Topoisomerase II– and Condensin-Dependent Breakage of -Sensitive Fragile Sites Occurs Independently of Spindle Tension, Anaphase, or Cytokinesis

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Fragile sites are loci of recurrent chromosome breakage in the genome. They are found in organisms ranging from bacteria to humans and are implicated in genome instability, evolution, and cancer. In budding yeast, inactivation of Mec1, a homolog of mammalian ATR, leads to chromosome breakage at fragile sites referred to as replication slow zones (RSZs). RSZs are proposed to be homologous to mammalian common fragile sites (CFSs) whose stability is regulated by ATR. Perturbation during S phase, leading to elevated levels of stalled replication forks, is necessary but not sufficient for chromosome breakage at RSZs or CFSs. To address the nature of additional event(s) required for the break formation, we examined involvement of the currently known or implicated mechanisms of endogenous chromosome breakage, including errors in replication fork restart, premature mitotic chromosome condensation, spindle tension, anaphase, and cytokinesis. Results revealed that chromosome breakage at RSZs is independent of the RAD52 epistasis group genes and of TOP3, SGS1, SRS2, MMS4, or MUS81, indicating that homologous recombination and other recombination-related processes associated with replication fork restart are unlikely to be involved. We also found spindle force, anaphase, or cytokinesis to be dispensable. RSZ breakage, however, required genes encoding condensin subunits (YCG1, YSC4) and topoisomerase II (TOP2). We propose that chromosome break formation at RSZs following Mec1 inactivation, a model for mammalian fragile site breakage, is mediated by internal chromosomal stress generated during mitotic chromosome condensation.

Vyšlo v časopise: Topoisomerase II– and Condensin-Dependent Breakage of -Sensitive Fragile Sites Occurs Independently of Spindle Tension, Anaphase, or Cytokinesis. PLoS Genet 8(10): e32767. doi:10.1371/journal.pgen.1002978
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002978

Souhrn

Zdroje

1. BidnenkoV, EhrlichS, MichelB (2002) Replication fork collapse at replication terminator sequences. EMBO J 21: 3898–3907.

2. ChaRS, KlecknerN (2002) ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones. Science 297: 602–606.

3. MagenisR, HechtR, LovrienE (1970) Heritable fragile site on chromosome 16: probable localization of haptoglobin locus in man. Science 170: 85–87.

4. Sutherland G, Hecht F (1985) Fragile sites on human chromosomes. New York: Oxford University Press.

5. Hill T (1996) Features of the chromosome terminus region. In: Neidhardt F, editor. Escherichia coli and Salmonella: Cellular and Molecular Biology. Washington DC: ASM Press. pp. 1602–1615.

6. DurkinS, GloverT (2007) Chromosome fragile sites. Ann Rev Gen 41: 169–192.

7. GloverT, SteinC (1987) Induction of sister chromatid exchanges at common fragile sites. Am J Hum Genet 41: 882–890.

8. SmeetsD, van de KlundertF (1990) Common fragile sites in man and three closely related primate species. Cytogenet Cell Genet 53: 8–14.

9. ElderF, RobinsonT (1989) Rodent common fragile sites: are they conserved? Evidence from mouse and rat. Chromosoma 97: 459–464.

10. LairdC, JaffeE, KarpenG, LambM, NelsonR (1987) Fragile sites in human chromosomes as regions of late-replicating DNA. TIB 3: 274–281.

11. GloverT, BergerC, CoyleJ, EchoB (1984) DNA polymerase alpha inhibition by aphidicolin induces gaps and breaks at common fragile sites in human chromosomes. Hum Genet 67: 136–142.

12. CasperA, NghiemP, ArltM, GloverT (2002) ATR regulates fragile site stability. Cell 111: 779–789.

13. Ozer-GalaiE, SchwartzM, RahatA, KeremB (2008) Interplay between ATM and ATR in the regulation of common fragile site stability. Oncogene 27: 2109–2117.

14. SchwartzM, ZlotorynskiE, GoldbergM, OzeriE, RahatA, et al. (2005) Homologous recombination and nonhomologous end-joining repair pathways regulate fragile site stability. Genes Dev 19: 2715–2726.

15. El AchkarE, Gerbault-SeureauM, MulerisM, DutrillauxB, DebatisseM (2005) Premature condensation induces breaks at the interface of early and late replicating chromosome bands bearing common fragile sites. Proc Natl Acad Sci U S A 102: 18069–18074.

16. NaimV, RosselliF (2009) The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. Nat Cell Biol 11: 761–768.

17. ChanK, Palmai-PallagT, YingS, HicksonI (2009) Replication stress induces sister-chromatid bridging at fragile site loci in mitosis. Nat Cell Biol 11: 753–760.

18. AdmireA, ShanksL, DanzlN, WangM, WeierU, et al. (2006) Cycles of chromosome instability are associated with a fragile site and are increased by defects in DNA replication and checkpoint controls in yeast. Genes Dev 20: 159–173.

19. HashashN, JohnsonAL, ChaRS (2011) Regulation of fragile sites expression in budding yeast by MEC1, RRM3 and hydroxyurea. J Cell Sci 124: 181–185.

20. LemoineF, DegtyarevaN, LobachevK, PetesT (2005) Chromosomal translocations in yeast induced by low levels of DNA polymerase: A model for chromosome fragile sites. Cell 120: 587–598.

21. TorresJ, BesslerJ, ZakianV (2004) Local chromatin structure at the ribosomal DNA causes replication fork pausing and genome instability in the absence of the S. cerevisiae DNA helicase Rrm3p. Genes Dev 18: 498–503.

22. SpellRM, HolmC (1994) Nature and distribution of chromosomal intertwinings in Saccharomyces cerevisiae. Mol Cell Biol 14: 1465–1476.

23. BermejoR, CarpraT, Gonzalez-HuiciV, FachinettiD, CocitoA, et al. (2009) Genome-organizing factors Top2 and Hmo1 prevent chromosome fragility at sites of S phase transcription. Cell 138: 870–884.

24. KatoR, OgawaH (1994) An essential gene, ESR1, is required for mitotic cell growth, DNA repair and meiotic recombination in Saccharomyces cerevisiae. Nucleic Acids Res 22: 3104–3112.

25. CarballoJA, ChaRS (2007) Meiotic roles of Mec1, a budding yeast homolog of mammalian ATR/ATM. Chromosome Res 15: 539–550.

26. CarballoJA, JohnsonAL, SedgwickSG, ChaRS (2008) Phosphorylation of the axial element protein Hop1 by Mec1/Tel1 ensures meiotic interhomolog recombination. Cell 132: 758–770.

27. WeinertTA, KiserGL, HartwellLH (1994) Mitotic checkpoint genes in budding yeast and the dependence of mitosis on DNA replication and repair. Genes Dev 8: 652–665.

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

29. ZhaoX, ChabesA, DomkinV, ThelanderL, RothsteinR (2001) The ribonucleotide reductase inhibitor Sml1 is a new target of the Mec1/Rad53 kinase cascade during growth and in response to DNA damage. EMBO J 20: 3544–3553.

30. DesanyB, AlcasabasAA, BachantJB, ElledgeSJ (1998) Recovery from DNA replicational stress is the essential function of the S phase checkpoint pathway. Genes Dev 12: 2956–2970.

31. AndresonB, GuptaA, GeorgievaB, RothsteinR (2010) The ribonucleotide reductase inhibitor, Sml1, is sequentially phosphorylated, ubiquitylated and degraded in response to DNA damage. Nucleic Acids Res 38: 6490–6501.

32. LopesM, Cotta-RamusinoC, PellicioliA, LiberiG, PlevaniP, et al. (2001) The DNA replication checkpoint response stablizes stalled replication forks. Nature 412: 557–561.

33. TerceroJ, DiffleyJ (2001) Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 412: 553–556.

34. MishmarD, RahatA, SchererS, NyakaturaG, HinzmannB, et al. (1998) Molecular characterization of a common fragile site (FRA7H) on human chromosome 7 by the cloning of a simian virus 40 integration site. Proc Natl Acad Sci U S A 95: 8141–8146.

35. ZhangH, FreudenreichC (2007) An AT-rich sequence in human common fragile site FRA16D causes fork stalling and chromosome breakage in S. cerevisiae. Mol Cell 27: 367–379.

36. BrewerBJ, FangmanWL (1988) A replication fork barrier at the 3′ end of yeast ribosomal RNA genes. Cell 55: 637–643.

37. DalgaardJ, KlarA (2000) swi1 and swi3 perform imprinting, pausing, and termination of DNA replication in S. pombe. Cell 102: 745–751.

38. CoxM, GoodmanM, KreuzerK, SherrattD, SandlerS, et al. (2000) The importance of repairing stalled replication forks. Nature 404: 37–41.

39. CollinsS, MillerK, MaasN, RoguevA, FillinghamJ, et al. (2007) Functional dissection of protein complexes involved in yeast chromosome biology using a genetic interaction map. Nature 446: 806–810.

40. LambertS, MizunoK, BlaisonneauJ, MartineauS, ChanetR, et al. (2010) Homologous recombination restarts blocked replication forks at the expense of genome rearrangements by template exchange. Mol Cell 346–359.

41. LobachevK, GordeninD, ResnickM (2002) The Mre11 complex is required for repair of hairpin-capped double-strand breaks and prevention of chromosome rearrangements. Cell 108: 183–193.

42. CotéA, LewisS (2008) Mus81-dependent double-strand DNA breaks at in vivo-generated cruciform structures in S. cerevisiae. Mol Cell 31: 800–812.

43. LewD, BurkeD (2003) The spindle assembly and spindle position checkpoints. Annu Rev Genet 37: 251–282.

44. KimE, BurkeD (2008) DNA damage activates the SAC in an ATM/ATR dependent manner, independently of the kinetochore. PLoS Genetics 4: e1000015 doi:10.1371/journal.pgen.1000015.

45. KrishnanV, NirantarS, CrastaK, ChengA, SuranaU (2004) DNA replication checkpoint prevents precocious chromosome segregation by regulating spindle behavior. Mol Cell 16: 687–700.

46. BachantJ, JessenS, KavanaughS, FieldingC (2005) The yeast S phase checkpoint enables replicating chromosomes to bi-orient and restrain spindle extension during S phase distress. J Cell Biol 168: 999–1012.

47. UhlmannF, WernicD, PoupartM-A, KooninE, NasmythK (2000) Cleavage of cohesin by the CD clan protease separin triggers anaphase in yeast. Cell 103: 375–386.

48. UemuraT, OhkuraH, AdachiY, MorinoK, ShiozakiK, et al. (1987) DNA topoisomerase II is required for condensation and separation of mitotic chromosomes in S. pombe. Cell 50: 917–925.

49. Gimenez-AbianJ, ClarkeD, DevlinJ, Gimenez-AbianM, De la TorreC, et al. (2000) Premitotic chromosome individualization in mammalian cells depends on topoisomerase II activity. Chromosoma 109: 235–244.

50. GuacciV, KoshlandD, StrunnikovA (1997) A direct link between sister chromtid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae. Cell 91: 47–57.

51. CioskR, ZachariaeW, MichaelisC, ShevchenkoA, MannM, et al. (1998) An ESP1/PDS1 complex regulates loss of sister chromatid cohesion at the metaphase to anaphase transition in yeast. Cell 93: 1067–1076.

52. LavoieB, TuffoK, OhS, KoshlandD, HolmC (2000) Mitotic chromosome condensation requires Brn1p, the yeast homologue of Barren. Mol Biol Cell 11: 1293–1304.

53. LosadaA, HiranoT (2005) Dynamic molecular linkers of the genome: the first decade of SMC proteins. Genes Dev 19: 1269–1287.

54. Gimenez-AbianJ, ClarkeD, MullingerA, DownesC, JohnstonR (1995) A postprophase topoisomerase II-dependent chromatid core separation step in the formation of metaphase chromosomes. J Cell Biol 131: 7–17.

55. AlexandruG, ZachariaeW, SchleifferA, NasmythK (1999) Sister chromatid separation and chromosome re-duplication are regulated by different mechanisms in response to spindle damage. EMBO J 18: 2707–2721.

56. BiE, MaddoxP, LewD, SalmonE, McMillanJ, et al. (1998) Involvement of an actomyosin contractile ring in Saccharomyces cerevisiae cytokinesis. J Cell Biol 142: 1301–1312.

57. LavoieB, HoganE, KoshlandD (2002) In vivo dissection of the chromosome condensation machinery: reversibility of condensation distinguishes contributions of condensin and cohesin. J Cell Biol 156: 805–815.

58. GuacciV, HoganE, KoshlandD (1994) Chromosome condensation and sister chromatid pairing in budding yeast. J Cell Biol 125: 517–530.

59. StrunnikovA, HoganE, KoshlandD (1995) SMC2, a Saccharomyces cerevisiae gene essential for chromosome segregation and condensation, defines a subgroup within the SMC family. Genes Dev 9: 587–599.

60. VasA, AndrewsC, Kirkland MateskyK, ClarkeD (2007) In vivo analysis of chromosome condensation in Saccharomyces cerevisiae. Mol Biol Cell 18: 557–568.

61. LosadaA, HiranoM, HiranoT (2002) Cohesin release is required for sister chromatid resolution, but not for condensin-mediated compaction, at the onset of mitosis. Genes Dev 16: 3004–3016.

62. DiNardoS, VoelkelK, SternglanzR (1984) DNA topoisomearse II mutant of Saccharomyces cerevisiae: Topoisomerase II is required for segregation of daughter molecules at the termination of DNA replication. Proc Natl Acad Sci U S A 81: 2616–2620.

63. FengW, BachantJ, CollingwoodD, RaghuramanM, BrewerB (2009) Centromere replication timing determines different forms of genomic instability in Saccharomyces cerevisiae checkpoint mutants during replication stress. Genetics 183: 1249–1260.

64. BloomK (2008) Beyond the code: the mechanical properties of DNA as they relate to mitosis. Chromosoma 117: 103–110.

65. BensimonD, SimonA, CroquetteV, BensimonA (1995) Stretching DNA with a receding meniscus: Experiments and models. Phys Rev Lett 74: 4754–4757.

66. MatosJ, BlancoM, MaslenS, SkehelJ, SCW (2011) Regulatory control of the resolution of DNA recombination intermediates during meiosis and mitosis. Cell 147: 158–172.

67. BroomfieldS, HryciwT, XiaoW (2001) DNA postreplication repair and mutagenesis in Saccharomyces cerevisiae.. Mutat Res 486: 167–184.

68. FengW, Di RienziS, RaghuramanM, BrewerB (2011) Replication stress-induced chromosome breakage is correlated with replication fork progression and is preceded by single-stranded DNA formation. G3 1: 327–335.

69. BaxterJ, DiffleyJ (2008) Topoisomerase II inactivation prevents the completion of DNA replication in budding yeast. Mol Cell 30: 790–802.

70. LosadaA, HiranoM, HiranoT (1998) Identification of Xenopus SMC protein complexes required for sister chromatid cohesion. Gene Dev 12: 1986–1997.

71. LambertS, WatsonD, SheedyD, MartinB, CarrA (2005) Gross chromosomal rearrangements and elevated recombination at an inducible site-specific recombination fork barrier. Cell 121: 689–702.

72. BordeV, GoldmanAS, LichtenM (2000) Direct coupling between meiotic DNA replication and recombination initiation. Science 290: 806–809.

73. ChaRS, WeinerBM, KeeneyS, DekkerJ, KlecknerN (2000) Progression of meiotic DNA replication is modulated by interchromosomal interaction proteins, negatively by Spo11p and positively by Rec8p. Genes Dev 14: 493–503.