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Vincent Geli (Instabilité du Génome Et Cancérogénèse, IGC, Marseille)

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Présentation au sujet: "Vincent Geli (Instabilité du Génome Et Cancérogénèse, IGC, Marseille)"— Transcription de la présentation:

1 Vincent Geli (Instabilité du Génome Et Cancérogénèse, IGC, Marseille)

2 LES TELOMERES SONT MULTIFONCTIONNELS ET CONTROLENT LA PROLIFERATION CELLULAIRE ET LA STABILITE DU GENOME - PROTECTION DES EXTREMITES -REPLICATION COMPLETE -DES CHROMOSOMES - ORGANISATION DES CHROMOSOMES

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4 cancerageing DNA damage

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6 Rif1 Rif2 Rif1 TRF2 TRF1 Pot1 TPP1 Taz1 Taz1 Pot1 Rap1 Cdc13 Ten1 Rif1 Rif2 Rif1 swi6 Sir HP1 Rap1 RAP1 TRF1 Tin2 HP1 Pot1 TPP1 Pot1 TPP1 Pot1 TPP1 Ciliate Budding yeast Fission yeast Mammals Stn E. Gilson and V. Géli, 2007.

7 Titia de Lange, 2004, 2005

8 Repeated sequences at the end of linear chromosomes (TTAGGG in humans) Protects against environmental damage, recombination with other chromosomes, & from loss of information during replication Forms a guanine- quadraduplex

9 Dysfunctional telomeres Genomic instability

10 The Eukaryotic Problem of Telomere Replication RNA primer near end of the chromosome on lagging strand cant be replaced with DNA since DNA polymerase must add to a primer sequence. Do chromosomes get shorter with each replication?

11 Replication of the ends of linear DNA ? 5' 3' Eukaryotes TELOMERES and TELOMERASE Telomeric DNA consists of TANDEM REPEATS of simple sequences: TetrahymenaTTGGGG HumansTTAGGG 5-15 kbp D. Termination

12 3 Telomeric DNA is synthesized by the semi-conservative replication machinery Gradual telomere shortening Unprotected telomere Apoptosis Senescence

13 La télomérase est régulée au cours du développement Cellules germinales Cellules somatiques NaissanceMort Taille des télomères Télomérase Taille des télomères Télomérase

14 Structure des télomères temps

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17 Diapositive 23 Permanent arrest = senescence Proliferation of primary normal human cells is not indefinite 1. period of rapid proliferation 2. slowing of the proliferation rate 3. cessation of proliferation = replicative senescence Senescent cells permanently arrested remains viable for extended periods of time changes in morphology, nuclear structure gene expression, metabolism

18 The role of senescence : a limit to proliferation Suggested purpose : to limit the proliferative capacity of normal cells -> a mechanism involved in normal development & tissue maintenance -> a potent tumor-protection mechanism -> must be prevented in proliferative cell compartments (stem cells)

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20 Sénescence (M1) Crise (M2) Immortalité P53 RB hTERT +++

21 Random DNA break Anaphase Telomere dysfunction can initiate genome instability Repeated generation of DNA breaks through breakage-fusion-bridge cycles End-to-end fusion

22 Telomere length dynamics during malignant transformation Telomerase activity Telomere length Extensive proliferation Abnormal proliferation

23 90 % des cancers surexpriment la télomérase 5 % des cancers ne surexpriment pas la télomérase mais activent une voie alternative du maintien de lADN télomérique = ALT

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25 3 Most telomeric DNA is synthesized by the semi-conservative replication machinery Telomerase Gradual telomere shortening (only 7% of cell cycles)

26 THE TELOMERASE The telomerase complex

27 AACCCCAAC 3' 5' RNA AACCCCAAC 3' 5' RNA TELOMERASEThese repeat sequences are found as 3' overhangs: 5'TTGGGGTTGGGGTTGGGG 3' 3'AACCCC 5' (TTGGGG) n 5'TTGGGGTTGGGGTTGGGG 3'AACCCC 5' 3' TGT 5'TTGGGGTTGGGGTTGGGGTTG 3'AACCCC 5' GGGTTG Translocation

28 How is telomerase recruited to the telomere? How is telomerase action coupled to DNA replication? What tell us the yeast system model

29 Rif1 Rif2 Rap1 Cdc13 Ten1 Rif1 Rif2 Sir Budding yeast Stn1 3 E. Gilson and V. Géli, 2007.

30 Est 2 TLC1 ADN Pol ADN Pol RFC RPA FEN-1 DNA ligase 1 Rnase H1 PCNA Primase Helicase Okasaki fragments 5 3 Cdc13-Stn1-Ten1 Rap1 Ku Late S-phase

31 N. Hug and J. Lingner Chromosoma, june 2006

32 Est1-Myc Est2-Myc Cdc13-Myc yKu80-Myc Time (min) Fold enrichment (Tel/Background) wt Ku Est 2 Est1 Est Cdc13

33 Telomerase is acting in S-phase (E. Gilson, D. Gottschling) Telomerase action requires fork passage (E. Gilson, D. Gottschling) Generation of ssDNA G-tails is required for telomerase action (R. Wellinger)

34 G1 Early S Late S M Ten1 Est 2 TLC1 Ku Rap1 Cdc13 Stn1 Ten1 Rap1 3 Rif1 Rif2 Rif1 Rif2 Rif1 Rif2 Sir Ten1 Leading strand Lagging strand Rap1 Ku Cdc13 Stn1 3 Est 2 Rap1

35 G1 Early S Late S S/G2 M Est3 Est1 TLC1 Est2 Cdc13 RPA Rap1 Ku ? Cdk1 ? TLC1 Est3 Tel1 Cdc13 Est2 Rap1 MRX Exo? Cdk1 ? Lagging telomerase Leading telomerase Ku ? Ten1 Leading strand Lagging strand Rap1 Ku Cdc13 Stn1 3 Est 2 Rap1 Est1 Telomerase activation is linked to the passage of the replication fork

36 G1 Early S Late S S/G2 M Est3 Est2 TLC1 Pol /Pol12 Primase Est1 Pif1 RPA Rap1 Rif1 Rif2 Cdc13 Rap1 Est3 Est1 TLC1 RPA Est2 Cdc13 RPA Rap1 Ku ? Cdk1 ? TLC1 Est3 RPA Tel1 Cdc13 Est2 Rap1 MRX Exo? Cdk1 ? Lagging telomerase Leading telomerase Ku ? Est1

37 G1 Early S Late S S/G2 M Ten1 Est 2 TLC1 Ku Rap1 Cdc13 Stn1 Ten1 Rap1 3 Rif1 Rif2 Rif1 Rif2 Rif1 Rif2 Sir Ten1 Ku Rap1 Cdc13 Stn1 Ten1 Rap1 3 Rif1 Rif2 Rif1 Rif2 Rif1 Rif2 Sir Est3 Est2 TLC1 Pol /Pol12 Primase Est1 Pif1 RPA Rap1 Rif1 Rif2 Cdc13 Rap1

38 G1 Early S Late S S/G2 M Ten1 Est 2 TLC1 Ku Rap1 Cdc13 Stn1 Ten1 Rap1 3 Rif1 Rif2 Rif1 Rif2 Rif1 Rif2 Sir Ten1 Ku Rap1 Cdc13 Stn1 Ten1 Rap1 3 Rif1 Rif2 Rif1 Rif2 Rif1 Rif2 Sir Est3 Est2 TLC1 Pol /Pol12 Primase Est1 Pif1 RPA Rap1 Rif1 Rif2 Cdc13 Rap1 Est3 Est1 TLC1 Est2 Cdc13 RPA Rap1 Ku ? Cdk1 ? TLC1 Est3 Tel1 Cdc13 Est2 Rap1 MRX Exo? Cdk1 ? Lagging telomerase Leading telomerase Ku ? Ten1 Leading strand Lagging strand Rap1 Ku Cdc13 Stn1 3 Est 2 Rap1 Est1 E. Gilson and V. Géli, 2007 The telomerase cycle

39 G1 Early S Late S S/G2 M Ten1 Est 2 TLC1 Ku Rap1 Cdc13 Stn1 Ten1 Rap1 3 Rif1 Rif2 Rif1 Rif2 Rif1 Rif2 Sir Ten1 Ku Rap1 Cdc13 Stn1 Ten1 Rap1 3 Rif1 Rif2 Rif1 Rif2 Rif1 Rif2 Sir Est3 Est2 TLC1 Pol /Pol12 Primase Est1 Pif1 RPA Rap1 Rif1 Rif2 Cdc13 Rap1 Est3 Est1 TLC1 RPA Est2 Cdc13 RPA Rap1 Ku ? Cdk1 ? TLC1 Est3 RPA Tel1 Cdc13 Est2 Rap1 MRX Exo? Cdk1 ? Lagging telomerase Leading telomerase Ku ? Ten1 Leading strand Lagging strand Rap1 Ku Cdc13 Stn1 3 Est 2 Rap1 Est1 E. Gilson and V. Géli, 2007


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