Skip to main content

Checkpoint and Coordinated Cellular Responses to DNA Damage

  • Chapter
  • First Online:
Cell Cycle Regulation

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 42))

Abstract

The DNA damage and replication checkpoints are signaling mechanisms that regulate and coordinate cellular responses to genotoxic conditions. The activation of checkpoints not only attenuates cell cycle progression, but also facilitates DNA repair and recovery of faulty replication forks, thereby preventing DNA lesions from being converted to inheritable mutations. It has become increasingly clear that the activation and signaling of the checkpoint are intimately linked to the cellular processes directly involved in chromosomal metabolism, such as DNA replication and DNA repair. Thus, the checkpoint pathway is not just a surveillance system that monitors genomic integrity and regulates cell proliferation, but also an integral part of the processes that work directly on chromosomes to maintain genomic stability. In this article, we discuss the current models of DNA damage and replication checkpoints, and highlight recent advances in the field.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15:2177–2196

    PubMed  CAS  Google Scholar 

  2. Ali A, Zhang J, Bao S, Liu I, Otterness D, Dean NM, Abraham RT, Wang XF (2004) Requirement of protein phosphatase 5 in DNA-damage-induced ATM activation. Genes Dev 18:249–254

    PubMed  CAS  Google Scholar 

  3. Andreassen PR, D'Andrea AD, Taniguchi T (2004) ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev 18:1958–1963

    PubMed  CAS  Google Scholar 

  4. Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506

    PubMed  CAS  Google Scholar 

  5. Bao S, Lu T, Wang X, Zheng H, Wang LE, Wei Q, Hittelman WN, Li L (2004) Disruption of the Rad9/Rad1/Hus1 (9-1-1) complex leads to checkpoint signaling and replication defects. Oncogene 23:5586–5593

    PubMed  CAS  Google Scholar 

  6. Bashkirov VI, King JS, Bashkirova EV, Schmuckli-Maurer J, Heyer WD (2000) DNA repair protein Rad55 is a terminal substrate of the DNA damage checkpoints. Mol Cell Biol 20:4393–4404

    PubMed  CAS  Google Scholar 

  7. Bassing CH, Chua KF, Sekiguchi J, Suh H, Whitlow SR, Fleming JC, Monroe BC, Ciccone DN, Yan C, Vlasakova K, Livingston DM, Ferguson DO, Scully R, Alt FW (2002) Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc Natl Acad Sci USA 99:8173–8178

    PubMed  CAS  Google Scholar 

  8. Beamish H, Williams R, Chen P, Lavin MF (1996) Defect in multiple cell cycle checkpoints in ataxia-telangiectasia postirradiation. J Biol Chem 271:20486–20493

    PubMed  CAS  Google Scholar 

  9. Bird AW, Yu DY, Pray-Grant MG, Qiu Q, Harmon KE, Megee PC, Grant PA, Smith MM, Christman MF (2002) Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature 419:411–415

    PubMed  CAS  Google Scholar 

  10. Block WD, Yu Y, Lees-Miller SP (2004) Phosphatidyl inositol 3-kinase-like serine/threonine protein kinases (PIKKs) are required for DNA damage-induced phosphorylation of the 32 kDa subunit of replication protein A at threonine 21. Nucleic Acids Res 32:997–1005

    PubMed  CAS  Google Scholar 

  11. Boddy MN, Lopez-Girona A, Shanahan P, Interthal H, Heyer WD, Russell P (2000) Damage tolerance protein Mus81 associates with the FHA1 domain of checkpoint kinase Cds1. Mol Cell Biol 20:8758–8766

    PubMed  CAS  Google Scholar 

  12. Brown EJ, Baltimore D (2000) ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev 14:397–402

    PubMed  CAS  Google Scholar 

  13. Brown EJ, Baltimore D (2003) Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev 17:615–628

    PubMed  CAS  Google Scholar 

  14. Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276:42462–42467

    PubMed  CAS  Google Scholar 

  15. Buscemi G, Savio C, Zannini L, Micciche F, Masnada D, Nakanishi M, Tauchi H, Komatsu K, Mizutani S, Khanna K, Chen P, Concannon P, Chessa L, Delia D (2001) Chk2 activation dependence on Nbs1 after DNA damage. Mol Cell Biol 21:5214–5222

    PubMed  CAS  Google Scholar 

  16. Busino L, Donzelli M, Chiesa M, Guardavaccaro D, Ganoth D, Dorrello NV, Hershko A, Pagano M, Draetta GF (2003) Degradation of Cdc25A by beta-TrCP during S phase and in response to DNA damage. Nature 426:87–91

    PubMed  CAS  Google Scholar 

  17. Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD (1998) Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281:1677–1679

    PubMed  CAS  Google Scholar 

  18. Carson CT, Schwartz RA, Stracker TH, Lilley CE, Lee DV, Weitzman MD (2003) The Mre11 complex is required for ATM activation and the G2/M checkpoint. Embo J 22:6610–6620

    PubMed  CAS  Google Scholar 

  19. Casper AM, Nghiem P, Arlt MF, Glover TW (2002) ATR regulates fragile site stability. Cell 111:779–789

    PubMed  CAS  Google Scholar 

  20. Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A (2002) Genomic instability in mice lacking histone H2AX. Science 296:922–927

    PubMed  CAS  Google Scholar 

  21. Cha RS, Kleckner N (2002) ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones. Science 297:602–606

    PubMed  CAS  Google Scholar 

  22. Chahwan C, Nakamura TM, Sivakumar S, Russell P, Rhind N (2003) The fission yeast Rad32 (Mre11)-Rad50-Nbs1 complex is required for the S-phase DNA damage checkpoint. Mol Cell Biol 23:6564–6573

    PubMed  CAS  Google Scholar 

  23. Chan SW, Blackburn EH (2003) Telomerase and ATM/Tel1p protect telomeres from nonhomologous end joining. Mol Cell 11:1379–1387

    PubMed  CAS  Google Scholar 

  24. Chang DY, Lu AL (2005) Interaction of checkpoint proteins Hus1/Rad1/Rad9 with DNA base excision repair enzyme MutY homolog in fission yeast, Schizosaccharomyces pombe. J Biol Chem 280:408–417

    PubMed  CAS  Google Scholar 

  25. 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 8:1105–1115

    PubMed  CAS  Google Scholar 

  26. Chini CC, Chen J (2003) Human claspin is required for replication checkpoint control. J Biol Chem 278:30057–30062

    PubMed  CAS  Google Scholar 

  27. Cortez D (2003) Caffeine inhibits checkpoint responses without inhibiting the ataxia-telangiectasia-mutated (ATM) and ATM- and Rad3-related (ATR) protein kinases. J Biol Chem 278:37139–37145

    PubMed  CAS  Google Scholar 

  28. Cortez D, Wang Y, Qin J, Elledge SJ (1999) Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286:1162–1166

    PubMed  CAS  Google Scholar 

  29. Cortez D, Guntuku S, Qin J, Elledge SJ (2001) ATR and ATRIP: partners in checkpoint signaling. Science 294:1713–1716

    PubMed  CAS  Google Scholar 

  30. Cortez D, Glick G, Elledge SJ (2004) Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Proc Natl Acad Sci USA 101:10078–10083

    PubMed  CAS  Google Scholar 

  31. Costanzo V, Shechter D, Lupardus PJ, Cimprich KA, Gottesman M, Gautier J (2003) An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication. Mol Cell 11:203–213

    PubMed  CAS  Google Scholar 

  32. D'Amours D, Jackson SP (2001) The yeast Xrs2 complex functions in S phase checkpoint regulation. Genes Dev 15:2238–2249

    PubMed  Google Scholar 

  33. Davies SL, North PS, Dart A, Lakin ND, Hickson ID (2004) Phosphorylation of the Bloom's syndrome helicase and its role in recovery from S-phase arrest. Mol Cell Biol 24:1279–1291

    PubMed  CAS  Google Scholar 

  34. Delia D, Mizutani S, Panigone S, Tagliabue E, Fontanella E, Asada M, Yamada T, Taya Y, Prudente S, Saviozzi S, Frati L, Pierotti MA, Chessa L (2000) ATM protein and p53-serine 15 phosphorylation in ataxia-telangiectasia (AT) patients and at heterozygotes. Br J Cancer 82:1938–1945

    PubMed  CAS  Google Scholar 

  35. Desany BA, Alcasabas AA, Bachant JB, Elledge SJ (1998) Recovery from DNA replicational stress is the essential function of the S-phase checkpoint pathway. Genes Dev 12:2956–2970

    PubMed  CAS  Google Scholar 

  36. Downs JA, Allard S, Jobin-Robitaille O, Javaheri A, Auger A, Bouchard N, Kron SJ, Jackson SP, Cote J (2004) Binding of chromatin-modifying activities to phosphorylated histone H2A at DNA damage sites. Mol Cell 16:979–990

    PubMed  CAS  Google Scholar 

  37. Durocher D, Henckel J, Fersht AR, Jackson SP (1999) The FHA domain is a modular phosphopeptide recognition motif. Mol Cell 4:387–394

    PubMed  CAS  Google Scholar 

  38. Ellison V, Stillman B (2003) Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5′ recessed DNA. PLoS Biol 1:E33

    PubMed  Google Scholar 

  39. Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410:842–847

    PubMed  CAS  Google Scholar 

  40. Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, Carpenter PB, Bonner WM, Chen J, Nussenzweig A (2002) DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol 4:993–997

    PubMed  CAS  Google Scholar 

  41. Foray N, Marot D, Gabriel A, Randrianarison V, Carr AM, Perricaudet M, Ashworth A, Jeggo P (2003) A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. Embo J 22:2860–2871

    PubMed  CAS  Google Scholar 

  42. Ghaemmaghami S, Huh WK, Bower K, Howson RW, Belle A, Dephoure N, O'Shea EK, Weissman JS (2003) Global analysis of protein expression in yeast. Nature 425:737–741

    PubMed  CAS  Google Scholar 

  43. Giannattasio M, Lazzaro F, Longhese MP, Plevani P, Muzi-Falconi M (2004) Physical and functional interactions between nucleotide excision repair and DNA damage checkpoint. Embo J 23:429–438

    PubMed  CAS  Google Scholar 

  44. Giannattasio M, Lazzaro F, Plevani P, Muzi-Falconi M (2005) The DNA damage checkpoint response requires histone H2B ubiquitination by Rad6-Bre1 and H3 methylation by Dot1. J Biol Chem 280:9879–9886

    PubMed  CAS  Google Scholar 

  45. Goldberg M, Stucki M, Falck J, D'Amours D, Rahman D, Pappin D, Bartek J, Jackson SP (2003) MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature 421:952–956

    PubMed  CAS  Google Scholar 

  46. Goodarzi AA, Jonnalagadda JC, Douglas P, Young D, Ye R, Moorhead GB, Lees-Miller SP, Khanna KK (2004) Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2A. Embo J 23:4451–4461

    PubMed  CAS  Google Scholar 

  47. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T (1999) Mammalian telomeres end in a large duplex loop. Cell 97:503–514

    PubMed  CAS  Google Scholar 

  48. Hartwell LH, Weinert TA (1989) Checkpoints: controls that ensure the order of cell cycle events. Science 246:629–634

    PubMed  CAS  Google Scholar 

  49. Hekmat-Nejad M, You Z, Yee MC, Newport JW, Cimprich KA (2000) Xenopus ATR is a replication-dependent chromatin-binding protein required for the DNA replication checkpoint. Curr Biol 10:1565–1573

    PubMed  CAS  Google Scholar 

  50. Hirao A, Cheung A, Duncan G, Girard PM, Elia AJ, Wakeham A, Okada H, Sarkissian T, Wong JA, Sakai T, De Stanchina E, Bristow RG, Suda T, Lowe SW, Jeggo PA, Elledge SJ, Mak TW (2002) Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Mol Cell Biol 22:6521–6532

    PubMed  CAS  Google Scholar 

  51. Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW (2000) DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287:1824–1827

    PubMed  CAS  Google Scholar 

  52. Huyen Y, Zgheib O, Ditullio RA, Jr, Gorgoulis VG, Zacharatos P, Petty TJ, Sheston EA, Mellert HS, Stavridi ES, Halazonetis TD (2004) Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432:406–411

    PubMed  CAS  Google Scholar 

  53. Ira G, Pellicioli A, Balijja A, Wang X, Fiorani S, Carotenuto W, Liberi G, Bressan D, Wan L, Hollingsworth NM, Haber JE, Foiani M (2004) DNA end resection, homologous recombination and DNA damage checkpoint activation require Cdk1. Nature 431:1011–1017

    PubMed  CAS  Google Scholar 

  54. Ivessa AS, Lenzmeier BA, Bessler JB, Goudsouzian LK, Schnakenberg SL, Zakian VA (2003) The Saccharomyces cerevisiae helicase Rrm3p facilitates replication past nonhistone protein-DNA complexes. Mol Cell 12:1525–1536

    PubMed  CAS  Google Scholar 

  55. Jack MT, Woo RA, Hirao A, Cheung A, Mak TW, Lee PW (2002) Chk2 is dispensable for p53-mediated G1 arrest but is required for a latent p53-mediated apoptotic response. Proc Natl Acad Sci USA 99:9825–9829

    PubMed  CAS  Google Scholar 

  56. Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ, Harper JW (2003) SCFβ−TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev 17:3062–3074

    PubMed  CAS  Google Scholar 

  57. Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316–323

    PubMed  CAS  Google Scholar 

  58. Katou Y, Kanoh Y, Bando M, Noguchi H, Tanaka H, Ashikari T, Sugimoto K, Shirahige K (2003) S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 424:1078–1083

    PubMed  CAS  Google Scholar 

  59. Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, Taya Y, Gabrielli B, Chan D, Lees-Miller SP, Lavin MF (1998) ATM associates with and phosphorylates p53: mapping the region of interaction. Nat Genet 20:398–400

    PubMed  CAS  Google Scholar 

  60. Kim HS, Brill SJ (2001) Rfc4 interacts with Rpa1 and is required for both DNA replication and DNA damage checkpoints in Saccharomyces cerevisiae. Mol Cell Biol 21:3725–3737

    PubMed  CAS  Google Scholar 

  61. Kim ST, Xu B, Kastan MB (2002) Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. Genes Dev 16:560–570

    PubMed  CAS  Google Scholar 

  62. Kitagawa R, Bakkenist CJ, McKinnon PJ, Kastan MB (2004) Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway. Genes Dev 18:1423–1438

    PubMed  CAS  Google Scholar 

  63. 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 12:1846–1851

    PubMed  CAS  Google Scholar 

  64. Kondo T, Wakayama T, Naiki T, Matsumoto K, Sugimoto K (2001) Recruitment of Mec1 and Ddc1 checkpoint proteins to double-strand breaks through distinct mechanisms. Science 294:867–870

    PubMed  CAS  Google Scholar 

  65. Krogan NJ, Lam MH, Fillingham J, Keogh MC, Gebbia M, Li J, Datta N, Cagney G, Buratowski S, Emili A, Greenblatt JF (2004) Proteasome involvement in the repair of DNA double-strand breaks. Mol Cell 16:1027–1034

    PubMed  CAS  Google Scholar 

  66. Kumagai A, Dunphy WG (2000) Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts. Mol Cell 6:839–849

    PubMed  CAS  Google Scholar 

  67. Kumagai A, Dunphy WG (2003) Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1. Nat Cell Biol 5:161–165

    PubMed  CAS  Google Scholar 

  68. Kumagai A, Kim SM, Dunphy WG (2004) Claspin and the activated form of ATR-ATRIP collaborate in the activation of Chk1. J Biol Chem 279:49599–49608

    PubMed  CAS  Google Scholar 

  69. Lee J, Kumagai A, Dunphy WG (2003) Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17. Mol Cell 11:329–340

    PubMed  CAS  Google Scholar 

  70. Lee JH, Paull TT (2004) Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304:93–96

    PubMed  CAS  Google Scholar 

  71. 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 94:399–409

    PubMed  CAS  Google Scholar 

  72. Lee SJ, Duong JK, Stern DF (2004) A Ddc2-Rad53 fusion protein can bypass the requirements for RAD9 and MRC1 in Rad53 activation. Mol Biol Cell 15:5443–5455

    PubMed  CAS  Google Scholar 

  73. 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 404:613–617

    PubMed  CAS  Google Scholar 

  74. Lin SY, Li K, Stewart GS, Elledge SJ (2004) Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation. Proc Natl Acad Sci USA 101:6484–6489

    PubMed  CAS  Google Scholar 

  75. Lindsey-Boltz LA, Bermudez VP, Hurwitz J, Sancar A (2001) Purification and characterization of human DNA damage checkpoint Rad complexes. Proc Natl Acad Sci USA 98:11236–1141

    PubMed  CAS  Google Scholar 

  76. Lisby M, Barlow JH, Burgess RC, Rothstein R (2004) Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell 118:699–713

    PubMed  CAS  Google Scholar 

  77. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ (2000) Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes Dev 14:1448–1459

    PubMed  CAS  Google Scholar 

  78. Loegering D, Arlander SJ, Hackbarth J, Vroman BT, Roos-Mattjus P, Hopkins KM, Lieberman HB, Karnitz LM, Kaufmann SH (2004) Rad9 protects cells from topoisomerase poison-induced cell death. J Biol Chem 279:18641–18647

    PubMed  CAS  Google Scholar 

  79. Lopes M, Cotta-Ramusino C, Pellicioli A, Liberi G, Plevani P, Muzi-Falconi M, Newlon CS, Foiani M (2001) The DNA replication checkpoint response stabilizes stalled replication forks. Nature 412:557–661

    PubMed  CAS  Google Scholar 

  80. Lopez-Girona A, Furnari B, Mondesert O, Russell P (1999) Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein. Nature 397:172–175

    PubMed  CAS  Google Scholar 

  81. Lopez-Girona A, Kanoh J, Russell P (2001) Nuclear exclusion of Cdc25 is not required for the DNA damage checkpoint in fission yeast. Curr Biol 11:50–54

    PubMed  CAS  Google Scholar 

  82. Lou Z, Minter-Dykhouse K, Wu X, Chen J (2003) MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature 421:957–961

    PubMed  CAS  Google Scholar 

  83. Lucca C, Vanoli F, Cotta-Ramusino C, Pellicioli A, Liberi G, Haber J, Foiani M (2004) Checkpoint-mediated control of replisome-fork association and signalling in response to replication pausing. Oncogene 23:1206–1213

    PubMed  CAS  Google Scholar 

  84. Lupardus PJ, Byun T, Yee MC, Hekmat-Nejad M, Cimprich KA (2002) A requirement for replication in activation of the ATR-dependent DNA damage checkpoint. Genes Dev 16:2327–2332

    PubMed  CAS  Google Scholar 

  85. Lydall D, Weinert T (1995) Yeast checkpoint genes in DNA damage processing: implications for repair and arrest. Science 270:1488–1491

    PubMed  CAS  Google Scholar 

  86. Manke IA, Lowery DM, Nguyen A, Yaffe MB (2003) BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302:636–639

    PubMed  CAS  Google Scholar 

  87. Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, Weinberg RA, Stewart SA, Hahn WC (2003) Telomerase maintains telomere structure in normal human cells. Cell 114:241–253

    PubMed  CAS  Google Scholar 

  88. Matsuoka S, Huang M, Elledge SJ (1998) Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282:1893–1897

    PubMed  CAS  Google Scholar 

  89. Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ (2000) Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci USA 97:10389–10394

    PubMed  CAS  Google Scholar 

  90. Melo JA, Cohen J, Toczyski DP (2001) Two checkpoint complexes are independently recruited to sites of DNA damage in vivo. Genes Dev 15:2809–28021

    PubMed  CAS  Google Scholar 

  91. Merrick CJ, Jackson D, Diffley JF (2004) Visualization of altered replication dynamics after DNA damage in human cells. J Biol Chem 279:20067–20075

    PubMed  CAS  Google Scholar 

  92. Michael WM, Ott R, Fanning E, Newport J (2000) Activation of the DNA replication checkpoint through RNA synthesis by primase. Science 289:2133–2137

    PubMed  CAS  Google Scholar 

  93. Mochan TA, Venere M, DiTullio RA, Jr, Halazonetis TD (2003) 53BP1 and NFBD1/MDC1-Nbs1 function in parallel interacting pathways activating ataxia-telangiectasia mutated (ATM) in response to DNA damage. Cancer Res 63:8586–8591

    PubMed  CAS  Google Scholar 

  94. Morrison AJ, Highland J, Krogan NJ, Arbel-Eden A, Greenblatt JF, Haber JE, Shen X (2004) INO80 and gamma-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair. Cell 119:767–775

    PubMed  CAS  Google Scholar 

  95. Moynahan ME, Chiu JW, Koller BH, Jasin M (1999) Brca1 controls homology-directed DNA repair. Mol Cell 4:511–518

    PubMed  CAS  Google Scholar 

  96. 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 24:10016–10025

    PubMed  CAS  Google Scholar 

  97. Nakamura TM, Moser BA, Russell P (2002) Telomere binding of checkpoint sensor and DNA repair proteins contributes to maintenance of functional fission yeast telomeres. Genetics 161:1437–1452

    CAS  Google Scholar 

  98. Neecke H, Lucchini G, Longhese MP (1999) Cell cycle progression in the presence of irreparable DNA damage is controlled by a Mec1- and Rad53-dependent checkpoint in budding yeast. Embo J 18:4485–4497

    PubMed  CAS  Google Scholar 

  99. O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA (2003) A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33:497–501

    PubMed  Google Scholar 

  100. Ono Y, Tomita K, Matsuura A, Nakagawa T, Masukata H, Uritani M, Ushimaru T, Ueno M (2003) A novel allele of fission yeast rad11 that causes defects in DNA repair and telomere length regulation. Nucleic Acids Res 31:7141–7149

    PubMed  CAS  Google Scholar 

  101. Osborn AJ, Elledge SJ, Zou L (2002) Checking on the fork: the DNA-replication stress-response pathway. Trends Cell Biol 12:509–516

    PubMed  CAS  Google Scholar 

  102. Paciotti V, Clerici M, Lucchini G, Longhese MP (2000) The checkpoint protein Ddc2, functionally related to S. pombe Rad26, interacts with Mec1 and is regulated by Mec1-dependent phosphorylation in budding yeast. Genes Dev 14:2046–2059

    PubMed  CAS  Google Scholar 

  103. Park BJ, Kang JW, Lee SW, Choi SJ, Shin YK, Ahn YH, Choi YH, Choi D, Lee KS, Kim S (2005) The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR. Cell 120:209–221

    PubMed  CAS  Google Scholar 

  104. Paull TT, Gellert M (1999) Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex. Genes Dev 13:1276–1288

    PubMed  CAS  Google Scholar 

  105. Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M (2001) Direct DNA binding by Brca1. Proc Natl Acad Sci USA 98:6086–6091

    PubMed  CAS  Google Scholar 

  106. Pellicioli A, Lee SE, Lucca C, Foiani M, Haber JE (2001) Regulation of Saccharomyces Rad53 checkpoint kinase during adaptation from DNA damage-induced G2/M arrest. Mol Cell 7:293–300

    PubMed  CAS  Google Scholar 

  107. Peng A, Chen PL (2003) NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. J Biol Chem 278:8873–8876

    PubMed  CAS  Google Scholar 

  108. Pichierri P, Rosselli F (2004) The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways. Embo J 23:1178–1187

    PubMed  CAS  Google Scholar 

  109. Riballo E, Kuhne M, Rief N, Doherty A, Smith GC, Recio MJ, Reis C, Dahm K, Fricke A, Krempler A, Parker AR, Jackson SP, Gennery A, Jeggo PA, Lobrich M (2004) A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol Cell 16:715–724

    PubMed  CAS  Google Scholar 

  110. Rodriguez M, Yu X, Chen J, Songyang Z (2003) Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains. J Biol Chem 278:52914–52918

    PubMed  CAS  Google Scholar 

  111. Rogakou EP, Boon C, Redon C, Bonner WM (1999) Megabase chromatin domains involved in DNA double-strand breaks in vivo. J Cell Biol 146:905–916

    PubMed  CAS  Google Scholar 

  112. Roos-Mattjus P, Hopkins KM, Oestreich AJ, Vroman BT, Johnson KL, Naylor S, Lieberman HB, Karnitz LM (2003) Phosphorylation of human Rad9 is required for genotoxin-activated checkpoint signaling. J Biol Chem 278:24428–24437

    PubMed  CAS  Google Scholar 

  113. Rouse J, Jackson SP (2000) LCD1: an essential gene involved in checkpoint control and regulation of the MEC1 signalling pathway in Saccharomyces cerevisiae. Embo J 19:5801–58012

    PubMed  CAS  Google Scholar 

  114. Rouse J, Jackson SP (2002) Lcd1p recruits Mec1p to DNA lesions in vitro and in vivo. Mol Cell 9:857–869

    PubMed  CAS  Google Scholar 

  115. Sanders SL, Portoso M, Mata J, Bahler J, Allshire RC, Kouzarides T (2004) Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell 119:603–614

    PubMed  CAS  Google Scholar 

  116. Santocanale C, Diffley JF (1998) A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication. Nature 395:615–618

    PubMed  CAS  Google Scholar 

  117. Sar F, Lindsey-Boltz LA, Subramanian D, Croteau DL, Hutsell SQ, Griffith JD, Sancar A (2004) Human claspin is a ring-shaped DNA-binding protein with high affinity to branched DNA structures. J Biol Chem 279:39289–39295

    PubMed  CAS  Google Scholar 

  118. Schultz LB, Chehab NH, Malikzay A, Halazonetis TD (2000) p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J Cell Biol 151:1381–1390

    PubMed  CAS  Google Scholar 

  119. Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, Livingston DM (1997) Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90:425–435

    PubMed  CAS  Google Scholar 

  120. Shiomi Y, Shinozaki A, Nakada D, Sugimoto K, Usukura J, Obuse C, Tsurimoto T (2002) Clamp and clamp loader structures of the human checkpoint protein complexes, Rad9-1-1 and Rad17-RFC. Genes Cells 7:861–868

    PubMed  CAS  Google Scholar 

  121. Shroff R, Arbel-Eden A, Pilch D, Ira G, Bonner WM, Petrini JH, Haber JE, Lichten M (2004) Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break. Curr Biol 14:1703–1711

    PubMed  CAS  Google Scholar 

  122. Smith J, Zou H, Rothstein R (2000) Characterization of genetic interactions with RFA1: the role of RPA in DNA replication and telomere maintenance. Biochimie 82:71–78

    PubMed  CAS  Google Scholar 

  123. Sogo JM, Lopes M, Foiani M (2002) Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297:599–602

    PubMed  CAS  Google Scholar 

  124. Sorensen CS, Syljuasen RG, Falck J, Schroeder T, Ronnstrand L, Khanna KK, Zhou BB, Bartek J, Lukas J (2003) Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell 3:247–258

    PubMed  CAS  Google Scholar 

  125. 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 99:577–587

    PubMed  CAS  Google Scholar 

  126. Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ (2003) MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421:961–966

    PubMed  CAS  Google Scholar 

  127. Stiff T, Reis C, Alderton GK, Woodbine L, O'Driscoll M, Jeggo PA (2005) Nbs1 is required for ATR-dependent phosphorylation events. Embo J 24:199–208

    PubMed  CAS  Google Scholar 

  128. Stokes MP, Van Hatten R, Lindsay HD, Michael WM (2002) DNA replication is required for the checkpoint response to damaged DNA in Xenopus egg extracts. J Cell Biol 158:863–872

    PubMed  CAS  Google Scholar 

  129. Takai H, Naka K, Okada Y, Watanabe M, Harada N, Saito S, Anderson CW, Appella E, Nakanishi M, Suzuki H, Nagashima K, Sawa H, Ikeda K, Motoyama N (2002) Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. Embo J 21:5195–5205

    PubMed  CAS  Google Scholar 

  130. Takata H, Kanoh Y, Gunge N, Shirahige K, Matsuura A (2004) Reciprocal association of the budding yeast ATM-related proteins Tel1 and Mec1 with telomeres in vivo. Mol Cell 14:515–522

    PubMed  CAS  Google Scholar 

  131. Tanaka K, Russell P (2004) Cds1 phosphorylation by Rad3-Rad26 kinase is mediated by forkhead-associated domain interaction with Mrc1. J Biol Chem 279:32079–32086

    PubMed  CAS  Google Scholar 

  132. Tanaka T, Nasmyth K (1998) Association of RPA with chromosomal replication origins requires an Mcm protein, and is regulated by Rad53, and cyclin- and Dbf4-dependent kinases. Embo J 17:5182–5191

    PubMed  CAS  Google Scholar 

  133. Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, Lane WS, Kastan MB, D'Andrea AD (2002) Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109:459–472

    PubMed  CAS  Google Scholar 

  134. Tauchi H, Kobayashi J, Morishima K, van Gent DC, Shiraishi T, Verkaik NS, vanHeems D, Ito E, Nakamura A, Sonoda E, Takata M, Takeda S, Matsuura S, Komatsu K (2002) Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells. Nature 420:93–98

    PubMed  CAS  Google Scholar 

  135. Tercero JA, Diffley JF (2001) Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 412:553–557

    PubMed  CAS  Google Scholar 

  136. Tercero JA, Longhese MP, Diffley JF (2003) A central role for DNA replication forks in checkpoint activation and response. Mol Cell 11:1323–1336

    PubMed  CAS  Google Scholar 

  137. Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT (2000) Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev 14:2989–3002

    PubMed  CAS  Google Scholar 

  138. Tsao CC, Geisen C, Abraham RT (2004) Interaction between human MCM7 and Rad17 proteins is required for replication checkpoint signaling. Embo J 23:4660–4669

    PubMed  CAS  Google Scholar 

  139. Umezu K, Sugawara N, Chen C, Haber JE, Kolodner RD (1998) Genetic analysis of yeast RPA1 reveals its multiple functions in DNA metabolism. Genetics 148:989–1005

    CAS  Google Scholar 

  140. Unal E, Arbel-Eden A, Sattler U, Shroff R, Lichten M, Haber JE, Koshland D (2004) DNA damage response pathway uses histone modification to assemble a double-strand break-specific cohesin domain. Mol Cell 16:991–1002

    PubMed  Google Scholar 

  141. 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 22:5612–5621

    PubMed  CAS  Google Scholar 

  142. van Attikum H, Fritsch O, Hohn B, Gasser SM (2004) Recruitment of the INO80 complex by H2A phosphorylation links ATP-dependent chromatin remodeling with DNA double-strand break repair. Cell 119:777–788

    PubMed  Google Scholar 

  143. Vaziri H, West MD, Allsopp RC, Davison TS, Wu YS, Arrowsmith CH, Poirier GG, Benchimol S (1997) ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase. Embo J 16:6018–6033

    PubMed  CAS  Google Scholar 

  144. Venclovas C, Thelen MP (2000) Structure-based predictions of Rad1, Rad9, Hus1 and Rad17 participation in sliding clamp and clamp-loading complexes. Nucleic Acids Res 28:2481–2493

    PubMed  CAS  Google Scholar 

  145. Volkmer E, Karnitz LM (1999) Human homologs of Schizosaccharomyces pombe rad1, hus1, and rad9 form a DNA damage-responsive protein complex. J Biol Chem 274:567–570

    PubMed  CAS  Google Scholar 

  146. Wakayama T, Kondo T, Ando S, Matsumoto K, Sugimoto K (2001) Pie1, a protein interacting with Mec1, controls cell growth and checkpoint responses in Saccharomyces cerevisiae. Mol Cell Biol 21:755–764

    PubMed  CAS  Google Scholar 

  147. Wang B, Matsuoka S, Carpenter PB, Elledge SJ (2002) 53BP1, a mediator of the DNA damage checkpoint. Science 298:1435–1438

    PubMed  CAS  Google Scholar 

  148. Wang X, Haber JE (2004) Role of saccharomyces single-stranded DNA-binding protein RPA in the strand invasion step of double-strand break repair. PLoS Biol 2:E21

    PubMed  Google Scholar 

  149. Wang X, Zou L, Zheng H, Wei Q, Elledge SJ, Li L (2003) Genomic instability and endoreduplication triggered by RAD17 deletion. Genes Dev 17:965–970

    PubMed  CAS  Google Scholar 

  150. Wang Y, Qin J (2003) MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation. Proc Natl Acad Sci USA 100:15387–15392

    PubMed  CAS  Google Scholar 

  151. Ward IM, Minn K, Jorda G, Chen (2003) Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX. J Biol Chem 278:19579–19582

    PubMed  CAS  Google Scholar 

  152. Weiss S, Matsuoka S, Elledge SJ, Leder P (2002) Hus1 acts upstream of chk1 in a mammalian DNA damage response pathway. Curr Biol 12:73–77

    PubMed  CAS  Google Scholar 

  153. Wu X, Ranganathan V, Weisman DS, Heine WF, Ciccone DN, O'Neill TB, Crick KE, Pierce KA, Lane WS, Rathbun G, Livingston DM, Weaver DT (2000) ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 405:477–482

    PubMed  CAS  Google Scholar 

  154. Xu X, Stern DF (2003) NFBD1/KIAA0170 is a chromatin-associated protein involved in DNA damage signaling pathways. J Biol Chem 278:8795–8803

    PubMed  CAS  Google Scholar 

  155. Yamane K, Chen J, Kinsella TJ (2003) Both DNA topoisomerase II-binding protein 1 and BRCA1 regulate the G2-M cell cycle checkpoint. Cancer Res 63:3049–3053

    PubMed  CAS  Google Scholar 

  156. Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC (2002) BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nat Genet 30:285–289

    PubMed  Google Scholar 

  157. Yazdi PT, Wang Y, Zhao S, Patel N, Lee EY, Qin J (2002) SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. Genes Dev 16:571–582

    PubMed  CAS  Google Scholar 

  158. Yoo HY, Kumagai A, Shevchenko A, Shevchenko A, Dunphy WG (2004a) Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase. Cell 117:575–588

    CAS  Google Scholar 

  159. Yoo HY, Shevchenko A, Shevchenko A, Dunphy WG (2004b) Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses. J Biol Chem 279:53353–53364

    CAS  Google Scholar 

  160. You Z, Kong L, Newport J (2002) The role of single-stranded DNA and polymerase alpha in establishing the ATR, Hus1 DNA replication checkpoint. J Biol Chem 277:27088–27093

    PubMed  CAS  Google Scholar 

  161. 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 24:9478–9486

    PubMed  CAS  Google Scholar 

  162. Yu X, Chini CC, He M, Mer G, Chen J (2003) The BRCT domain is a phospho-protein binding domain. Science 302:639–642

    PubMed  CAS  Google Scholar 

  163. Zachos G, Rainey MD, Gillespie DA (2003) Chk1-deficient tumour cells are viable but exhibit multiple checkpoint and survival defects. Embo J 22:713–723

    PubMed  CAS  Google Scholar 

  164. Zhang J, Willers H, Feng Z, Ghosh JC, Kim S, Weaver DT, Chung JH, Powell SN, Xia F (2004) Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Mol Cell Biol 24:708–718

    PubMed  CAS  Google Scholar 

  165. Zhao H, Piwnica-Worms H (2001) ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol 21:4129–4139

    PubMed  CAS  Google Scholar 

  166. Zhao H, Watkins JL, Piwnica-Worms H (2002) Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proc Natl Acad Sci USA 99:14795–14800

    PubMed  CAS  Google Scholar 

  167. Zhao S, Weng YC, Yuan SS, Lin YT, Hsu HC, Lin SC, Gerbino E, Song MH, Zdzienicka MZ, Gatti RA, Shay JW, Ziv Y, Shiloh Y, Lee EY (2000) Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature 405:473–477

    PubMed  CAS  Google Scholar 

  168. Zhao X, Muller EG, Rothstein R (1998) A suppressor of two essential checkpoint genes identifies a novel protein that negatively affects dNTP pools. Mol Cell 2:329–340

    PubMed  CAS  Google Scholar 

  169. Zhong Q, Boyer TG, Chen PL, Lee WH (2002a) Deficient nonhomologous end-joining activity in cell-free extracts from Brca1-null fibroblasts. Cancer Res 62:3966–3970

    CAS  Google Scholar 

  170. Zhong Q, Chen CF, Chen PL, Lee WH (2002b) BRCA1 facilitates microhomology-mediated end joining of DNA double strand breaks. J Biol Chem 277:28641–28647

    CAS  Google Scholar 

  171. Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439

    PubMed  CAS  Google Scholar 

  172. Zhu XD, Kuster B, Mann M, Petrini JH, de Lange T (2000) Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat Genet 25:347–352

    PubMed  CAS  Google Scholar 

  173. Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300:1542–1548

    PubMed  CAS  Google Scholar 

  174. Zou L, Cortez D, Elledge SJ (2002) Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes Dev 16:198–208

    PubMed  CAS  Google Scholar 

  175. Zou L, Liu D, Elledge SJ (2003) Replication protein A-mediated recruitment and activation of Rad17 complexes. Proc Natl Acad Sci USA 100:13827–13832

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lee Zou .

Editor information

Philipp Kaldis

Rights and permissions

Reprints and permissions

About this chapter

Cite this chapter

Yang, X., Zou, L. Checkpoint and Coordinated Cellular Responses to DNA Damage . In: Kaldis, P. (eds) Cell Cycle Regulation. Results and Problems in Cell Differentiation, vol 42. Springer, Berlin, Heidelberg. https://doi.org/10.1007/b136684

Download citation

Publish with us

Policies and ethics