% 9 0 - " 0 # < 0 0 !

+ ; @ !

$

; F ! 2 ; 9 ; # " 0 " 0

4 8 0 J 8 0 # < 0

"8 0 # 0 < 8 0 5 3 !

(64)

, ! " 2

% - 0 4# # # ( # # " $ 4

* * ' % # # # ( # 4

! " ' " ' % # % O

: : 8

o Checkpoint and dNTP synthesis

& J ! 8 9 "

2 J

) # -$

- @ / 1 > F / 6 8

! 6 6$ 2 # J

9 0 #

9 0 ; A 3 $ 1 . . ' ! 9 0

# 0 < 0

1 . . ' ! J 9 0 #

1 . . ' !#

J ; 9 ; # ; 9 ; 5

; ; D ; !

(65)

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