The Role of ATM in the Deficiency in Nonhomologous End-Joining near Telomeres in a Human Cancer Cell Line

English version České info

Telomeres distinguish chromosome ends from double-strand breaks (DSBs) and prevent chromosome fusion. However, telomeres can also interfere with DNA repair, as shown by a deficiency in nonhomologous end joining (NHEJ) and an increase in large deletions at telomeric DSBs. The sensitivity of telomeric regions to DSBs is important in the cellular response to ionizing radiation and oncogene-induced replication stress, either by preventing cell division in normal cells, or by promoting chromosome instability in cancer cells. We have previously proposed that the telomeric protein TRF2 causes the sensitivity of telomeric regions to DSBs, either through its inhibition of ATM, or by promoting the processing of DSBs as though they are telomeres, which is independent of ATM. Our current study addresses the mechanism responsible for the deficiency in repair of DSBs near telomeres by combining assays for large deletions, NHEJ, small deletions, and gross chromosome rearrangements (GCRs) to compare the types of events resulting from DSBs at interstitial and telomeric DSBs. Our results confirm the sensitivity of telomeric regions to DSBs by demonstrating that the frequency of GCRs is greatly increased at DSBs near telomeres and that the role of ATM in DSB repair is very different at interstitial and telomeric DSBs. Unlike at interstitial DSBs, a deficiency in ATM decreases NHEJ and small deletions at telomeric DSBs, while it increases large deletions. These results strongly suggest that ATM is functional near telomeres and is involved in end protection at telomeric DSBs, but is not required for the extensive resection at telomeric DSBs. The results support our model in which the deficiency in DSB repair near telomeres is a result of ATM-independent processing of DSBs as though they are telomeres, leading to extensive resection, telomere loss, and GCRs involving alternative NHEJ.

Vyšlo v časopise: The Role of ATM in the Deficiency in Nonhomologous End-Joining near Telomeres in a Human Cancer Cell Line. PLoS Genet 9(3): e32767. doi:10.1371/journal.pgen.1003386
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003386

Souhrn

Zdroje

1. ThompsonLH (2012) Recognition, signaling, and repair of DNA double-strand breaks produced by ionizing radiation in mammalian cells: The molecular choreography. Mutat Res 751: 158–246.

2. MoynahanME, JasinM (2010) Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 11: 196–207.

3. ZhaS, BoboilaC, AltFW (2009) Mre11: roles in DNA repair beyond homologous recombination. Nat Struct Mol Biol 16: 798–800.

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

5. MladenovE, IliakisG (2011) Induction and repair of DNA double strand breaks: the increasing spectrum of non-homologous end joining pathways. Mutat Res 711: 61–72.

6. LavinMF (2007) ATM and the Mre11 complex combine to recognize and signal DNA double-strand breaks. Oncogene 26: 7749–7758.

7. BothmerA, RobbianiDF, FeldhahnN, GazumyanA, NussenzweigA, et al. (2010) 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J Exp Med 207: 855–865.

8. BouwmanP, AlyA, EscandellJM, PieterseM, BartkovaJ, et al. (2010) 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol 17: 688–695.

9. BuntingSF, CallenE, WongN, ChenHT, PolatoF, et al. (2010) 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141: 243–254.

10. CaoL, XuX, BuntingSF, LiuJ, WangRH, et al. (2009) A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol Cell 35: 534–541.

11. HelminkBA, TubbsAT, DorsettY, BednarskiJJ, WalkerLM, et al. (2011) H2AX prevents CtIP-mediated DNA end resection and aberrant repair in G1-phase lymphocytes. Nature 469: 245–249.

12. LangerakP, Mejia-RamirezE, LimboO, RussellP (2011) Release of Ku and MRN from DNA ends by Mre11 nuclease activity and Ctp1 Is required for homologous recombination repair of double-strand breaks. PLoS Genet 7: e1002271 doi:10.1371/journal.pgen.1002271

13. SunJ, LeeKJ, DavisAJ, ChenDJ (2012) Human Ku70/80 protein blocks exonuclease 1-mediated DNA resection in the presence of human Mre11 or Mre11/Rad50 protein complex. J Biol Chem 287: 4936–4945.

14. ShibataA, ConradS, BirrauxJ, GeutingV, BartonO, et al. (2011) Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO J 30: 1079–1092.

15. WilliamsRS, MoncalianG, WilliamsJS, YamadaY, LimboO, et al. (2008) Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair. Cell 135: 97–109.

16. SartoriAA, LukasC, CoatesJ, MistrikM, FuS, et al. (2007) Human CtIP promotes DNA end resection. Nature 450: 509–514.

17. YouZ, ShiLZ, ZhuQ, WuP, ZhangYW, et al. (2009) CtIP links DNA double-strand break sensing to resection. Mol Cell 36: 954–969.

18. YunMH, HiomK (2009) CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 459: 460–463.

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

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

21. TomimatsuN, MukherjeeB, DelandK, KurimasaA, BoldersonE, et al. (2012) Exo1 plays a major role in DNA end resection in humans and influences double-strand break repair and damage signaling decisions. DNA Repair (Amst) 11: 441–448.

22. RassE, GrabarzA, PloI, GautierJ, BertrandP, et al. (2009) Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells. Nat Struct Mol Biol 16: 819–824.

23. XieA, KwokA, ScullyR (2009) Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat Struct Mol Biol 16: 814–818.

24. ZhuangJ, JiangG, WillersH, XiaF (2009) Exonuclease function of human Mre11 promotes deletional nonhomologous end joining. J Biol Chem 284: 30565–30573.

25. Della-MariaJ, ZhouY, TsaiMS, KuhnleinJ, CarneyJP, et al. (2011) Human Mre11/human Rad50/Nbs1 and DNA Ligase IIIα/XRCC1 protein complexes act together in an alternative nonhomologous end joining pathway. J Biol Chem 286: 33845–33853.

26. ZhangY, JasinM (2011) An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Nat Struct Mol Biol 18: 80–84.

27. 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

28. TaylorEM, CecillonSM, BonisA, ChapmanJR, PovirkLF, et al. (2010) The Mre11/Rad50/Nbs1 complex functions in resection-based DNA end joining in Xenopus laevis. Nucleic Acids Res 38: 441–454.

29. YanCT, BoboilaC, SouzaEK, FrancoS, HickernellTR, et al. (2007) IgH class switching and translocations use a robust non-classical end-joining pathway. Nature 449: 478–482.

30. Guirouilh-BarbatJ, RassE, PloI, BertrandP, LopezBS (2007) Defects in XRCC4 and KU80 differentially affect the joining of distal nonhomologous ends. Proc Natl Acad Sci U S A 104: 20902–20907.

31. Guirouilh-BarbatJ, HuckS, BertrandP, PirzioL, DesmazeC, et al. (2004) Impact of the KU80 pathway on NHEJ-induced genome rearrangements in mammalian cells. Mol Cell 14: 611–623.

32. ZhuC, MillsKD, FergusionDO, LeeC, ManisJ, et al. (2002) Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109: 811–821.

33. WeinstockDM, BrunetE, JasinM (2007) Formation of NHEJ-derived reciprocal chromosomal translocations does not require Ku70. Nat Cell Biol 9: 978–981.

34. SymingtonLS, GautierJ (2011) Double-strand break end resection and repair pathway choice. Annu Rev Genet 45: 247–271.

35. LobrichM, ShibataA, BeucherA, FisherA, EnsmingerM, et al. (2010) γH2AX foci analysis for monitoring DNA double-strand break repair: strengths, limitations and optimization. Cell Cycle 9: 662–669.

36. AsaithambyA, HuB, ChenDJ (2011) Unrepaired clustered DNA lesions induce chromosome breakage in human cells. Proc Natl Acad Sci U S A 108: 8293–8298.

37. SchwartzJL, VaughanAT (1989) Association among DNA/chromosome break rejoining rates, chromatin structure alterations, and radiation sensitivity in human tumor cell lines. Cancer Res 49: 5054–5057.

38. WardJF (2000) Complexity of damage produced by ionizing radiation. Cold Spring Harb Symp Quant Biol 65: 377–382.

39. GoodarziAA, NoonAT, JeggoPA (2009) The impact of heterochromatin on DSB repair. Biochem Soc Trans 37: 569–576.

40. ChioloI, MinodaA, ColmenaresSU, PolyzosA, CostesSV, et al. (2011) Double-strand breaks in heterochromatin move outside of a dynamic HP1a domain to complete recombinational repair. Cell 144: 732–744.

41. BeucherA, BirrauxJ, TchouandongL, BartonO, ShibataA, et al. (2009) ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. EMBO J 28: 3413–3427.

42. BlackburnEH, GreiderCW, SzostakJW (2006) Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12: 1133–1138.

43. PalmW, de LangeT (2008) How shelterin protects mammalian telomeres. Annu Rev Genet 42: 301–334.

44. MurakiK, NyhanK, HanL, MurnaneJP (2012) Mechanisms of telomere loss and their consequences for chromosome instability. Front Oncol 2: 135.

45. MurnaneJP (2006) Telomeres and chromosome instability. DNA Repair (Amst) 5: 1082–1092.

46. MurnaneJP (2010) Telomere loss as a mechanism for chromosomal instability in human cancer. Cancer Res 70: 4255–4259.

47. WuP, van OverbeekM, RooneyS, de LangeT (2010) Apollo contributes to G overhang maintenance and protects leading-end telomeres. Mol Cell 39: 606–617.

48. LamYC, AkhterS, GuP, YeJ, PouletA, et al. (2010) SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair. EMBO J 29: 2230–2241.

49. LarriveeM, LeBelC, WellingerRJ (2004) The generation of proper constitutive G-tails on yeast telomeres is dependent on the MRX complex. Genes Dev 18: 1391–1396.

50. ChaiW, SfeirAJ, HoshiyamaH, ShayJW, WrightWE (2006) The involvement of the Mre11/Rad50/Nbs1 complex in the generation of G-overhangs at human telomeres. EMBO Rep 7: 225–230.

51. DengY, GuoX, FergusonDO, ChangS (2009) Multiple roles for MRE11 at uncapped telomeres. Nature 460: 914–918.

52. WuP, TakaiH, de LangeT (2012) Telomeric 3′ overhangs derive from resection by Exo1 and Apollo and fill-in by POT1b-associated CST. Cell 150: 39–52.

53. HockemeyerD, DanielsJP, TakaiH, de LangeT (2006) Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres. Cell 126: 63–77.

54. WuL, MultaniAS, HeH, Cosme-BlancoW, DengY, et al. (2006) Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 126: 49–62.

55. HockemeyerD, PalmW, ElseT, DanielsJP, TakaiKK, et al. (2007) Telomere protection by mammalian Pot1 requires interaction with Tpp1. Nat Struct Mol Biol 14: 754–761.

56. MillerD, ReynoldsGE, MejiaR, StarkJM, MurnaneJP (2011) Subtelomeric regions in mammalian cells are deficient in DNA double-strand break repair. DNA Repair (Amst) 10: 536–544.

57. KarlsederJ, HokeK, MirzoevaOK, BakkenistC, KastanMB, et al. (2004) The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response. PLoS Biol 2: e240 doi:10.1371/journal.pbio.0020240

58. BenettiR, Garcia-CaoM, BlascoMA (2007) Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nat Genet 39: 243–250.

59. PedramM, SprungCN, GaoQ, LoAW, ReynoldsGE, et al. (2006) Telomere position effect and silencing of transgenes near telomeres in the mouse. Mol Cell Biol 26: 1865–1878.

60. AttwoollCL, AkpinarM, PetriniJH (2009) The mre11 complex and the response to dysfunctional telomeres. Mol Cell Biol 29: 5540–5551.

61. DimitrovaN, de LangeT (2009) Cell cycle-dependent role of MRN at dysfunctional telomeres: ATM signaling-dependent induction of nonhomologous end joining (NHEJ) in G1 and resection-mediated inhibition of NHEJ in G2. Mol Cell Biol 29: 5552–5563.

62. HewittG, JurkD, MarquesFD, Correia-MeloC, HardyT, et al. (2012) Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat Commun 3: 708.

63. FumagalliM, RossielloF, ClericiM, BarozziS, CittaroD, et al. (2012) Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol 14: 355–365.

64. SuramA, KaplunovJ, PatelPL, RuanH, CeruttiA, et al. (2012) Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J 31: 2839–2851.

65. HonmaM, SakurabaM, KoizumiT, TakashimaY, SakamotoH, et al. (2007) Non-homologous end-joining for repairing I-SceI-induced DNA double strand breaks in human cells. DNA Repair (Amst) 6: 781–788.

66. RebuzziniP, KhoriauliL, AzzalinCM, MagnaniE, MondelloC, et al. (2005) New mammalian cellular systems to study mutations introduced at the break site by non-homologous end-joining. DNA Repair (Amst) 4: 546–555.

67. VargaT, AplanPD (2005) Chromosomal aberrations induced by double strand DNA breaks. DNA Repair (Amst) 4: 1038–1046.

68. ZschenkerO, KulkarniA, MillerD, ReynoldsGE, Granger-LocatelliM, et al. (2009) Increased sensitivity of subtelomeric regions to DNA double-strand breaks in a human tumor cell line. DNA Repair (Amst) 8: 886–900.

69. FouladiB, MillerD, SabatierL, MurnaneJP (2000) The relationship between spontaneous telomere loss and chromosome instability in a human tumor cell line. Neoplasia 2: 540–554.

70. SabatierL, RicoulM, PottierG, MurnaneJP (2005) The loss of a single telomere can result in genomic instability involving multiple chromosomes in a human tumor cell line. Mol Cancer Res 3: 139–150.

71. KulkarniA, ZschenkerO, ReynoldsG, MillerD, MurnaneJP (2010) The effect of telomere proximity on telomere position effect, chromosome healing and sensitivity to DNA double-strand breaks in a human tumor cell line. Mol Cell Biol 30: 578–589.

72. KoeringCE, PolliceA, ZibellaMP, BauwensS, PuisieuxA, et al. (2002) Human telomeric position effect is determined by chromosomal context and telomeric chromatin integrity. EMBO Rep 3: 1055–1061.

73. BaurJA, ZouY, ShayJW, WrightWE (2001) Telomere position effect in human cells. Science 292: 2075–2077.

74. SimsekD, JasinM (2010) Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4-ligase IV during chromosomal translocation formation. Nat Struct Mol Biol 17: 410–416.

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

76. WilliamsRS, DodsonGE, LimboO, YamadaY, WilliamsJS, et al. (2009) Nbs1 flexibly tethers Ctp1 and Mre11-Rad50 to coordinate DNA double-strand break processing and repair. Cell 139: 87–99.

77. GrabarzA, BarascuA, Guirouilh-BarbatJ, LopezBS (2012) Initiation of DNA double strand break repair: signaling and single-stranded resection dictate the choice between homologous recombination, non-homologous end-joining and alternative end-joining. Am J Cancer Res 2: 249–268.

78. 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

79. WhiteJS, ChoiS, BakkenistCJ (2010) Transient ATM kinase inhibition disrupts DNA damage-induced sister chromatid exchange. Sci Signal 3: ra44.

80. DanielJA, PellegriniM, LeeBS, GuoZ, FilsufD, et al. (2012) Loss of ATM kinase activity leads to embryonic lethality in mice. J Cell Biol 198: 295–304.

81. YamamotoK, WangY, JiangW, LiuX, DuboisRL, et al. (2012) Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice. J Cell Biol 198: 305–313.

82. BaroneG, GroomA, ReimanA, SrinivasanV, ByrdPJ, et al. (2009) Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat 30: 1222–1230.

83. ChoiS, GamperAM, WhiteJS, BakkenistCJ (2010) Inhibition of ATM kinase activity does not phenocopy ATM protein disruption: implications for the clinical utility of ATM kinase inhibitors. Cell Cycle 9: 4052–4057.

84. BennardoN, GunnA, ChengA, HastyP, StarkJM (2009) Limiting the persistence of a chromosome break diminishes its mutagenic potential. PLoS Genet 5: e1000683 doi:10.1371/journal.pgen.1000683

85. ShaharOD, RamEV, ShimshoniE, HareliS, MeshorerE, et al. (2012) Live imaging of induced and controlled DNA double-strand break formation reveals extremely low repair by homologous recombination in human cells. Oncogene 31: 3495–3504.

86. Kanikarla-MarieP, RonaldS, De BenedettiA (2011) Nucleosome resection at a double-strand break during Non-Homologous Ends Joining in mammalian cells - implications from repressive chromatin organization and the role of ARTEMIS. BMC Res Notes 4: 13.

87. GoodarziAA, NoonAT, DeckbarD, ZivY, ShilohY, et al. (2008) ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell 31: 167–177.

88. RaiR, ZhengH, HeH, LuoY, MultaniA, et al. (2010) The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres. EMBO J 29: 2598–2610.

89. LoAWI, SprungCN, FouladiB, PedramM, SabatierL, et al. (2002) Chromosome instability as a result of double-strand breaks near telomeres in mouse embryonic stem cells. Mol Cell Biol 22: 4836–4850.

90. CapperR, Britt-ComptonB, TankimanovaM, RowsonJ, LetsoloB, et al. (2007) The nature of telomere fusion and a definition of the critical telomere length in human cells. Genes Dev 21: 2495–2508.

91. TanakaH, AbeS, HudaN, TuL, BeamMJ, et al. (2012) Telomere fusions in early human breast carcinoma. Proc Natl Acad Sci U S A 109: 14098–14103.

92. ChapmanJR, TaylorMR, BoultonSJ (2012) Playing the end game: DNA double-strand break repair pathway choice. Mol Cell 47: 497–510.

93. LoAWI, SabatierL, FouladiB, PottierG, RicoulM, et al. (2002) DNA amplification by breakage/fusion/bridge cycles initiated by spontaneous telomere loss in a human cancer cell line. Neoplasia 6: 531–538.

94. GisselssonD, JonsonT, PetersenA, StrombeckB, Dal CinP, et al. (2001) Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc Natl Acad Sci USA 98: 12683–12688.

95. LinardopoulouEV, WilliamsEM, FanY, FriedmanC, YoungJM, et al. (2005) Human subtelomeres are hot spots of interchromosomal recombination and segmental duplication. Nature 437: 94–100.

96. CotterPD, KaffeS, LiL, GershinIF, HirschhornK (2001) Loss of subtelomeric sequence associated with a terminal inversion duplication of the short arm of chromosome 4. Am J Med Genet 102: 76–80.

97. HooJJ, ChaoM, SzegoK, RauerM, EchiverriSC, et al. (1995) Four new cases of inverted terminal duplication: a modified hypothesis of mechanism of origin. Am J Med Genet 58: 299–304.

98. SouthST, SwensenJJ, MaxwellT, RopeA, BrothmanAR, et al. (2006) A new genomic mechanism leading to cri-du-chat syndrome. Am J Med Genet A 140: 2714–2720.

99. YuS, GrafWD (2010) Telomere capture as a frequent mechanism for stabilization of the terminal chromosomal deletion associated with inverted duplication. Cytogenet Genome Res 129: 265–274.

100. ZuffardiO, BonagliaM, CicconeR, GiordaR (2009) Inverted duplications deletions: underdiagnosed rearrangements?? Clin Genet 75: 505–513.

101. O'TooleCM, PoveyS, HepburnP, FranksLM (1983) Identity of some human bladder cancer cell lines. Nature 301: 429–430.

102. HicksonI, ZhaoY, RichardsonCJ, GreenSJ, MartinNM, et al. (2004) Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res 64: 9152–9159.

103. StohrBA, BlackburnEH (2008) ATM mediates cytotoxicity of a mutant telomerase RNA in human cancer cells. Cancer Res 68: 5309–5317.

104. GaoQ, ReynoldsGE, WilcoxA, MillerD, CheungP, et al. (2008) Telomerase-dependent and -independent chromosome healing in mouse embryonic stem cells. DNA Repair (Amst) 7: 1233–1249.