Microhomology Directs Diverse DNA Break Repair Pathways and Chromosomal Translocations

English version České info

Chromosomal structural change triggers carcinogenesis and the formation of other genetic diseases. The breakpoint junctions of these rearrangements often contain small overlapping sequences called “microhomology,” yet the genetic pathway(s) responsible have yet to be defined. We report a simple genetic system to detect microhomology-mediated repair (MHMR) events after a DNA double-strand break (DSB) in budding yeast cells. MHMR using >15 bp operates as a single-strand annealing variant, requiring the non-essential DNA polymerase subunit Pol32. MHMR is inhibited by sequence mismatches, but independent of extensive DNA synthesis like break-induced replication. However, MHMR using less than 14 bp is genetically distinct from that using longer microhomology and far less efficient for the repair of distant DSBs. MHMR catalyzes chromosomal translocation almost as efficiently as intra-chromosomal repair. The results suggest that the intrinsic annealing propensity between microhomology sequences efficiently leads to chromosomal rearrangements.

Vyšlo v časopise: Microhomology Directs Diverse DNA Break Repair Pathways and Chromosomal Translocations. PLoS Genet 8(11): e32767. doi:10.1371/journal.pgen.1003026
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003026

Souhrn

Zdroje

1. HastingsPJ, LupskiJR, RosenbergSM, IraG (2009) Mechanisms of change in gene copy number. Nat Rev Genet 10: 551–564.

2. KiddJM, GravesT, NewmanTL, FultonR, HaydenHS, et al. (2010) A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell 143: 837–847.

3. ConradDF, BirdC, BlackburneB, LindsayS, MamanovaL, et al. (2010) Mutation spectrum revealed by breakpoint sequencing of human germline CNVs. Nat Genet 42: 385–391.

4. AplanPD (2006) Causes of oncogenic chromosomal translocation. Trends Genet 22: 46–55.

5. ElliottB, JasinM (2002) Double-strand breaks and translocations in cancer. Cell Mol Life Sci 59: 373–385.

6. HaluskaFG, TsujimotoY, CroceCM (1987) Oncogene activation by chromosome translocation in human malignancy. Annu Rev Genet 21: 321–345.

7. MitelmanF (2000) Recurrent chromosome aberrations in cancer. Mutat Res 462: 247–253.

8. MauroMJ, DrukerBJ (2001) Chronic myelogenous leukemia. Curr Opin Oncol 13: 3–7.

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

10. PutnamCD, PennaneachV, KolodnerRD (2005) Saccharomyces cerevisiae as a model system to define the chromosomal instability phenotype. Mol Cell Biol 25: 7226–7238.

11. WeinstockDM, ElliottB, JasinM (2006) A model of oncogenic rearrangements: differences between chromosomal translocation mechanisms and simple double-strand break repair. Blood 107: 777–780.

12. PardoB, Gomez-GonzalezB, AguileraA (2009) DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship. Cell Mol Life Sci 66: 1039–1056.

13. LieberMR, YuK, RaghavanSC (2006) Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. DNA Repair (Amst) 5: 1234–1245.

14. HeyerWD, EhmsenKT, LiuJ (2010) Regulation of homologous recombination in eukaryotes. Annu Rev Genet 44: 113–139.

15. McVeyM, LeeSE (2008) MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings. Trends Genet 24: 529–538.

16. CampbellPJ, StephensPJ, PleasanceED, O'MearaS, LiH, et al. (2008) Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 40: 722–729.

17. ChenC, UmezuK, KolodnerRD (1998) Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair. Mol Cell 2: 9–22.

18. BentleyJ, L'HoteC, PlattF, HurstCD, LoweryJ, et al. (2009) Papillary and muscle invasive bladder tumors with distinct genomic stability profiles have different DNA repair fidelity and KU DNA-binding activities. Genes Chromosomes Cancer 48: 310–321.

19. ShinKH, KangMK, KimRH, KametaA, BaludaMA, et al. (2006) Abnormal DNA end-joining activity in human head and neck cancer. Int J Mol Med 17: 917–924.

20. LawsonAR, HindleyGF, ForshewT, TatevossianRG, JamieGA, et al. (2011) RAF gene fusion breakpoints in pediatric brain tumors are characterized by significant enrichment of sequence microhomology. Genome Res 21: 505–514.

21. LeeK, LeeSE (2007) Saccharomyces cerevisiae Sae2- and Tel1-dependent single-strand DNA formation at DNA break promotes microhomology-mediated end joining. Genetics 176: 2003–2014.

22. YuAM, McVeyM (2010) Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions. Nucleic Acids Res 38: 5706–5717.

23. HicksWM, KimM, HaberJE (2010) Increased mutagenesis and unique mutation signature associated with mitotic gene conversion. Science 329: 82–85.

24. PayenC, KoszulR, DujonB, FischerG (2008) Segmental duplications arise from Pol32-dependent repair of broken forks through two alternative replication-based mechanisms. PLoS Genet 4: e1000175 doi:10.1371/journal.pgen.1000175

25. MaJL, KimEM, HaberJE, LeeSE (2003) Yeast Mre11 and Rad1 proteins define a Ku-independent mechanism to repair double-strand breaks lacking overlapping end sequences. Mol Cell Biol 23: 8820–8828.

26. MooreJK, HaberJE (1996) Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae. Mol Cell Biol 16: 2164–2173.

27. ZhuZ, ChungWH, ShimEY, LeeSE, IraG (2008) Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134: 981–994.

28. ShimEY, ChungWH, NicoletteML, ZhangY, DavisM, et al. (2010) Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaks. EMBO J 29: 3370–3380.

29. MimitouEP, SymingtonLS (2008) Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455: 770–774.

30. Fishman-LobellJ, HaberJE (1992) Removal of nonhomologous DNA ends in double-strand break recombination: the role of the yeast ultraviolet repair gene RAD1. Science 258: 480–484.

31. DecottigniesA (2007) Microhomology-mediated end joining in fission yeast is repressed by pku70 and relies on genes involved in homologous recombination. Genetics 176: 1403–1415.

32. AlaniE, ReenanRA, KolodnerRD (1994) Interaction between mismatch repair and genetic recombination in Saccharomyces cerevisiae.. Genetics 137: 19–39.

33. BailisAM, RothsteinR (1990) A defect in mismatch repair in Saccharomyces cerevisiae stimulates ectopic recombination between homeologous genes by an excision repair dependent process. Genetics 126: 535–547.

34. MezardC, PomponD, NicolasA (1992) Recombination between similar but not identical DNA sequences during yeast transformation occurs within short stretches of identity. Cell 70: 659–670.

35. SelvaEM, NewL, CrouseGF, LahueRS (1995) Mismatch correction acts as a barrier to homeologous recombination in Saccharomyces cerevisiae. Genetics 139: 1175–1188.

36. SugawaraN, GoldfarbT, StudamireB, AlaniE, HaberJE (2004) Heteroduplex rejection during single-strand annealing requires Sgs1 helicase and mismatch repair proteins Msh2 and Msh6 but not Pms1. Proc Natl Acad Sci U S A 101: 9315–9320.

37. SchmidtKH, WuJ, KolodnerRD (2006) Control of translocations between highly diverged genes by Sgs1, the Saccharomyces cerevisiae homolog of the Bloom's syndrome protein. Mol Cell Biol 26: 5406–5420.

38. BennardoN, ChengA, HuangN, StarkJM (2008) Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet 4: e1000110 doi:10.1371/journal.pgen.1000110

39. DaleyJM, PalmbosPL, WuD, WilsonTE (2005) Nonhomologous end joining in yeast. Annu Rev Genet 39: 431–451.

40. IvanovEL, SugawaraN, Fishman-LobellJ, HaberJE (1996) Genetic requirements for the single-strand annealing pathway of double-strand break repair in Saccharomyces cerevisiae. Genetics 142: 693–704.

41. StarkJM, PierceAJ, OhJ, PastinkA, JasinM (2004) Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Mol Cell Biol 24: 9305–9316.

42. IraG, HaberJE (2002) Characterization of RAD51-independent break-induced replication that acts preferentially with short homologous sequences. Mol Cell Biol 22: 6384–6392.

43. SungP (1994) Catalysis of ATP-dependent homologous DNA pairing and strand exchange by yeast RAD51 protein. Science 265: 1241–1243.

44. MalkovaA, NaylorML, YamaguchiM, IraG, HaberJE (2005) RAD51-dependent break-induced replication differs in kinetics and checkpoint responses from RAD51-mediated gene conversion. Mol Cell Biol 25: 933–944.

45. SymingtonLS (2002) Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair. Microbiol Mol Biol Rev 66: 630–670 table of contents.

46. SugawaraN, IraG, HaberJE (2000) DNA length dependence of the single-strand annealing pathway and the role of Saccharomyces cerevisiae RAD59 in double-strand break repair. Mol Cell Biol 20: 5300–5309.

47. SignonL, MalkovaA, NaylorML, KleinH, HaberJE (2001) Genetic requirements for RAD51- and RAD54-independent break-induced replication repair of a chromosomal double-strand break. Mol Cell Biol 21: 2048–2056.

48. GerikKJ, LiX, PautzA, BurgersPM (1998) Characterization of the two small subunits of Saccharomyces cerevisiae DNA polymerase delta. J Biol Chem 273: 19747–19755.

49. JainS, SugawaraN, LydeardJ, VazeM, Tanguy Le GacN, et al. (2009) A recombination execution checkpoint regulates the choice of homologous recombination pathway during DNA double-strand break repair. Genes Dev 23: 291–303.

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

51. DeemA, BarkerK, VanhulleK, DowningB, VaylA, et al. (2008) Defective break-induced replication leads to half-crossovers in Saccharomyces cerevisiae. Genetics 179: 1845–1860.

52. DeemA, KeszthelyiA, BlackgroveT, VaylA, CoffeyB, et al. (2011) Break-induced replication is highly inaccurate. PLoS Biol 9: e1000594 doi:10.1371/journal.pbio.1000594

53. PaquesF, HaberJE (1997) Two pathways for removal of nonhomologous DNA ends during double-strand break repair in Saccharomyces cerevisiae. Mol Cell Biol 17: 6765–6771.

54. HaberJE, LeungWY (1996) Lack of chromosome territoriality in yeast: promiscuous rejoining of broken chromosome ends. Proc Natl Acad Sci U S A 93: 13949–13954.

55. LieberMR (2010) The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem 79: 181–211.

56. StasiakAZ, LarquetE, StasiakA, MullerS, EngelA, et al. (2000) The human Rad52 protein exists as a heptameric ring. Curr Biol 10: 337–340.

57. PannunzioNR, MantheyGM, BailisAM (2008) RAD59 is required for efficient repair of simultaneous double-strand breaks resulting in translocations in Saccharomyces cerevisiae. DNA Repair (Amst) 7: 788–800.

58. KeimlingM, DenizM, VargaD, StahlA, SchrezenmeierH, et al. (2012) The power of DNA double-strand break (DSB) repair testing to predict breast cancer susceptibility. FASEB J

59. LeeK, ZhangY, LeeSE (2008) Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations. Nature 454: 543–546.

60. BennardoN, StarkJM (2010) ATM limits incorrect end utilization during non-homologous end joining of multiple chromosome breaks. PLoS Genet 6: e1001194 doi:10.1371/journal.pgen.1001194

61. LeeSE, MooreJK, HolmesA, UmezuK, KolodnerRD, et al. (1998) Saccharomyces Ku70, mre11/rad50 and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 94: 399–409.

62. WachA, BrachatA, PohlmannR, PhilippsenP (1994) New heterologous modules for classical or PCR-based gene disruptions in Saccharomyces cerevisiae. Yeast 10: 1793–1808.