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Chromosoma

, Volume 119, Issue 2, pp 115–135 | Cite as

MRN and the race to the break

  • Agnieszka Rupnik
  • Noel F. Lowndes
  • Muriel Grenon
Review

Abstract

In all living cells, DNA is constantly threatened by both endogenous and exogenous agents. In order to protect genetic information, all cells have developed a sophisticated network of proteins, which constantly monitor genomic integrity. This network, termed the DNA damage response, senses and signals the presence of DNA damage to effect numerous biological responses, including DNA repair, transient cell cycle arrests (“checkpoints”) and apoptosis. The MRN complex (MRX in yeast), composed of Mre11, Rad50 and Nbs1 (Xrs2), is a key component of the immediate early response to DNA damage, involved in a cross-talk between the repair and checkpoint machinery. Using its ability to bind DNA ends, it is ideally placed to sense and signal the presence of double strand breaks and plays an important role in DNA repair and cellular survival. Here, we summarise recent observation on MRN structure, function, regulation and emerging mechanisms by which the MRN nano-machinery protects genomic integrity. Finally, we discuss the biological significance of the unique MRN structure and summarise the emerging sequence of early events of the response to double strand breaks orchestrated by the MRN complex.

Keywords

Cystic Fibrosis Transmembrane Regulator Exo1 BRCT Domain Checkpoint Signalling Mre11 Complex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors thank Sunichi Takeda for his authorisation to cite unpublished results, Serge Gravel and Karl Peter Hopfner for critical reading of the manuscript and John Eykelenboom for his comments. The work in Noel Lowndes laboratory is supported by Cancer Research Ireland under grant CR105GRE, European Commission Integrated project “DNA Repair” contract number 512113 and Science Foundation Ireland Principal Investigator award 07/IN1/B958.

References

  1. Ajimura M, Leem SH, Ogawa H (1993) Identification of new genes required for meiotic recombination in Saccharomyces cerevisiae. Genetics 133:51–66PubMedGoogle Scholar
  2. Akamatsu Y, Murayama Y, Yamada T, Nakazaki T, Tsutsui Y, Ohta K, Iwasaki H (2008) Molecular characterization of the role of the Schizosaccharomyces pombe nip1 + /ctp1 + gene in DNA double-strand break repair in association with the Mre11-Rad50-Nbs1 complex. Mol Cell Biol 28:3639–3651PubMedGoogle Scholar
  3. Alani E, Padmore R, Kleckner N (1990) Analysis of wild-type and rad50 mutants of yeast suggests an intimate relationship between meiotic chromosome synapsis and recombination. Cell 61:419–436PubMedGoogle Scholar
  4. Aylon Y, Liefshitz B, Kupiec M (2004) The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycle. EMBO J 23:4868–4875PubMedGoogle Scholar
  5. Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506PubMedGoogle Scholar
  6. Barlow JH, Lisby M, Rothstein R (2008) Differential regulation of the cellular response to DNA double-strand breaks in G1. Mol Cell 30:73–85PubMedGoogle Scholar
  7. Baroni E, Viscardi V, Cartagena-Lirola H, Lucchini G, Longhese MP (2004) The functions of budding yeast Sae2 in the DNA damage response require Mec1- and Tel1-dependent phosphorylation. Mol Cell Biol 24:4151–4165PubMedGoogle Scholar
  8. Bartek J, Bartkova J, Lukas J (2007) DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 26:7773–7779PubMedGoogle Scholar
  9. Baudat F, de Massy B (2007) Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis. Chromosome Res 15:565–577PubMedGoogle Scholar
  10. Becker E, Meyer V, Madaoui H, Guerois R (2006) Detection of a tandem BRCT in Nbs1 and Xrs2 with functional implications in the DNA damage response. Bioinformatics 22:1289–1292PubMedGoogle Scholar
  11. Berkovich E, Monnat RJ Jr, Kastan MB (2007) Roles of ATM and NBS1 in chromatin structure modulation and DNA double-strand break repair. Nat Cell Biol 9:683–690PubMedGoogle Scholar
  12. Bernardi R, Pandolfi PP (2007) Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 8:1006–1016PubMedGoogle Scholar
  13. Bhaskara V, Dupre A, Lengsfeld B, Hopkins BB, Chan A, Lee JH, Zhang X, Gautier J, Zakian V, Paull TT (2007) Rad50 adenylate kinase activity regulates DNA tethering by Mre11/Rad50 complexes. Mol Cell 25:647–661PubMedGoogle Scholar
  14. Boisvert FM, Dery U, Masson JY, Richard S (2005a) Arginine methylation of MRE11 by PRMT1 is required for DNA damage checkpoint control. Genes Dev 19:671–676PubMedGoogle Scholar
  15. Boisvert FM, Hendzel MJ, Masson JY, Richard S (2005b) Methylation of MRE11 regulates its nuclear compartmentalization. Cell Cycle 4:981–989PubMedGoogle Scholar
  16. Borde V (2007) The multiple roles of the Mre11 complex for meiotic recombination. Chromosome Res 15:551–563PubMedGoogle Scholar
  17. Borde V, Cobb J (2009) Double functions for the Mre11 complex during DNA double-strand break repair and replication. Int J Biochem Cell Biol 41:1249–1253PubMedGoogle Scholar
  18. Bork P, Hofmann K, Bucher P, Neuwald AF, Altschul SF, Koonin EV (1997) A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. FASEB J 11:68–76PubMedGoogle Scholar
  19. Bressan DA, Baxter BK, Petrini JH (1999) The Mre11-Rad50-xrs2 protein complex facilitates homologous recombination-based double-strand break repair in Saccharomyces cerevisiae. Mol Cell Biol 19:7681–7687PubMedGoogle Scholar
  20. Bressan DA, Olivares HA, Nelms BE, Petrini JH (1998) Alteration of N- terminal phosphoesterase signature motifs inactivates Saccharomyces cerevisiae Mre11. Genetics 150:591–600PubMedGoogle Scholar
  21. Buis J, Wu Y, Deng Y, Leddon J, Westfield G, Eckersdorff M, Sekiguchi JM, Chang S, Ferguson DO (2008) Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 135:85–96PubMedGoogle Scholar
  22. Cahill D, Carney JP (2007) Dimerization of the Rad50 protein is independent of the conserved hook domain. Mutagenesis 22:269–274PubMedGoogle Scholar
  23. Callebaut I, Mornon JP (1997) From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair. FEBS Lett 400:25–30PubMedGoogle Scholar
  24. Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, Hays L, Morgan WF, Petrini JH (1998) The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–486PubMedGoogle Scholar
  25. Celeste A, Fernandez-Capetillo O, Kruhlak MJ, Pilch DR, Staudt DW, Lee A, Bonner RF, Bonner WM, Nussenzweig A (2003) Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol 5:675–679PubMedGoogle Scholar
  26. Cerosaletti KM, Desai-Mehta A, Yeo TC, Kraakman-Van Der Zwet M, Zdzienicka MZ, Concannon P (2000) Retroviral expression of the NBS1 gene in cultured Nijmegen breakage syndrome cells restores normal radiation sensitivity and nuclear focus formation. Mutagenesis 15:281–286PubMedGoogle Scholar
  27. Chapman JR, Jackson SP (2008) Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage. EMBO Rep 9:795–801PubMedGoogle Scholar
  28. Chen L, Trujillo K, Ramos W, Sung P, Tomkinson AE (2001) Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes. Mol Cell 8:1105–1115PubMedGoogle Scholar
  29. Chen L, Trujillo KM, Van Komen S, Roh DH, Krejci L, Lewis LK, Resnick MA, Sung P, Tomkinson AE (2005a) Effect of amino acid substitutions in the rad50 ATP binding domain on DNA double strand break repair in yeast. J Biol Chem 280:2620–2627PubMedGoogle Scholar
  30. Chen PL, Liu F, Cai S, Lin X, Li A, Chen Y, Gu B, Lee EY, Lee WH (2005b) Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Mol Cell Biol 25:3535–3542PubMedGoogle Scholar
  31. Chen L, Nievera CJ, Lee AY, Wu X (2008a) Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J Biol Chem 283:7713–7720PubMedGoogle Scholar
  32. Chen YC, Chiang HY, Yang MH, Chen PM, Chang SY, Teng SC, Vanhaesebroeck B, Wu KJ (2008b) Activation of phosphoinositide 3-kinase by the NBS1 DNA repair protein through a novel activation motif. J Mol Med 86:401–412PubMedGoogle Scholar
  33. Clerici M, Mantiero D, Lucchini G, Longhese MP (2005) The Saccharomyces cerevisiae Sae2 protein promotes resection and bridging of double strand break ends. J Biol Chem 280:38631–38638PubMedGoogle Scholar
  34. Clerici M, Mantiero D, Lucchini G, Longhese MP (2006) The Saccharomyces cerevisiae Sae2 protein negatively regulates DNA damage checkpoint signalling. EMBO Rep 7:212–218PubMedGoogle Scholar
  35. Clerici M, Mantiero D, Guerini I, Lucchini G, Longhese MP (2008) The Yku70-Yku80 complex contributes to regulate double-strand break processing and checkpoint activation during the cell cycle. EMBO Rep 9:810–818PubMedGoogle Scholar
  36. Costanzo V, Robertson K, Bibikova M, Kim E, Grieco D, Gottesman M, Carroll D, Gautier J (2001) Mre11 protein complex prevents double-strand break accumulation during chromosomal DNA replication. Mol Cell 8:137–147PubMedGoogle Scholar
  37. D’Amours D, Jackson SP (2001) The yeast Xrs2 complex functions in S phase checkpoint regulation. Genes Dev 15:2238–2249PubMedGoogle Scholar
  38. Daley JM, Palmbos PL, Wu D, Wilson TE (2005) Nonhomologous end joining in yeast. Annu Rev Genet 39:431–451PubMedGoogle Scholar
  39. de Jager M, Wyman C, van Gent DC, Kanaar R (2002) DNA end-binding specificity of human Rad50/Mre11 is influenced by ATP. Nucleic Acids Res 30:4425–4431PubMedGoogle Scholar
  40. Deng Y, Guo X, Ferguson DO, Chang S (2009) Multiple roles for MRE11 at uncapped telomeres. Nature 460:914–918PubMedGoogle Scholar
  41. Deriano L, Stracker TH, Baker A, Petrini JH, Roth DB (2009) Roles for NBS1 in alternative nonhomologous end-joining of V(D)J recombination intermediates. Mol Cell 34:13–25PubMedGoogle Scholar
  42. Dery U, Coulombe Y, Rodrigue A, Stasiak A, Richard S, Masson JY (2008) A glycine-arginine domain in control of the human MRE11 DNA repair protein. Mol Cell Biol 28:3058–3069PubMedGoogle Scholar
  43. Desai-Mehta A, Cerosaletti KM, Concannon P (2001) Distinct functional domains of nibrin mediate Mre11 binding, focus formation, and nuclear localization. Mol Cell Biol 21:2184–2191PubMedGoogle Scholar
  44. di Masi A, Viganotti M, Polticelli F, Ascenzi P, Tanzarella C, Antoccia A (2008) The R215W mutation in NBS1 impairs gamma-H2AX binding and affects DNA repair: molecular bases for the severe phenotype of 657del5/R215W Nijmegen breakage syndrome patients. Biochem Biophys Res Commun 369:835–840PubMedGoogle Scholar
  45. Di Virgilio M, Gautier J (2005) Repair of double-strand breaks by nonhomologous end joining in the absence of Mre11. J Cell Biol 171:765–771PubMedGoogle Scholar
  46. Dimitrova N, de Lange T (2009) Cell cycle dependent role of MRN at dysfunctional telomeres: ATM signaling-dependent induction of NHEJ in G1 and resection-mediated inhibition of NHEJ in G2. Mol Cell Biol 29(20):5552–5563PubMedGoogle Scholar
  47. Dinkelmann M, Spehalski E, Stoneham T, Buis J, Wu Y, Sekiguchi JM, Ferguson DO (2009) Multiple functions of MRN in end-joining pathways during isotype class switching. Nat Struct Mol Biol 16:808–813PubMedGoogle Scholar
  48. Dong Z, Zhong Q, Chen PL (1999) The Nijmegen breakage syndrome protein is essential for Mre11 phosphorylation upon DNA damage. J Biol Chem 274:19513–19516PubMedGoogle Scholar
  49. Dumon-Jones V, Frappart PO, Tong WM, Sajithlal G, Hulla W, Schmid G, Herceg Z, Digweed M, Wang ZQ (2003) Nbn heterozygosity renders mice susceptible to tumor formation and ionizing radiation-induced tumorigenesis. Cancer Res 63:7263–7269PubMedGoogle Scholar
  50. Durocher D, Henckel J, Fersht AR, Jackson SP (1999) The FHA domain is a modular phosphopeptide recognition motif. Mol Cell 4:387–394PubMedGoogle Scholar
  51. Dzikiewicz-Krawczyk A (2008) The importance of making ends meet: mutations in genes and altered expression of proteins of the MRN complex and cancer. Mutat Res 659:262–273PubMedGoogle Scholar
  52. Falck J, Coates J, Jackson SP (2005) Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 434:605–611PubMedGoogle Scholar
  53. Ferreira MG, Cooper JP (2004) Two modes of DNA double-strand break repair are reciprocally regulated through the fission yeast cell cycle. Genes Dev 18:2249–2254PubMedGoogle Scholar
  54. Frank-Vaillant M, Marcand S (2002) Transient stability of DNA ends allows nonhomologous end joining to precede homologous recombination. Mol Cell 10:1189–1199PubMedGoogle Scholar
  55. Furuse M, Nagase Y, Tsubouchi H, Murakami-Murofushi K, Shibata T, Ohta K (1998) Distinct roles of two separable in vitro activities of yeast Mre11 in mitotic and meiotic recombination. EMBO J 17:6412–6425PubMedGoogle Scholar
  56. Game JC, Mortimer RK (1974) A genetic study of x-ray sensitive mutants in yeast. Mutat Res 24:281–292PubMedGoogle Scholar
  57. Gatei M, Young D, Cerosaletti KM, Desai-Mehta A, Spring K, Kozlov S, Lavin MF, Gatti RA, Concannon P, Khanna K (2000) ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nat Genet 25:115–119PubMedGoogle Scholar
  58. Ghosal G, Muniyappa K (2007) The characterization of Saccharomyces cerevisiae Mre11/Rad50/Xrs2 complex reveals that Rad50 negatively regulates Mre11 endonucleolytic but not the exonucleolytic activity. J Mol Biol 372:864–882PubMedGoogle Scholar
  59. Gravel S, Chapman JR, Magill C, Jackson SP (2008) DNA helicases Sgs1 and BLM promote DNA double-strand break resection. Genes Dev 22:2767–2772PubMedGoogle Scholar
  60. Greenberg RA, Sobhian B, Pathania S, Cantor SB, Nakatani Y, Livingston DM (2006) Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes. Genes Dev 20:34–46PubMedGoogle Scholar
  61. Harper JW, Elledge SJ (2007) The DNA damage response: ten years after. Mol Cell 28:739–745PubMedGoogle Scholar
  62. Hartsuiker E, Mizuno K, Molnar M, Kohli J, Ohta K, Carr AM (2009a) Ctp1CtIP and Rad32Mre11 nuclease activity are required for Rec12Spo11 removal, but Rec12Spo11 removal is dispensable for other MRN-dependent meiotic functions. Mol Cell Biol 29:1671–1681PubMedGoogle Scholar
  63. Hartsuiker E, Neale MJ, Carr AM (2009b) Distinct requirements for the Rad32(Mre11) nuclease and Ctp1(CtIP) in the removal of covalently bound topoisomerase I and II from DNA. Mol Cell 33:117–123PubMedGoogle Scholar
  64. Heikkinen K, Rapakko K, Karppinen SM, Erkko H, Knuutila S, Lundan T, Mannermaa A, Borresen-Dale AL, Borg A, Barkardottir RB et al (2006) RAD50 and NBS1 are breast cancer susceptibility genes associated with genomic instability. Carcinogenesis 27:1593–1599PubMedGoogle Scholar
  65. Helmink BA, Bredemeyer AL, Lee BS, Huang CY, Sharma GG, Walker LM, Bednarski JJ, Lee WL, Pandita TK, Bassing CH, Sleckman BP (2009) MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks. J Exp Med 206:669–679PubMedGoogle Scholar
  66. Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, Adams SL, Millar A, Taylor P, Bennett K, Boutilier K et al (2002) Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415:180–183PubMedGoogle Scholar
  67. Hofmann K, Bucher P (1995) The FHA domain: a putative nuclear signalling domain found in protein kinases and transcription factors. Trends Biochem Sci 20:347–349PubMedGoogle Scholar
  68. Holland IB, Blight MA (1999) ABC-ATPases, adaptable energy generators fuelling transmembrane movement of a variety of molecules in organisms from bacteria to humans. J Mol Biol 293:381–399PubMedGoogle Scholar
  69. Hopfner KP, Tainer JA (2003) Rad50/SMC proteins and ABC transporters: unifying concepts from high-resolution structures. Curr Opin Struct Biol 13:249–255PubMedGoogle Scholar
  70. Hopfner KP, Karcher A, Shin D, Fairley C, Tainer JA, Carney JP (2000a) Mre11 and Rad50 from Pyrococcus furiosus: cloning and biochemical characterization reveal an evolutionarily conserved multiprotein machine. J Bacteriol 182:6036–6041PubMedGoogle Scholar
  71. Hopfner KP, Karcher A, Shin DS, Craig L, Arthur LM, Carney JP, Tainer JA (2000b) Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell 101:789–800PubMedGoogle Scholar
  72. Hopfner KP, Karcher A, Craig L, Woo TT, Carney JP, Tainer JA (2001) Structural biochemistry and interaction architecture of the DNA double-strand break repair Mre11 nuclease and Rad50-ATPase. Cell 105:473–485PubMedGoogle Scholar
  73. Hopfner KP, Craig L, Moncalian G, Zinkel RA, Usui T, Owen BA, Karcher A, Henderson B, Bodmer JL, McMurray CT et al (2002) The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair. Nature 418:562–566PubMedGoogle Scholar
  74. Hopkins BB, Paull TT (2008) the p. furiosus mre11/rad50 complex promotes 5′ strand resection at a DNA double-strand break. Cell 135:250–260PubMedGoogle Scholar
  75. Horejsi Z, Falck J, Bakkenist CJ, Kastan MB, Lukas J, Bartek J (2004) Distinct functional domains of Nbs1 modulate the timing and magnitude of ATM activation after low doses of ionizing radiation. Oncogene 23:3122–3127PubMedGoogle Scholar
  76. Huang J, Gong Z, Ghosal G, Chen J (2009) SOSS complexes participate in the maintenance of genomic stability. Mol Cell 35:384–393PubMedGoogle Scholar
  77. Huertas P, Jackson SP (2009) Human CtIP mediates cell-cycle control of DNA- end resection and double-strand-break repair. J Biol Chem 284(14):9558–9565PubMedGoogle Scholar
  78. Huertas P, Cortes-Ledesma F, Sartori AA, Aguilera A, Jackson SP (2008) CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455:689–692PubMedGoogle Scholar
  79. Iijima K, Muranaka C, Kobayashi J, Sakamoto S, Komatsu K, Matsuura S, Kubota N, Tauchi H (2008a) NBS1 regulates a novel apoptotic pathway through Bax activation. DNA Repair (Amst) 7:1705–1716Google Scholar
  80. Iijima K, Ohara M, Seki R, Tauchi H (2008b) Dancing on damaged chromatin: functions of ATM and the RAD50/MRE11/NBS1 complex in cellular responses to DNA damage. J Radiat Res (Tokyo) 49:451–464Google Scholar
  81. Ira G, Pellicioli A, Balijja A, Wang X, Fiorani S, Carotenuto W, Liberi G, Bressan D, Wan L, Hollingsworth NM et al (2004) DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431:1011–1017PubMedGoogle Scholar
  82. Ivanov EL, Korolev VG, Fabre F (1992) XRS2, a DNA repair gene of Saccharomyces cerevisiae, is needed for meiotic recombination. Genetics 132:651–664PubMedGoogle Scholar
  83. Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP (2006) ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8:37–45PubMedGoogle Scholar
  84. Jazayeri A, Balestrini A, Garner E, Haber JE, Costanzo V (2008) Mre11- Rad50-Nbs1-dependent processing of DNA breaks generates oligonucleotides that stimulate ATM activity. EMBO J 27:1953–1962PubMedGoogle Scholar
  85. Johzuka K, Ogawa H (1995) Interaction of Mre11 and Rad50: two proteins required for DNA repair and meiosis-specific double-strand break formation in Saccharomyces cerevisiae. Genetics 139:1521–1532PubMedGoogle Scholar
  86. Kanaar R, Wyman C, Rothstein R (2008) Quality control of DNA break metabolism: in the ‘end’, it’s a good thing. EMBO J 27:581–588PubMedGoogle Scholar
  87. Kim YC, Gerlitz G, Furusawa T, Catez F, Nussenzweig A, Oh KS, Kraemer KH, Shiloh Y, Bustin M (2009) Activation of ATM depends on chromatin interactions occurring before induction of DNA damage. Nat Cell Biol 11:92–96PubMedGoogle Scholar
  88. Kobayashi J (2004) Molecular mechanism of the recruitment of NBS1/hMRE11/hRAD50 complex to DNA double-strand breaks: NBS1 binds to gamma-H2AX through FHA/BRCT domain. J Radiat Res (Tokyo) 45:473–478Google Scholar
  89. Kobayashi J, Tauchi H, Sakamoto S, Nakamura A, Morishima K, Matsuura S, Kobayashi T, Tamai K, Tanimoto K, Komatsu K (2002) NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain. Curr Biol 12:1846–1851PubMedGoogle Scholar
  90. Kozlov SV, Graham ME, Peng C, Chen P, Robinson PJ, Lavin MF (2006) Involvement of novel autophosphorylation sites in ATM activation. EMBO J 25:3504–3514PubMedGoogle Scholar
  91. Krogh BO, Llorente B, Lam A, Symington LS (2005) Mutations in Mre11 phosphoesterase motif I that impair Saccharomyces cerevisiae Mre11-Rad50-Xrs2 complex stability in addition to nuclease activity. Genetics 171:1561–1570PubMedGoogle Scholar
  92. Lee JH, Paull TT (2004) Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304:93–96PubMedGoogle Scholar
  93. Lee JH, Paull TT (2005) ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308:551–554PubMedGoogle Scholar
  94. Lee SE, Moore JK, Holmes A, Umezu K, Kolodner RD, Haber JE (1998) Saccharomyces Ku70, mre11/rad50 and RPA proteins regulate adaptation to G2/M arrest after DNA damage. Cell 94:399–409PubMedGoogle Scholar
  95. Lee JH, Ghirlando R, Bhaskara V, Hoffmeyer MR, Gu J, Paull TT (2003) Regulation of Mre11/Rad50 by Nbs1: effects on nucleotide-dependent DNA binding and association with ataxia-telangiectasia-like disorder mutant complexes. J Biol Chem 278:45171–45181PubMedGoogle Scholar
  96. Lengsfeld BM, Rattray AJ, Bhaskara V, Ghirlando R, Paull TT (2007) Sae2 is an endonuclease that processes hairpin DNA cooperatively with the Mre11/Rad50/Xrs2 complex. Mol Cell 28:638–651PubMedGoogle Scholar
  97. Lewis HA, Buchanan SG, Burley SK, Conners K, Dickey M, Dorwart M, Fowler R, Gao X, Guggino WB, Hendrickson WA et al (2004) Structure of nucleotide-binding domain 1 of the cystic fibrosis transmembrane conductance regulator. EMBO J 23:282–293PubMedGoogle Scholar
  98. Li X, Heyer WD (2008) Homologous recombination in DNA repair and DNA damage tolerance. Cell Res 18:99–113PubMedGoogle Scholar
  99. Li J, Lee GI, Van Doren SR, Walker JC (2000) The FHA domain mediates phosphoprotein interactions. J Cell Sci 113(Pt 23):4143–4149PubMedGoogle Scholar
  100. Li Y, Bolderson E, Kumar R, Muniandy PA, Xue Y, Richard DJ, Seidman M, Pandita TK, Khanna KK, Wang W (2009) hSSB1 and hSSB2 form similar multiprotein complexes that participate in DNA damage response. J Biol Chem 284:23525–23531PubMedGoogle Scholar
  101. Lim DS, Kim ST, Xu B, Maser RS, Lin J, Petrini JH, Kastan MB (2000) ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 404:613–617PubMedGoogle Scholar
  102. Limbo O, Chahwan C, Yamada Y, de Bruin RA, Wittenberg C, Russell P (2007) Ctp1 is a cell-cycle-regulated protein that functions with Mre11 complex to control double-strand break repair by homologous recombination. Mol Cell 28:134–146PubMedGoogle Scholar
  103. Lisby M, Barlow JH, Burgess RC, Rothstein R (2004) Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell 118:699–713PubMedGoogle Scholar
  104. Llorente B, Symington LS (2004) The Mre11 nuclease is not required for 5′ to 3′ resection at multiple HO-induced double-strand breaks. Mol Cell Biol 24:9682–9694PubMedGoogle Scholar
  105. Luo G, Yao MS, Bender CF, Mills M, Bladl AR, Bradley A, Petrini JH (1999) Disruption of mRad50 causes embryonic stem cell lethality, abnormal embryonic development, and sensitivity to ionizing radiation. Proc Natl Acad Sci USA 96:7376–7381PubMedGoogle Scholar
  106. Mahajan A, Yuan C, Lee H, Chen ES, Wu PY, Tsai MD (2008) Structure and function of the phosphothreonine-specific FHA domain. Sci Signal 1:re12PubMedGoogle Scholar
  107. Manolis KG, Nimmo ER, Hartsuiker E, Carr AM, Jeggo PA, Allshire RC (2001) Novel functional requirements for non-homologous DNA end joining in Schizosaccharomyces pombe. EMBO J 20:210–221PubMedGoogle Scholar
  108. Mantiero D, Clerici M, Lucchini G, Longhese MP (2007) Dual role for Saccharomyces cerevisiae Tel1 in the checkpoint response to double-strand breaks. EMBO Rep 8:380–387PubMedGoogle Scholar
  109. Maser RS, Monsen KJ, Nelms BE, Petrini JH (1997) hMre11 and hRad50 nuclear foci are induced during the normal cellular response to DNA double-strand breaks. Mol Cell Biol 17:6087–6096PubMedGoogle Scholar
  110. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y et al (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316:1160–1166PubMedGoogle Scholar
  111. Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto S, Endo S, Smeets D, Solder B, Belohradsky BH, Der Kaloustian VM et al (1998) Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet 19:179–181PubMedGoogle Scholar
  112. Matsuzaki K, Shinohara A, Shinohara M (2008) Forkhead-associated domain of yeast Xrs2, a homolog of human Nbs1, promotes nonhomologous end joining through interaction with a ligase IV partner protein, Lif1. Genetics 179:213–225PubMedGoogle Scholar
  113. Milne GT, Jin S, Shannon KB, Weaver DT (1996) Mutations in two Ku homologs define a DNA end-joining repair pathway in Saccharomyces cerevisiae. Mol Cell Biol 16:4189–4198PubMedGoogle Scholar
  114. Mimitou EP, Symington LS (2008) Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455:770–774PubMedGoogle Scholar
  115. Mirzoeva OK, Petrini JH (2001) DNA damage-dependent nuclear dynamics of the Mre11 complex. Mol Cell Biol 21:281–288PubMedGoogle Scholar
  116. Moncalian G, Lengsfeld B, Bhaskara V, Hopfner KP, Karcher A, Alden E, Tainer JA, Paull TT (2004) The rad50 signature motif: essential to ATP binding and biological function. J Mol Biol 335:937–951PubMedGoogle Scholar
  117. Moore JK, Haber JE (1996) Cell cycle and genetic requirements of two pathways of nonhomologous end-joining repair of double-strand breaks in Saccharomyces cerevisiae. Mol Cell Biol 16:2164–2173PubMedGoogle Scholar
  118. Moreau S, Ferguson JR, Symington LS (1999) The nuclease activity of Mre11 is required for meiosis but not for mating type switching, end joining, or telomere maintenance. Mol Cell Biol 19:556–566PubMedGoogle Scholar
  119. Moreau S, Morgan EA, Symington LS (2001) Overlapping functions of the Saccharomyces cerevisiae Mre11, Exo1 and Rad27 nucleases in DNA metabolism. Genetics 159:1423–1433PubMedGoogle Scholar
  120. Moreno-Herrero F, de Jager M, Dekker NH, Kanaar R, Wyman C, Dekker C (2005) Mesoscale conformational changes in the DNA-repair complex Rad50/Mre11/Nbs1 upon binding DNA. Nature 437:440–443PubMedGoogle Scholar
  121. Mu JJ, Wang Y, Luo H, Leng M, Zhang J, Yang T, Besusso D, Jung SY, Qin J (2007) A proteomic analysis of ataxia telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) substrates identifies the ubiquitin-proteasome system as a regulator for DNA damage checkpoints. J Biol Chem 282:17330–17334PubMedGoogle Scholar
  122. Nairz K, Klein F (1997) mre11S—a yeast mutation that blocks double-strand- break processing and permits nonhomologous synapsis in meiosis. Genes Dev 11:2272–2290PubMedGoogle Scholar
  123. Nakada D, Matsumoto K, Sugimoto K (2003) ATM-related Tel1 associates with double-strand breaks through an Xrs2-dependent mechanism. Genes Dev 17:1957–1962PubMedGoogle Scholar
  124. Nakada D, Hirano Y, Sugimoto K (2004) Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway. Mol Cell Biol 24:10016–10025PubMedGoogle Scholar
  125. Nam EA, Cortez D (2009) SOSS1/2: sensors of single-stranded DNA at a break. Mol Cell 35:258–259PubMedGoogle Scholar
  126. Nimonkar AV, Ozsoy AZ, Genschel J, Modrich P, Kowalczykowski SC (2008) Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair. Proc Natl Acad Sci USA 105:16906–16911PubMedGoogle Scholar
  127. Niu H, Raynard S, Sung P (2009) Multiplicity of DNA end resection machineries in chromosome break repair. Genes Dev 23:1481–1486PubMedGoogle Scholar
  128. Olson E, Nievera CJ, Lee AY, Chen L, Wu X (2007) The Mre11-Rad50-Nbs1 complex acts both upstream and downstream of ataxia telangiectasia mutated and Rad3-related protein (ATR) to regulate the S-phase checkpoint following UV treatment. J Biol Chem 282:22939–22952PubMedGoogle Scholar
  129. Palmbos PL, Daley JM, Wilson TE (2005) Mutations of the Yku80 C terminus and Xrs2 FHA domain specifically block yeast nonhomologous end joining. Mol Cell Biol 25:10782–10790PubMedGoogle Scholar
  130. Palmbos PL, Wu D, Daley JM, Wilson TE (2008) Recruitment of Saccharomyces cerevisiae Dnl4-Lif1 complex to a double-strand break requires interactions with Yku80 and the Xrs2 FHA domain. Genetics 180:1809–1819PubMedGoogle Scholar
  131. Paull TT, Gellert M (1998) The 3′ to 5′ exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaks. Mol Cell 1:969–979PubMedGoogle Scholar
  132. Paull TT, Gellert M (1999) Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex. Genes Dev 13:1276–1288PubMedGoogle Scholar
  133. Penkner A, Portik-Dobos Z, Tang L, Schnabel R, Novatchkova M, Jantsch V, Loidl J (2007) A conserved function for a Caenorhabditis elegans Com1/Sae2/CtIP protein homolog in meiotic recombination. EMBO J 26:5071–5082PubMedGoogle Scholar
  134. Rass E, Grabarz A, Plo I, Gautier J, Bertrand P, Lopez BS (2009) Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells. Nat Struct Mol Biol 16:819–824PubMedGoogle Scholar
  135. Raymond WE, Kleckner N (1993) RAD50 protein of S.cerevisiae exhibits ATP- dependent DNA binding. Nucleic Acids Res 21:3851–3856PubMedGoogle Scholar
  136. Richard DJ, Bolderson E, Cubeddu L, Wadsworth RI, Savage K, Sharma GG, Nicolette ML, Tsvetanov S, McIlwraith MJ, Pandita RK et al (2008) Single-stranded DNA-binding protein hSSB1 is critical for genomic stability. Nature 453:677–681PubMedGoogle Scholar
  137. Rodriguez MC, Songyang Z (2008) BRCT domains: phosphopeptide binding and signaling modules. Front Biosci 13:5905–5915PubMedGoogle Scholar
  138. Rupnik A, Grenon M, Lowndes N (2008) The MRN complex. Curr Biol 18:R455–R457PubMedGoogle Scholar
  139. Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J, Baer R, Lukas J, Jackson SP (2007) Human CtIP promotes DNA end resection. Nature 450:509–514PubMedGoogle Scholar
  140. Schaetzlein S, Kodandaramireddy NR, Ju Z, Lechel A, Stepczynska A, Lilli DR, Clark AB, Rudolph C, Kuhnel F, Wei K et al (2007) Exonuclease-1 deletion impairs DNA damage signaling and prolongs lifespan of telomere-dysfunctional mice. Cell 130:863–877PubMedGoogle Scholar
  141. Shima H, Suzuki M, Shinohara M (2005) Isolation and characterization of novel xrs2 mutations in Saccharomyces cerevisiae. Genetics 170:71–85PubMedGoogle Scholar
  142. Shimada M, Sagae R, Kobayashi J, Habu T, Komatsu K (2009) Inactivation of the Nijmegen breakage syndrome gene leads to excess centrosome duplication via the ATR/BRCA1 pathway. Cancer Res 69:1768–1775PubMedGoogle Scholar
  143. Shiotani B, Zou L (2009) Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks. Mol Cell 33:547–558PubMedGoogle Scholar
  144. Shrivastav M, De Haro LP, Nickoloff JA (2008) Regulation of DNA double-strand break repair pathway choice. Cell Res 18:134–147PubMedGoogle Scholar
  145. Sinha KM, Unciuleac MC, Glickman MS, Shuman S (2009) AdnAB: a new DSB-resecting motor-nuclease from mycobacteria. Genes Dev 23:1423–1437PubMedGoogle Scholar
  146. Slijepcevic P (2006) The role of DNA damage response proteins at telomeres—an “integrative” model. DNA Repair (Amst) 5:1299–1306Google Scholar
  147. Soutoglou E, Misteli T (2008) Activation of the cellular DNA damage response in the absence of DNA lesions. Science 320:1507–1510PubMedGoogle Scholar
  148. Squatrito M, Gorrini C, Amati B (2006) Tip60 in DNA damage response and growth control: many tricks in one HAT. Trends Cell Biol 16:433–442PubMedGoogle Scholar
  149. Stewart GS, Maser RS, Stankovic T, Bressan DA, Kaplan MI, Jaspers NG, Raams A, Byrd PJ, Petrini JH, Taylor AM (1999) The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99:577–587PubMedGoogle Scholar
  150. Stracker TH, Theunissen JW, Morales M, Petrini JH (2004) The Mre11 complex and the metabolism of chromosome breaks: the importance of communicating and holding things together. DNA Repair (Amst) 3:845–854Google Scholar
  151. Sun Y, Xu Y, Roy K, Price BD (2007) DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. Mol Cell Biol 27:8502–8509PubMedGoogle Scholar
  152. Takeda S, Nakamura K, Taniguchi Y, Paull TT (2007) Ctp1/CtIP and the MRN complex collaborate in the initial steps of homologous recombination. Mol Cell 28:351–352PubMedGoogle Scholar
  153. Tauchi H, Kobayashi J, Morishima K, Matsuura S, Nakamura A, Shiraishi T, Ito E, Masnada D, Delia D, Komatsu K (2001) The forkhead-associated domain of NBS1 is essential for nuclear foci formation after irradiation but not essential for hRAD50·hMRE11·NBS1 complex DNA repair activity. J Biol Chem 276:12–15PubMedGoogle Scholar
  154. Tauchi H, Kobayashi J, Morishima K, van Gent DC, Shiraishi T, Verkaik NS, vanHeems D, Ito E, Nakamura A, Sonoda E et al (2002) Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells. Nature 420:93–98PubMedGoogle Scholar
  155. Taylor AM, Groom A, Byrd PJ (2004) Ataxia-telangiectasia-like disorder (ATLD)-its clinical presentation and molecular basis. DNA Repair (Amst) 3:1219–1225Google Scholar
  156. The International Nijmegen Breakage Syndrome Study Group (2000) Nijmegen Breakage Syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child 82:400–406Google Scholar
  157. Tomita K, Matsuura A, Caspari T, Carr AM, Akamatsu Y, Iwasaki H, Mizuno KI, Ohta K, Uritani M, Ushimaru T et al (2003) Competition between the Rad50 complex and the Ku Heterodimer reveals a role for exo1 in processing double-strand breaks but not telomeres. Mol Cell Biol 23:5186–5197PubMedGoogle Scholar
  158. Tommiska J, Seal S, Renwick A, Barfoot R, Baskcomb L, Jayatilake H, Bartkova J, Tallila J, Kaare M, Tamminen A et al (2006) Evaluation of RAD50 in familial breast cancer predisposition. Int J Cancer 118:2911–2916PubMedGoogle Scholar
  159. Trujillo KM, Sung P (2001) DNA structure-specific nuclease activities in the Saccharomyces cerevisiae Rad50*Mre11 complex. J Biol Chem 276:35458–35464PubMedGoogle Scholar
  160. Trujillo KM, Yuan SS, Lee EY, Sung P (1998) Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95. J Biol Chem 273:21447–21450PubMedGoogle Scholar
  161. Tsubouchi H, Ogawa H (2000) Exo1 roles for repair of DNA double-strand breaks and meiotic crossing over in Saccharomyces cerevisiae. Mol Biol Cell 11:2221–2233PubMedGoogle Scholar
  162. Tsukamoto Y, Mitsuoka C, Terasawa M, Ogawa H, Ogawa T (2005) Xrs2p regulates Mre11p translocation to the nucleus and plays a role in telomere elongation and meiotic recombination. Mol Biol Cell 16:597–608PubMedGoogle Scholar
  163. Uanschou C, Siwiec T, Pedrosa-Harand A, Kerzendorfer C, Sanchez-Moran E, Novatchkova M, Akimcheva S, Woglar A, Klein F, Schlogelhofer P (2007) A novel plant gene essential for meiosis is related to the human CtIP and the yeast COM1/SAE2 gene. EMBO J 26:5061–5070PubMedGoogle Scholar
  164. Usui T, Ohta T, Oshiumi H, Tomizawa J, Ogawa H, Ogawa T (1998) Complex formation and functional versatility of Mre11 of budding yeast in recombination. Cell 95:705–716PubMedGoogle Scholar
  165. Usui T, Ogawa H, Petrini JH (2001) A DNA damage response pathway controlled by Tel1 and the Mre11 complex. Mol Cell 7:1255–1266PubMedGoogle Scholar
  166. Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y (2003) Requirement of the MRN complex for ATM activation by DNA damage. EMBO J 22:5612–5621PubMedGoogle Scholar
  167. van der Linden E, Sanchez H, Kinoshita E, Kanaar R, Wyman C (2009) RAD50 and NBS1 form a stable complex functional in DNA binding and tethering. Nucleic Acids Res 37(5):1580–1588PubMedGoogle Scholar
  168. Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanova E, Cooper PR, Nowak NJ et al (1998) Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93:467–476PubMedGoogle Scholar
  169. Wang Z, Cummins JM, Shen D, Cahill DP, Jallepalli PV, Wang TL, Parsons DW, Traverso G, Awad M, Silliman N et al (2004) Three classes of genes mutated in colorectal cancers with chromosomal instability. Cancer Res 64:2998–3001PubMedGoogle Scholar
  170. Weterings E, Chen DJ (2008) The endless tale of non-homologous end-joining. Cell Res 18:114–124PubMedGoogle Scholar
  171. Williams RS, Williams JS, Tainer JA (2007) Mre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template. Biochem Cell Biol 85:509–520PubMedGoogle Scholar
  172. Williams RS, Moncalian G, Williams JS, Yamada Y, Limbo O, Shin DS, Groocock LM, Cahill D, Hitomi C, Guenther G et al (2008) Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair. Cell 135:97–109PubMedGoogle Scholar
  173. Wiltzius JJ, Hohl M, Fleming JC, Petrini JH (2005) The Rad50 hook domain is a critical determinant of Mre11 complex functions. Nat Struct Mol Biol 12:403–407PubMedGoogle Scholar
  174. Wu G, Lee WH (2006) CtIP, a multivalent adaptor connecting transcriptional regulation, checkpoint control and tumor suppression. Cell Cycle 5:1592–1596PubMedGoogle Scholar
  175. Wu X, Ranganathan V, Weisman DS, Heine WF, Ciccone DN, O’Neill TB, Crick KE, Pierce KA, Lane WS, Rathbun G et al (2000) ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 405:477–482PubMedGoogle Scholar
  176. Wu L, Luo K, Lou Z, Chen J (2008) MDC1 regulates intra-S-phase checkpoint by targeting NBS1 to DNA double-strand breaks. Proc Natl Acad Sci USA 105:11200–11205PubMedGoogle Scholar
  177. Xiao Y, Weaver DT (1997) Conditional gene targeted deletion by Cre recombinase demonstrates the requirement for the double-strand break repair Mre11 protein in murine embryonic stem cells. Nucleic Acids Res 25:2985–2991PubMedGoogle Scholar
  178. Xie A, Kwok A, Scully R (2009) Role of mammalian Mre11 in classical and alternative nonhomologous end joining. Nat Struct Mol Biol 16:814–818PubMedGoogle Scholar
  179. Yamaguchi-Iwai Y, Sonoda E, Sasaki MS, Morrison C, Haraguchi T, Hiraoka Y, Yamashita YM, Yagi T, Takata M, Price C et al (1999) Mre11 is essential for the maintenance of chromosomal DNA in vertebrate cells. EMBO J 18:6619–6629PubMedGoogle Scholar
  180. Yang YG, Saidi A, Frappart PO, Min W, Barrucand C, Dumon-Jones V, Michelon J, Herceg Z, Wang ZQ (2006) Conditional deletion of Nbs1 in murine cells reveals its role in branching repair pathways of DNA double-strand breaks. EMBO J 25:5527–5538PubMedGoogle Scholar
  181. Yoo HY, Kumagai A, Shevchenko A, Shevchenko A, Dunphy WG (2009) The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM. Mol Biol Cell 20:2351–2360PubMedGoogle Scholar
  182. You Z, Chahwan C, Bailis J, Hunter T, Russell P (2005) ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1. Mol Cell Biol 25:5363–5379PubMedGoogle Scholar
  183. Yu X, Baer R (2000) Nuclear localization and cell cycle-specific expression of CtIP, a protein that associates with the BRCA1 tumor suppressor. J Biol Chem 275:18541–18549PubMedGoogle Scholar
  184. Yu X, Chen J (2004) DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Mol Cell Biol 24:9478–9486PubMedGoogle Scholar
  185. Yu X, Chini CC, He M, Mer G, Chen J (2003) The BRCT domain is a phospho-protein binding domain. Science 302:639–642PubMedGoogle Scholar
  186. Yu X, Fu S, Lai M, Baer R, Chen J (2006) BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev 20:1721–1726PubMedGoogle Scholar
  187. Yuan Z, Zhang X, Sengupta N, Lane WS, Seto E (2007) SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol Cell 27:149–162PubMedGoogle Scholar
  188. Yun MH, Hiom K (2009) CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 459:460–463PubMedGoogle Scholar
  189. Zha S, Boboila C, Alt FW (2009) Mre11: roles in DNA repair beyond homologous recombination. Nat Struct Mol Biol 16:798–800PubMedGoogle Scholar
  190. Zhang Y, Zhou J, Lim CU (2006) The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control. Cell Res 16:45–54PubMedGoogle Scholar
  191. Zhu J, Petersen S, Tessarollo L, Nussenzweig A (2001) Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr Biol 11:105–109PubMedGoogle Scholar
  192. Zhu Z, Chung WH, Shim EY, Lee SE, Ira G (2008) Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134:981–994PubMedGoogle Scholar

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© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Centre for Chromosome Biology, School of Natural ScienceNational University of Ireland GalwayGalwayIreland

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