Advertisement

Checkpoint and Coordinated Cellular Responses to DNA Damage

  • Xiaohong H. Yang
  • Lee ZouEmail author
Chapter
Part of the Results and Problems in Cell Differentiation book series (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.

Keywords

Replication Fork Ataxia Telangiectasia Mutate Nijmegen Breakage Syndrome Checkpoint Pathway Stall Replication Fork 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 15:2177–2196 PubMedGoogle Scholar
  2. 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 PubMedGoogle Scholar
  3. 3.
    Andreassen PR, D'Andrea AD, Taniguchi T (2004) ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev 18:1958–1963 PubMedGoogle Scholar
  4. 4.
    Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506 PubMedGoogle Scholar
  5. 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 PubMedGoogle Scholar
  6. 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 PubMedGoogle Scholar
  7. 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 PubMedGoogle Scholar
  8. 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 PubMedGoogle Scholar
  9. 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 PubMedGoogle Scholar
  10. 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 PubMedGoogle Scholar
  11. 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 PubMedGoogle Scholar
  12. 12.
    Brown EJ, Baltimore D (2000) ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev 14:397–402 PubMedGoogle Scholar
  13. 13.
    Brown EJ, Baltimore D (2003) Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev 17:615–628 PubMedGoogle Scholar
  14. 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 PubMedGoogle Scholar
  15. 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 PubMedGoogle Scholar
  16. 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 PubMedGoogle Scholar
  17. 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 PubMedGoogle Scholar
  18. 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 PubMedGoogle Scholar
  19. 19.
    Casper AM, Nghiem P, Arlt MF, Glover TW (2002) ATR regulates fragile site stability. Cell 111:779–789 PubMedGoogle Scholar
  20. 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 PubMedGoogle Scholar
  21. 21.
    Cha RS, Kleckner N (2002) ATR homolog Mec1 promotes fork progression, thus averting breaks in replication slow zones. Science 297:602–606 PubMedGoogle Scholar
  22. 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 PubMedGoogle Scholar
  23. 23.
    Chan SW, Blackburn EH (2003) Telomerase and ATM/Tel1p protect telomeres from nonhomologous end joining. Mol Cell 11:1379–1387 PubMedGoogle Scholar
  24. 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 PubMedGoogle Scholar
  25. 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 PubMedGoogle Scholar
  26. 26.
    Chini CC, Chen J (2003) Human claspin is required for replication checkpoint control. J Biol Chem 278:30057–30062 PubMedGoogle Scholar
  27. 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 PubMedGoogle Scholar
  28. 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 PubMedGoogle Scholar
  29. 29.
    Cortez D, Guntuku S, Qin J, Elledge SJ (2001) ATR and ATRIP: partners in checkpoint signaling. Science 294:1713–1716 PubMedGoogle Scholar
  30. 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 PubMedGoogle Scholar
  31. 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 PubMedGoogle Scholar
  32. 32.
    D'Amours D, Jackson SP (2001) The yeast Xrs2 complex functions in S phase checkpoint regulation. Genes Dev 15:2238–2249 PubMedGoogle Scholar
  33. 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 PubMedGoogle Scholar
  34. 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 PubMedGoogle Scholar
  35. 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 PubMedGoogle Scholar
  36. 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 PubMedGoogle Scholar
  37. 37.
    Durocher D, Henckel J, Fersht AR, Jackson SP (1999) The FHA domain is a modular phosphopeptide recognition motif. Mol Cell 4:387–394 PubMedGoogle Scholar
  38. 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 PubMedGoogle Scholar
  39. 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 PubMedGoogle Scholar
  40. 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 PubMedGoogle Scholar
  41. 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 PubMedGoogle Scholar
  42. 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 PubMedGoogle Scholar
  43. 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 PubMedGoogle Scholar
  44. 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 PubMedGoogle Scholar
  45. 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 PubMedGoogle Scholar
  46. 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 PubMedGoogle Scholar
  47. 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 PubMedGoogle Scholar
  48. 48.
    Hartwell LH, Weinert TA (1989) Checkpoints: controls that ensure the order of cell cycle events. Science 246:629–634 PubMedGoogle Scholar
  49. 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 PubMedGoogle Scholar
  50. 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 PubMedGoogle Scholar
  51. 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 PubMedGoogle Scholar
  52. 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 PubMedGoogle Scholar
  53. 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 PubMedGoogle Scholar
  54. 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 PubMedGoogle Scholar
  55. 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 PubMedGoogle Scholar
  56. 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 PubMedGoogle Scholar
  57. 57.
    Kastan MB, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316–323 PubMedGoogle Scholar
  58. 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 PubMedGoogle Scholar
  59. 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 PubMedGoogle Scholar
  60. 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 PubMedGoogle Scholar
  61. 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 PubMedGoogle Scholar
  62. 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 PubMedGoogle Scholar
  63. 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 PubMedGoogle Scholar
  64. 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 PubMedGoogle Scholar
  65. 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 PubMedGoogle Scholar
  66. 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 PubMedGoogle Scholar
  67. 67.
    Kumagai A, Dunphy WG (2003) Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1. Nat Cell Biol 5:161–165 PubMedGoogle Scholar
  68. 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 PubMedGoogle Scholar
  69. 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 PubMedGoogle Scholar
  70. 70.
    Lee JH, Paull TT (2004) Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304:93–96 PubMedGoogle Scholar
  71. 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 PubMedGoogle Scholar
  72. 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 PubMedGoogle Scholar
  73. 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 PubMedGoogle Scholar
  74. 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 PubMedGoogle Scholar
  75. 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 PubMedGoogle Scholar
  76. 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 PubMedGoogle Scholar
  77. 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 PubMedGoogle Scholar
  78. 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 PubMedGoogle Scholar
  79. 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 PubMedGoogle Scholar
  80. 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 PubMedGoogle Scholar
  81. 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 PubMedGoogle Scholar
  82. 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 PubMedGoogle Scholar
  83. 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 PubMedGoogle Scholar
  84. 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 PubMedGoogle Scholar
  85. 85.
    Lydall D, Weinert T (1995) Yeast checkpoint genes in DNA damage processing: implications for repair and arrest. Science 270:1488–1491 PubMedGoogle Scholar
  86. 86.
    Manke IA, Lowery DM, Nguyen A, Yaffe MB (2003) BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302:636–639 PubMedGoogle Scholar
  87. 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 PubMedGoogle Scholar
  88. 88.
    Matsuoka S, Huang M, Elledge SJ (1998) Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282:1893–1897 PubMedGoogle Scholar
  89. 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 PubMedGoogle Scholar
  90. 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 PubMedGoogle Scholar
  91. 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 PubMedGoogle Scholar
  92. 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 PubMedGoogle Scholar
  93. 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 PubMedGoogle Scholar
  94. 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 PubMedGoogle Scholar
  95. 95.
    Moynahan ME, Chiu JW, Koller BH, Jasin M (1999) Brca1 controls homology-directed DNA repair. Mol Cell 4:511–518 PubMedGoogle Scholar
  96. 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 PubMedGoogle Scholar
  97. 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 Google Scholar
  98. 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 PubMedGoogle Scholar
  99. 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 PubMedGoogle Scholar
  100. 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 PubMedGoogle Scholar
  101. 101.
    Osborn AJ, Elledge SJ, Zou L (2002) Checking on the fork: the DNA-replication stress-response pathway. Trends Cell Biol 12:509–516 PubMedGoogle Scholar
  102. 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 PubMedGoogle Scholar
  103. 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 PubMedGoogle Scholar
  104. 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 PubMedGoogle Scholar
  105. 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 PubMedGoogle Scholar
  106. 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 PubMedGoogle Scholar
  107. 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 PubMedGoogle Scholar
  108. 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 PubMedGoogle Scholar
  109. 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 PubMedGoogle Scholar
  110. 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 PubMedGoogle Scholar
  111. 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 PubMedGoogle Scholar
  112. 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 PubMedGoogle Scholar
  113. 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 PubMedGoogle Scholar
  114. 114.
    Rouse J, Jackson SP (2002) Lcd1p recruits Mec1p to DNA lesions in vitro and in vivo. Mol Cell 9:857–869 PubMedGoogle Scholar
  115. 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 PubMedGoogle Scholar
  116. 116.
    Santocanale C, Diffley JF (1998) A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication. Nature 395:615–618 PubMedGoogle Scholar
  117. 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 PubMedGoogle Scholar
  118. 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 PubMedGoogle Scholar
  119. 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 PubMedGoogle Scholar
  120. 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 PubMedGoogle Scholar
  121. 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 PubMedGoogle Scholar
  122. 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 PubMedGoogle Scholar
  123. 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 PubMedGoogle Scholar
  124. 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 PubMedGoogle Scholar
  125. 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 PubMedGoogle Scholar
  126. 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 PubMedGoogle Scholar
  127. 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 PubMedGoogle Scholar
  128. 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 PubMedGoogle Scholar
  129. 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 PubMedGoogle Scholar
  130. 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 PubMedGoogle Scholar
  131. 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 PubMedGoogle Scholar
  132. 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 PubMedGoogle Scholar
  133. 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 PubMedGoogle Scholar
  134. 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 PubMedGoogle Scholar
  135. 135.
    Tercero JA, Diffley JF (2001) Regulation of DNA replication fork progression through damaged DNA by the Mec1/Rad53 checkpoint. Nature 412:553–557 PubMedGoogle Scholar
  136. 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 PubMedGoogle Scholar
  137. 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 PubMedGoogle Scholar
  138. 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 PubMedGoogle Scholar
  139. 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 Google Scholar
  140. 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 PubMedGoogle Scholar
  141. 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 PubMedGoogle Scholar
  142. 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 PubMedGoogle Scholar
  143. 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 PubMedGoogle Scholar
  144. 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 PubMedGoogle Scholar
  145. 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 PubMedGoogle Scholar
  146. 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 PubMedGoogle Scholar
  147. 147.
    Wang B, Matsuoka S, Carpenter PB, Elledge SJ (2002) 53BP1, a mediator of the DNA damage checkpoint. Science 298:1435–1438 PubMedGoogle Scholar
  148. 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 PubMedGoogle Scholar
  149. 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 PubMedGoogle Scholar
  150. 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 PubMedGoogle Scholar
  151. 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 PubMedGoogle Scholar
  152. 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 PubMedGoogle Scholar
  153. 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 PubMedGoogle Scholar
  154. 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 PubMedGoogle Scholar
  155. 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 PubMedGoogle Scholar
  156. 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 PubMedGoogle Scholar
  157. 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 PubMedGoogle Scholar
  158. 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 Google Scholar
  159. 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 Google Scholar
  160. 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 PubMedGoogle Scholar
  161. 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 PubMedGoogle Scholar
  162. 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 PubMedGoogle Scholar
  163. 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 PubMedGoogle Scholar
  164. 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 PubMedGoogle Scholar
  165. 165.
    Zhao H, Piwnica-Worms H (2001) ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol Cell Biol 21:4129–4139 PubMedGoogle Scholar
  166. 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 PubMedGoogle Scholar
  167. 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 PubMedGoogle Scholar
  168. 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 PubMedGoogle Scholar
  169. 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 Google Scholar
  170. 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 Google Scholar
  171. 171.
    Zhou BB, Elledge SJ (2000) The DNA damage response: putting checkpoints in perspective. Nature 408:433–439 PubMedGoogle Scholar
  172. 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 PubMedGoogle Scholar
  173. 173.
    Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300:1542–1548 PubMedGoogle Scholar
  174. 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 PubMedGoogle Scholar
  175. 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 PubMedGoogle Scholar

Authors and Affiliations

  1. 1.MGH Cancer CenterHarvard Medical SchoolCharlestownUSA
  2. 2.Department of PathologyHarvard Medical SchoolCharlestownUSA

Personalised recommendations