Break-Induced Replication Requires DNA Damage-Induced Phosphorylation of Pif1 and Leads to Telomere Lengthening

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Telomeres are the ends of linear eukaryotic chromosomes maintained by an enzyme called telomerase. Non-telomeric DNA ends are often generated as a result of broken replication forks and are usually repaired by break-induced replication (BIR) or homologous recombination to avoid genomic instability. However, telomerase can interfere with the repair by adding a new telomere to a broken DNA end, or the break can be ligated to a telomere, thereby inducing genome re-arrangements that are often found in human genetic disorders and cancer. To understand how cells avoid erroneous repair, we studied cdc9-1 yeast mutant cells that generate broken replication forks with high frequency. We discovered that, in cells with DNA damage, a helicase called Pif1 is phosphorylated and this phosphorylation enables Pif1 not only to inhibit telomerase at broken DNA ends but also stimulate the break repair by BIR, which in turn leads to additional telomere lengthening. Thus, a new regulatory pathway stimulates accurate break repair by BIR and at the same time promotes telomerase activity at telomeres.

Vyšlo v časopise: Break-Induced Replication Requires DNA Damage-Induced Phosphorylation of Pif1 and Leads to Telomere Lengthening. PLoS Genet 10(10): e32767. doi:10.1371/journal.pgen.1004679
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004679

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Zdroje

1. MyungK, DattaA, KolodnerRD (2001) Suppression of spontaneous chromosomal rearrangements by S phase checkpoint functions in Saccharomyces cerevisiae. Cell 104: 397–408.

2. MirkinEV, MirkinSM (2007) Replication fork stalling at natural impediments. Microbiol Mol Biol Rev 71: 13–35.

3. MeloJ, ToczyskiD (2002) A unified view of the DNA-damage checkpoint. Curr Opin Cell Biol 14: 237–245.

4. AnandRP, LovettST, HaberJE (2013) Break-induced DNA replication. Cold Spring Harb Perspect Biol 5: a010397.

5. DonnianniRA, SymingtonLS (2013) Break-induced replication occurs by conservative DNA synthesis. Proc Natl Acad Sci U S A 110: 13475–13480.

6. SainiN, RamakrishnanS, ElangoR, AyyarS, ZhangY, et al. (2013) Migrating bubble during break-induced replication drives conservative DNA synthesis. Nature 502: 389–392.

7. LydeardJR, JainS, YamaguchiM, HaberJE (2007) Break-induced replication and telomerase-independent telomere maintenance require Pol32. Nature 448: 820–823.

8. WilsonMA, KwonY, XuY, ChungWH, ChiP, et al. (2013) Pif1 helicase and Poldelta promote recombination-coupled DNA synthesis via bubble migration. Nature 502: 393–396.

9. SingerMS, GottschlingDE (1994) TLC1: template RNA component of Saccharomyces cerevisiae telomerase. Science 266: 404–409.

10. LendvayTS, MorrisDK, SahJ, BalasubramanianB, LundbladV (1996) Senescence mutants of Saccharomyces cerevisiae with a defect in telomere replication identify three additional EST genes. Genetics 144: 1399–1412.

11. LingnerJ, HughesTR, ShevchenkoA, MannM, LundbladV, et al. (1997) Reverse transcriptase motifs in the catalytic subunit of telomerase. Science 276: 561–567.

12. DiedeSJ, GottschlingDE (1999) Telomerase-mediated telomere addition in vivo requires DNA primase and DNA polymerases alpha and delta. Cell 99: 723–733.

13. MarcandS, BrevetV, MannC, GilsonE (2000) Cell cycle restriction of telomere elongation. Curr Biol 10: 487–490.

14. HarringtonLA, GreiderCW (1991) Telomerase primer specificity and chromosome healing. Nature 353: 451–454.

15. MorinGB (1991) Recognition of a chromosome truncation site associated with alpha-thalassaemia by human telomerase. Nature 353: 454–456.

16. SchulzVP, ZakianVA (1994) The saccharomyces PIF1 DNA helicase inhibits telomere elongation and de novo telomere formation. Cell 76: 145–155.

17. MakovetsS, BlackburnEH (2009) DNA damage signalling prevents deleterious telomere addition at DNA breaks. Nat Cell Biol 11: 1383–1386.

18. MyungK, ChenC, KolodnerRD (2001) Multiple pathways cooperate in the suppression of genome instability in Saccharomyces cerevisiae. Nature 411: 1073–1076.

19. McEachernMJ, IyerS (2001) Short telomeres in yeast are highly recombinogenic. Mol Cell 7: 695–704.

20. JohnstonLH, NasmythKA (1978) Saccharomyces cerevisiae cell cycle mutant cdc9 is defective in DNA ligase. Nature 274: 891–893.

21. HartwellLH, MortimerRK, CulottiJ, CulottiM (1973) Genetic Control of the Cell Division Cycle in Yeast: V. Genetic Analysis of cdc Mutants. Genetics 74: 267–286.

22. SchiestlRH, ReynoldsP, PrakashS, PrakashL (1989) Cloning and sequence analysis of the Saccharomyces cerevisiae RAD9 gene and further evidence that its product is required for cell cycle arrest induced by DNA damage. Mol Cell Biol 9: 1882–1896.

23. AdamsAK, HolmC (1996) Specific DNA replication mutations affect telomere length in Saccharomyces cerevisiae. Mol Cell Biol 16: 4614–4620.

24. SanchezY, DesanyBA, JonesWJ, LiuQ, WangB, et al. (1996) Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science 271: 357–360.

25. ZhaoX, MullerEG, RothsteinR (1998) A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools. Mol Cell 2: 329–340.

26. OsbornAJ, ElledgeSJ (2003) Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53. Genes Dev 17: 1755–1767.

27. ZhaoX, RothsteinR (2002) The Dun1 checkpoint kinase phosphorylates and regulates the ribonucleotide reductase inhibitor Sml1. Proc Natl Acad Sci U S A 99: 3746–3751.

28. QiH, ZakianVA (2000) The Saccharomyces telomere-binding protein Cdc13p interacts with both the catalytic subunit of DNA polymerase alpha and the telomerase-associated est1 protein. Genes Dev 14: 1777–1788.

29. CarsonMJ, HartwellL (1985) CDC17: an essential gene that prevents telomere elongation in yeast. Cell 42: 249–257.

30. MartinSG, LarocheT, SukaN, GrunsteinM, GasserSM (1999) Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast. Cell 97: 621–633.

31. WellingerRJ, ZakianVA (2012) Everything you ever wanted to know about Saccharomyces cerevisiae telomeres: beginning to end. Genetics 191: 1073–1105.

32. PfingstenJS, GoodrichKJ, TaabazuingC, OuenzarF, ChartrandP, et al. (2012) Mutually exclusive binding of telomerase RNA and DNA by Ku alters telomerase recruitment model. Cell 148: 922–932.

33. MakovetsS, HerskowitzI, BlackburnEH (2004) Anatomy and dynamics of DNA replication fork movement in yeast telomeric regions. Mol Cell Biol 24: 4019–4031.

34. Cortes-LedesmaF, AguileraA (2006) Double-strand breaks arising by replication through a nick are repaired by cohesin-dependent sister-chromatid exchange. EMBO Rep 7: 919–926.

35. BernsteinKA, ReidRJ, SunjevaricI, DemuthK, BurgessRC, et al. (2011) The Shu complex, which contains Rad51 paralogues, promotes DNA repair through inhibition of the Srs2 anti-recombinase. Mol Biol Cell 22: 1599–1607.

36. SasanumaH, TawaramotoMS, LaoJP, HosakaH, SandaE, et al. (2013) A new protein complex promoting the assembly of Rad51 filaments. Nat Commun 4: 1676.

37. PrakashR, SatoryD, DrayE, PapushaA, SchellerJ, et al. (2009) Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination. Genes Dev 23: 67–79.

38. Luke-GlaserS, LukeB (2012) The Mph1 helicase can promote telomere uncapping and premature senescence in budding yeast. PLoS One 7: e42028.

39. RudinN, HaberJE (1988) Efficient repair of HO-induced chromosomal breaks in Saccharomyces cerevisiae by recombination between flanking homologous sequences. Mol Cell Biol 8: 3918–3928.

40. IvessaAS, LenzmeierBA, BesslerJB, GoudsouzianLK, SchnakenbergSL, et al. (2003) The Saccharomyces cerevisiae helicase Rrm3p facilitates replication past nonhistone protein-DNA complexes. Mol Cell 12: 1525–1536.

41. IvessaAS, ZhouJQ, SchulzVP, MonsonEK, ZakianVA (2002) Saccharomyces Rrm3p, a 5′ to 3′ DNA helicase that promotes replication fork progression through telomeric and subtelomeric DNA. Genes Dev 16: 1383–1396.

42. DeemA, KeszthelyiA, BlackgroveT, VaylA, CoffeyB, et al. (2011) Break-induced replication is highly inaccurate. PLoS Biol 9: e1000594.

43. VasanS, DeemA, RamakrishnanS, ArguesoJL, MalkovaA (2014) Cascades of genetic instability resulting from compromised break-induced replication. PLoS Genet 10: e1004119.

44. LitiG, LouisEJ (2005) Yeast evolution and comparative genomics. Annu Rev Microbiol 59: 135–153.

45. LydeardJR, Lipkin-MooreZ, SheuYJ, StillmanB, BurgersPM, et al. (2010) Break-induced replication requires all essential DNA replication factors except those specific for pre-RC assembly. Genes Dev 24: 1133–1144.

46. TorresJZ, SchnakenbergSL, ZakianVA (2004) Saccharomyces cerevisiae Rrm3p DNA helicase promotes genome integrity by preventing replication fork stalling: viability of rrm3 cells requires the intra-S-phase checkpoint and fork restart activities. Mol Cell Biol 24: 3198–3212.

47. AskreeSH, YehudaT, SmolikovS, GurevichR, HawkJ, et al. (2004) A genome-wide screen for Saccharomyces cerevisiae deletion mutants that affect telomere length. Proc Natl Acad Sci U S A 101: 8658–8663 Epub 2004 May 8625.

48. GatbontonT, ImbesiM, NelsonM, AkeyJM, RuderferDM, et al. (2006) Telomere length as a quantitative trait: genome-wide survey and genetic mapping of telomere length-control genes in yeast. PLoS Genet 2: e35 Epub 2006 Mar 2017.

49. ChangM, ArnericM, LingnerJ (2007) Telomerase repeat addition processivity is increased at critically short telomeres in a Tel1-dependent manner in Saccharomyces cerevisiae. Genes Dev 21: 2485–2494.

50. SabourinM, TuzonCT, ZakianVA (2007) Telomerase and Tel1p preferentially associate with short telomeres in S. cerevisiae. Mol Cell 27: 550–561.

51. PickettHA, ReddelRR (2012) The role of telomere trimming in normal telomere length dynamics. Cell Cycle 11: 1309–1315.

52. O'RourkeSM, HerskowitzI (1998) The Hog1 MAPK prevents cross talk between the HOG and pheromone response MAPK pathways in Saccharomyces cerevisiae. Genes Dev 12: 2874–2886.