Is Non-Homologous End-Joining Really an Inherently Error-Prone Process?

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DNA double-strand breaks (DSBs) are harmful lesions leading to genomic instability or diversity. Non-homologous end-joining (NHEJ) is a prominent DSB repair pathway, which has long been considered to be error-prone. However, recent data have pointed to the intrinsic precision of NHEJ. Three reasons can account for the apparent fallibility of NHEJ: 1) the existence of a highly error-prone alternative end-joining process; 2) the adaptability of canonical C-NHEJ (Ku- and Xrcc4/ligase IV–dependent) to imperfect complementary ends; and 3) the requirement to first process chemically incompatible DNA ends that cannot be ligated directly. Thus, C-NHEJ is conservative but adaptable, and the accuracy of the repair is dictated by the structure of the DNA ends rather than by the C-NHEJ machinery. We present data from different organisms that describe the conservative/versatile properties of C-NHEJ. The advantages of the adaptability/versatility of C-NHEJ are discussed for the development of the immune repertoire and the resistance to ionizing radiation, especially at low doses, and for targeted genome manipulation.

Vyšlo v časopise: Is Non-Homologous End-Joining Really an Inherently Error-Prone Process?. PLoS Genet 10(1): e32767. doi:10.1371/journal.pgen.1004086
Kategorie: Review
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004086

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1. 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.

2. 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.

3. 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.

4. AudebertM, SallesB, CalsouP (2004) Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem 279: 55117–55126.

5. CorneoB, WendlandRL, DerianoL, CuiX, KleinIA, et al. (2007) Rag mutations reveal robust alternative end joining. Nature 449: 483–486.

6. FeldmannE, SchmiemannV, GoedeckeW, ReichenbergerS, PfeifferP (2000) DNA double-strand break repair in cell-free extracts from Ku80-deficient cells: implications for Ku serving as an alignment factor in non-homologous DNA end joining. Nucleic Acids Res 28: 2585–2596.

7. 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.

8. WangH, PerraultAR, TakedaY, QinW, IliakisG (2003) Biochemical evidence for Ku-independent backup pathways of NHEJ. Nucleic Acids Res 31: 5377–5388.

9. WangH, RosidiB, PerraultR, WangM, ZhangL, et al. (2005) DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. Cancer Res 65: 4020–4030.

10. 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.

11. 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.

12. CharbonnelC, AllainE, GallegoME, WhiteCI (2011) Kinetic analysis of DNA double-strand break repair pathways in Arabidopsis. DNA Repair (Amst) 10: 611–619.

13. BennardoN, ChengA, HuangN, StarkJM (2008) Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet 4: e1000110.

14. 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.

15. GrabarzA, Guirouilh-BarbatJ, BarascuA, PennarunG, GenetD, et al. (2013) A role for BLM in double-strand break repair pathway choice: prevention of CtIP/Mre11-mediated alternative nonhomologous end-joining. Cell Rep 5: 21–28.

16. PierceAJ, HuP, HanM, EllisN, JasinM (2001) Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev 15: 3237–3242.

17. WangM, WuW, WuW, RosidiB, ZhangL, et al. (2006) PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res 34: 6170–6182.

18. BoultonSJ, JacksonSP (1996) Identification of a Saccharomyces cerevisiae Ku80 homologue: roles in DNA double strand break rejoining and in telomeric maintenance. Nucleic Acids Res 24: 4639–4648.

19. BoultonSJ, JacksonSP (1996) Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double- strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J 15: 5093–5103.

20. LiangF, RomanienkoPJ, WeaverDT, JeggoPA, JasinM (1996) Chromosomal double-strand break repair in Ku80-deficient cells. Proc Natl Acad Sci U S A 93: 8929–8933.

21. Schulte-UentropL, El-AwadyRA, SchlieckerL, WillersH, Dahm-DaphiJ (2008) Distinct roles of XRCC4 and Ku80 in non-homologous end-joining of endonuclease- and ionizing radiation-induced DNA double-strand breaks. Nucleic Acids Res 36: 2561–2569.

22. DelacoteF, LopezBS (2008) Importance of the cell cycle phase for the choice of the appropriate DSB repair pathway, for genome stability maintenance: the trans-S double-strand break repair model. Cell Cycle 7: 33–38.

23. Guirouilh-BarbatJ, HuckS, LopezBS (2008) S-phase progression stimulates both the mutagenic KU-independent pathway and mutagenic processing of KU-dependent intermediates, for nonhomologous end joining. Oncogene 27: 1726–1736.

24. RothkammK, KrugerI, ThompsonLH, LobrichM (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 23: 5706–5715.

25. SaintignyY, DelacoteF, BoucherD, AverbeckD, LopezBS (2007) XRCC4 in G1 suppresses homologous recombination in S/G2, in G1 checkpoint-defective cells. Oncogene 26: 2769–2780.

26. Saleh-GohariN, HelledayT (2004) Conservative homologous recombination preferentially repairs DNA double-strand breaks in the S phase of the cell cycle in human cells. Nucleic Acids Res 32: 3683–3688.

27. PiganeauM, GhezraouiH, De CianA, GuittatL, TomishimaM, et al. (2013) Cancer translocations in human cells induced by zinc finger and TALE nucleases. Genome Res 23: 1182–1193.

28. HollandAJ, ClevelandDW (2012) Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nat Med 18: 1630–1638.

29. JonesMJ, JallepalliPV (2012) Chromothripsis: chromosomes in crisis. Dev Cell 23: 908–917.

30. BoboilaC, JankovicM, YanCT, WangJH, WesemannDR, et al. (2010) Alternative end-joining catalyzes robust IgH locus deletions and translocations in the combined absence of ligase 4 and Ku70. Proc Natl Acad Sci U S A 107: 3034–3039.

31. DifilippantonioMJ, ZhuJ, ChenHT, MeffreE, NussenzweigMC, et al. (2000) DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature 404: 510–514.

32. DifilippantonioMJ, PetersenS, ChenHT, JohnsonR, JasinM, et al. (2002) Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification. J Exp Med 196: 469–480.

33. GaoY, FergusonDO, XieW, ManisJP, SekiguchiJ, et al. (2000) Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature 404: 897–900.

34. SundararajanR, GellonL, ZunderRM, FreudenreichCH (2010) Double-strand break repair pathways protect against CAG/CTG repeat expansions, contractions and repeat-mediated chromosomal fragility in Saccharomyces cerevisiae. Genetics 184: 65–77.

35. McVeyM, RadutD, SekelskyJJ (2004) End-joining repair of double-strand breaks in Drosophila melanogaster is largely DNA ligase IV independent. Genetics 168: 2067–2076.

36. 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.

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

38. SimsekD, BrunetE, WongSY-W, KatyalS, GaoY, et al. (2011) DNA ligase III promotes alternative nonhomologous end-joining during chromosomal translocation formation. PLoS Genet 7: e1002080.

39. 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.

40. SoutoglouE, DornJF, SenguptaK, JasinM, NussenzweigA, et al. (2007) Positional stability of single double-strand breaks in mammalian cells. Nat Cell Biol 9: 675–682.

41. CaryRB, PetersonSR, WangJ, BearDG, BradburyEM, et al. (1997) DNA looping by Ku and the DNA-dependent protein kinase. Proc Natl Acad Sci U S A 94: 4267–4272.

42. DeFazioLG, StanselRM, GriffithJD, ChuG (2002) Synapsis of DNA ends by DNA-dependent protein kinase. EMBO J 21: 3192–3200.

43. DionV, KalckV, HorigomeC, TowbinBD, GasserSM (2012) Increased mobility of double-strand breaks requires Mec1, Rad9 and the homologous recombination machinery. Nat Cell Biol 14: 502–509.

44. Mine-HattabJ, RothsteinR (2012) Increased chromosome mobility facilitates homology search during recombination. Nat Cell Biol 14: 510–517.

45. DuboisE, BischerourJ, MarmignonA, MathyN, RegnierV, et al. (2012) Transposon invasion of the Paramecium germline genome countered by a domesticated PiggyBac transposase and the NHEJ pathway. Int J Evol Biol 2012: 436196.

46. BetermierM (2004) Large-scale genome remodelling by the developmentally programmed elimination of germ line sequences in the ciliate Paramecium. Res Microbiol 155: 399–408.

47. ArnaizO, MathyN, BaudryC, MalinskyS, AuryJ-M, et al. (2012) The Paramecium germline genome provides a niche for intragenic parasitic DNA: evolutionary dynamics of internal eliminated sequences. PLoS Genet 8: e1002984.

48. GratiasA, BétermierM (2003) Processing of double-strand breaks is involved in the precise excision of Paramecium IESs. Mol Cell Biol 23: 7152–7162.

49. BetermierM, DuharcourtS, SeitzH, MeyerE (2000) Timing of developmentally programmed excision and circularization of Paramecium internal eliminated sequences. Mol Cell Biol 20: 1553–1561.

50. KapustaA, MatsudaA, MarmignonA, KuM, SilveA, et al. (2011) Highly precise and developmentally programmed genome assembly in Paramecium requires Ligase IV-dependent end joining. PLoS Genet 7: e1002049.

51. KabotyanskiEB, GomelskyL, HanJO, StamatoTD, RothDB (1998) Double-strand break repair in Ku86- and XRCC4-deficient cells. Nucleic Acids Res 26: 5333–5342.

52. SmithJ, BaldeyronC, De OliveiraI, Sala-TrepatM, PapadopouloD (2001) The influence of DNA double-strand break structure on end-joining in human cells. Nucleic Acids Res 29: 4783–4792.

53. SmithJ, RiballoE, KyselaB, BaldeyronC, ManolisK, et al. (2003) Impact of DNA ligase IV on the fidelity of end joining in human cells. Nucleic Acids Res 31: 2157–2167.

54. WillersH, HussonJ, LeeLW, HubbeP, GazemeierF, et al. (2006) Distinct mechanisms of nonhomologous end joining in the repair of site-directed chromosomal breaks with noncomplementary and complementary ends. Radiat Res 166: 567–574.

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

56. HegdeV, KleinH (2000) Requirement for the SRS2 DNA helicase gene in non-homologous end joining in yeast. Nucleic Acids Res 28: 2779–2783.

57. MoscarielloM, FlorioC, PulitzerJF (2010) Accurate repair of non-cohesive, double strand breaks in Saccharomyces cerevisiae: enhancement by homology-assisted end-joining. Yeast 27: 837–848.

58. YuX, GabrielA (2003) Ku-dependent and Ku-independent end-joining pathways lead to chromosomal rearrangements during double-strand break repair in Saccharomyces cerevisiae. Genetics 163: 843–856.

59. 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.

60. Frank-VaillantM, MarcandS (2002) Transient stability of DNA ends allows nonhomologous end joining to precede homologous recombination. Mol Cell 10: 1189–1199.

61. LeeSE, PaquesF, SylvanJ, HaberJE (1999) Role of yeast SIR genes and mating type in directing DNA double-strand breaks to homologous and non-homologous repair paths. Curr Biol 9: 767–770.

62. 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.

63. WilsonTE, LieberMR (1999) Efficient processing of DNA ends during yeast nonhomologous end joining. Evidence for a DNA polymerase beta (Pol4)-dependent pathway. J Biol Chem 274: 23599–23609.

64. BahmedK, NitissKC, NitissJL (2010) Yeast Tdp1 regulates the fidelity of nonhomologous end joining. Proc Natl Acad Sci U S A 107: 4057–4062.

65. ShumanS, GlickmanMS (2007) Bacterial DNA repair by non-homologous end joining. Nat Rev Microbiol 5: 852–861.

66. AniukwuJ, GlickmanMS, ShumanS (2008) The pathways and outcomes of mycobacterial NHEJ depend on the structure of the broken DNA ends. Genes Dev 22: 512–527.

67. ChayotR, MontagneB, MazelD, RicchettiM (2010) An end-joining repair mechanism in Escherichia coli. Proc Natl Acad Sci U S A 107: 2141–2146.

68. HuefnerND, MizunoY, WeilCF, KorfI, BrittAB (2011) Breadth by depth: expanding our understanding of the repair of transposon-induced DNA double strand breaks via deep-sequencing. DNA Repair (Amst) 10: 1023–1033.

69. LloydAH, WangD, TimmisJN (2012) Single molecule PCR reveals similar patterns of non-homologous DSB repair in tobacco and Arabidopsis. PLoS ONE 7: e32255.

70. OsakabeK, OsakabeY, TokiS (2010) Site-directed mutagenesis in Arabidopsis using custom-designed zinc finger nucleases. Proc Natl Acad Sci U S A 107: 12034–12039.

71. FeschotteC, PrithamEJ (2007) DNA transposons and the evolution of eukaryotic genomes. Annu Rev Genet 41: 331–368.

72. IzsvakZ, StuweEE, FiedlerD, KatzerA, JeggoPA, et al. (2004) Healing the wounds inflicted by sleeping beauty transposition by double-strand break repair in mammalian somatic cells. Mol Cell 13: 279–290.

73. YantSR, KayMA (2003) Nonhomologous-end-joining factors regulate DNA repair fidelity during Sleeping Beauty element transposition in mammalian cells. Mol Cell Biol 23: 8505–8518.

74. RobertV, BessereauJL (2007) Targeted engineering of the Caenorhabditis elegans genome following Mos1-triggered chromosomal breaks. EMBO J 26: 170–183.

75. BeallEL, RioDC (1996) Drosophila IRBP/Ku p70 corresponds to the mutagen-sensitive mus309 gene and is involved in P-element excision in vivo. Genes Dev 10: 921–933.

76. DudleyDD, ChaudhuriJ, BassingCH, AltFW (2005) Mechanism and control of V(D)J recombination versus class switch recombination: similarities and differences. Adv Immunol 86: 43–112.

77. JungD, AltFW (2004) Unraveling V(D)J recombination; insights into gene regulation. Cell 116: 299–311.

78. LieberMR, MaY, PannickeU, SchwarzK (2004) The mechanism of vertebrate nonhomologous DNA end joining and its role in V(D)J recombination. DNA Repair (Amst) 3: 817–826.

79. RooneyS, ChaudhuriJ, AltFW (2004) The role of the non-homologous end-joining pathway in lymphocyte development. Immunol Rev 200: 115–131.

80. BenedictCL, GilfillanS, ThaiTH, KearneyJF (2000) Terminal deoxynucleotidyl transferase and repertoire development. Immunol Rev 175: 150–157.

81. DesiderioSV, YancopoulosGD, PaskindM, ThomasE, BossMA, et al. (1984) Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells. Nature 311: 752–755.

82. LewisSM (1994) P nucleotide insertions and the resolution of hairpin DNA structures in mammalian cells. Proc Natl Acad Sci U S A 91: 1332–1336.

83. RobertsSA, StrandeN, BurkhalterMD, StromC, HavenerJM, et al. (2010) Ku is a 5′-dRP/AP lyase that excises nucleotide damage near broken ends. Nature 464: 1214–1217.

84. Boubakour-AzzouzI, BertrandP, ClaesA, LopezBS, RougeonF (2012) Terminal deoxynucleotidyl transferase requires KU80 and XRCC4 to promote N-addition at non-V(D)J chromosomal breaks in non-lymphoid cells. Nucleic Acids Res 40: 8381–8391.

85. CertoMT, GwiazdaKS, KuharR, SatherB, CuringaG, et al. (2012) Coupling endonucleases with DNA end-processing enzymes to drive gene disruption. Nat Methods 9: 973–975.

86. CappJP, BoudsocqF, BertrandP, Laroche-ClaryA, PourquierP, et al. (2006) The DNA polymerase lambda is required for the repair of non-compatible DNA double strand breaks by NHEJ in mammalian cells. Nucleic Acids Res 34: 2998–3007.

87. CappJP, BoudsocqF, BesnardAG, LopezBS, CazauxC, et al. (2007) Involvement of DNA polymerase mu in the repair of a specific subset of DNA double-strand breaks in mammalian cells. Nucleic Acids Res 35: 3551–3560.

88. MahaneyBL, MeekK, Lees-MillerSP (2009) Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem J 417: 639–650.

89. Nick McElhinnySA, RamsdenDA (2004) Sibling rivalry: competition between Pol X family members in V(D)J recombination and general double strand break repair. Immunol Rev 200: 156–164.

90. MoshousD, CallebautI, de ChassevalR, PoinsignonC, VilleyI, et al. (2003) The V(D)J recombination/DNA repair factor artemis belongs to the metallo-beta-lactamase family and constitutes a critical developmental checkpoint of the lymphoid system. Ann N Y Acad Sci 987: 150–157.

91. AhnesorgP, SmithP, JacksonSP (2006) XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining. Cell 124: 301–313.

92. BuckD, MalivertL, de ChassevalR, BarraudA, FondanecheMC, et al. (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124: 287–299.

93. RevyP, MalivertL, de VillartayJP (2006) Cernunnos-XLF, a recently identified non-homologous end-joining factor required for the development of the immune system. Curr Opin Allergy Clin Immunol 6: 416–420.

94. AudebertM, SallesB, WeinfeldM, CalsouP (2006) Involvement of polynucleotide kinase in a poly(ADP-ribose) polymerase-1-dependent DNA double-strand breaks rejoining pathway. J Mol Biol 356: 257–265.

95. RobertI, DantzerF, Reina-San-MartinB (2009) Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination. J Exp Med 206: 1047–1056.

96. RobbinsDJ, ColemanMS (1988) Initiator role of double stranded DNA in terminal transferase catalyzed polymerization reactions. Nucleic Acids Res 16: 2943–2957.

97. StrandeN, RobertsSA, OhS, HendricksonEA, RamsdenDA (2012) Specificity of the dRP/AP lyase of Ku promotes nonhomologous end joining (NHEJ) fidelity at damaged ends. J Biol Chem 287: 13686–13693.