Abstract
DNA replication is one of the most fundamental cellular processes. Faithful replication of the entire genome is a daunting task, especially when cells are under intrinsic or extrinsic stress. To maintain genomic stability during DNA replication, eukaryotic cells have evolved a sophisticated signaling network called the checkpoint to orchestrate cellular responses to different types of DNA replication problems. The ATR kinase is the master regulator of the DNA replication checkpoint. Activated by a wide spectrum of DNA damage and replication problems, ATR and its effector kinase Chk1 regulate and coordinate DNA replication, DNA repair, and cell cycle transitions. Mounting evidence has suggested that the ATR checkpoint pathway is crucial for the suppression of genomic instability and sustained cell survival. In this review, we will discuss the recent findings on how the ATR pathway is activated by replication stress and how this pathway functions to suppress genomic instability during DNA replication.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Balakrishnan L, Bambara RA (2013) Okazaki fragment metabolism. Cold Spring Harb Perspect Biol 5(2). doi:10.1101/cshperspect.a010173
Balakumaran BS, Freudenreich CH, Zakian VA (2000) CGG/CCG repeats exhibit orientation-dependent instability and orientation-independent fragility in Saccharomyces cerevisiae. Hum Mol Genet 9(1):93–100
Ball HL, Myers JS, Cortez D (2005) ATRIP binding to replication protein A-single-stranded DNA promotes ATR-ATRIP localization but is dispensable for Chk1 phosphorylation. Mol Biol Cell 16(5):2372–2381
Ball HL, Ehrhardt MR, Mordes DA, Glick GG, Chazin WJ, Cortez D (2007) Function of a conserved checkpoint recruitment domain in ATRIP proteins. Mol Cell Biol 27(9):3367–3377
Bansbach CE, Betous R, Lovejoy CA, Glick GG, Cortez D (2009) The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Genes Dev 23(20):2405–2414
Barlow JH, Faryabi RB, Callen E, Wong N, Malhowski A, Chen HT, Gutierrez-Cruz G, Sun HW, McKinnon P, Wright G, Casellas R, Robbiani DF, Staudt L, Fernandez-Capetillo O, Nussenzweig A (2013) Identification of early replicating fragile sites that contributes to genome instability. Cell 152(3):620–632
Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, Guldberg P, Sehested M, Nesland JM, Lukas C, Orntoft T, Lukas J, Bartek J (2005) DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434(7035):864–870
Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Orntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis VG (2006) Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444(7119):633–637
Betous R, Mason AC, Rambo RP, Bansbach CE, Badu-Nkansah A, Sirbu BM, Eichman BF, Cortez D (2012) SMARCAL1 catalyzes fork regression and Holliday junction migration to maintain genome stability during DNA replication. Genes Dev 26(2):151–162
Betous R, Couch FB, Mason AC, Eichman BF, Manosas M, Cortez D (2013) Substrate-selective repair and restart of replication forks by DNA translocases. Cell Rep 3(6):1958–1969
Bianchi J, Rudd SG, Jozwiakowski SK, Bailey LJ, Soura V, Taylor E, Stevanovic I, Green AJ, Stracker TH, Lindsay HD, Doherty AJ (2013) PrimPol bypasses UV photoproducts during eukaryotic chromosomal DNA replication. Mol Cell 52(4):566–573
Brown EJ, Baltimore D (2000) ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev 14(4):397–402
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(6962):87–91
Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA (2005) Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev 19(9):1040–1052
Casper AM, Nghiem P, Arlt MF, Glover TW (2002) ATR regulates fragile site stability. Cell 111(6):779–789
Charrier JD, Durrant SJ, Golec JM, Kay DP, Knegtel RM, MacCormick S, Mortimore M, O’Donnell ME, Pinder JL, Reaper PM, Rutherford AP, Wang PS, Young SC, Pollard JR (2011) Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents. J Med Chem 54(7):2320–2330
Chen T, Stephens PA, Middleton FK, Curtin NJ (2012) Targeting the S and G2 checkpoint to treat cancer. Drug Discov Today 17(5–6):194–202
Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40(2):179–204
Ciccia A, Nimonkar AV, Hu Y, Hajdu I, Achar YJ, Izhar L, Petit SA, Adamson B, Yoon JC, Kowalczykowski SC, Livingston DM, Haracska L, Elledge SJ (2012) Polyubiquitinated PCNA recruits the ZRANB3 translocase to maintain genomic integrity after replication stress. Mol Cell 47(3):396–409
Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9(8):616–627
Collis SJ, Ciccia A, Deans AJ, Horejsi Z, Martin JS, Maslen SL, Skehel JM, Elledge SJ, West SC, Boulton SJ (2008) FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Mol Cell 32(3):313–324
Cortez D, Guntuku S, Qin J, Elledge SJ (2001) ATR and ATRIP: partners in checkpoint signaling. Science 294(5547):1713–1716
Cotta-Ramusino C, McDonald ER 3rd, Hurov K, Sowa ME, Harper JW, Elledge SJ (2011) A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. Science 332(6035):1313–1317
Couch FB, Bansbach CE, Driscoll R, Luzwick JW, Glick GG, Betous R, Carroll CM, Jung SY, Qin J, Cimprich KA, Cortez D (2013) ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev 27(14):1610–1623
Davies KD, Cable PL, Garrus JE, Sullivan FX, von Carlowitz I, Huerou YL, Wallace E, Woessner RD, Gross S (2011) Chk1 inhibition and Wee1 inhibition combine synergistically to impede cellular proliferation. Cancer Biol Ther 12(9):788–796
Delacroix S, Wagner JM, Kobayashi M, Yamamoto K, Karnitz LM (2007) The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1. Genes Dev 21(12):1472–1477
Dominguez-Kelly R, Martin Y, Koundrioukoff S, Tanenbaum ME, Smits VA, Medema RH, Debatisse M, Freire R (2011) Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease. J Cell Biol 194(4):567–579
Duursma AM, Driscoll R, Elias JE, Cimprich KA (2013) A role for the MRN complex in ATR activation via TOPBP1 recruitment. Mol Cell 50(1):116–122
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(2), E33
Fang Y, Tsao CC, Goodman BK, Furumai R, Tirado CA, Abraham RT, Wang XF (2004) ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background. EMBO J 23(15):3164–3174
Flynn RL, Zou L (2011) ATR: a master conductor of cellular responses to DNA replication stress. Trends Biochem Sci 36(3):133–140
Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, Vallis KA, Hammond EM, Olcina MM, Gillies McKenna W, Muschel RJ, Brunner TB (2012) Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis 3, e441
Foote KM, Blades K, Cronin A, Fillery S, Guichard SS, Hassall L, Hickson I, Jacq X, Jewsbury PJ, McGuire TM, Nissink JW, Odedra R, Page K, Perkins P, Suleman A, Tam K, Thommes P, Broadhurst R, Wood C (2013) Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-y l}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity. J Med Chem 56(5):2125–2138
Forment JV, Blasius M, Guerini I, Jackson SP (2011) Structure-specific DNA endonuclease Mus81/Eme1 generates DNA damage caused by Chk1 inactivation. PLoS One 6(8), e23517
Fu YV, Yardimci H, Long DT, Ho TV, Guainazzi A, Bermudez VP, Hurwitz J, van Oijen A, Scharer OD, Walter JC (2011) Selective bypass of a lagging strand roadblock by the eukaryotic replicative DNA helicase. Cell 146(6):931–941
Fugger K, Chu WK, Haahr P, Kousholt AN, Beck H, Payne MJ, Hanada K, Hickson ID, Sorensen CS (2013) FBH1 cooperates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress. Nat Commun 4:1423
Garcia-Gomez S, Reyes A, Martinez-Jimenez MI, Chocron ES, Mouron S, Terrados G, Powell C, Salido E, Mendez J, Holt IJ, Blanco L (2013) PrimPol, an archaic primase/polymerase operating in human cells. Mol Cell 52(4):541–553
Giannattasio M, Follonier C, Tourriere H, Puddu F, Lazzaro F, Pasero P, Lopes M, Plevani P, Muzi-Falconi M (2010) Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation. Mol Cell 40(1):50–62
Glover TW, Arlt MF, Casper AM, Durkin SG (2005) Mechanisms of common fragile site instability. Hum Mol Genet 14(2):R197–R205
Gohler T, Sabbioneda S, Green CM, Lehmann AR (2011) ATR-mediated phosphorylation of DNA polymerase eta is needed for efficient recovery from UV damage. J Cell Biol 192(2):219–227
Gong Z, Kim JE, Leung CC, Glover JN, Chen J (2010) BACH1/FANCJ acts with TopBP1 and participates early in DNA replication checkpoint control. Mol Cell 37(3):438–446
Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B, Kletsas D, Yoneta A, Herlyn M, Kittas C, Halazonetis TD (2005) Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434(7035):907–913
Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O’Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR (2007) Patterns of somatic mutation in human cancer genomes. Nature 446(7132):153–158
Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319(5868):1352–1355
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Hoek M, Stillman B (2003) Chromatin assembly factor 1 is essential and couples chromatin assembly to DNA replication in vivo. Proc Natl Acad Sci USA 100(21):12183–12188
Huang M, Kim JM, Shiotani B, Yang K, Zou L, D’Andrea AD (2010) The FANCM/FAAP24 complex is required for the DNA interstrand cross-link-induced checkpoint response. Mol Cell 39(2):259–268
Huntoon CJ, Flatten KS, Wahner Hendrickson AE, Huehls AM, Sutor SL, Kaufmann SH, Karnitz LM (2013) ATR inhibition broadly sensitizes ovarian cancer cells to chemotherapy independent of BRCA status. Cancer Res 73(12):3683–3691
Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, Saberi A, Kinoshita E, Kinoshita-Kikuta E, Koike T, Tashiro S, Elledge SJ, Takata M (2008) FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat Struct Mol Biol 15(11):1138–1146
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(1):37–45
** J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ, Harper JW (2003) SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev 17(24):3062–3074
Johansson E, Dixon N (2013) Replicative DNA polymerases. Cold Spring Harb Perspect Biol 5(6). doi: 10.1101/cshperspect.a012799
Kaur H, Halliwell B (1996) Measurement of oxidized and methylated DNA bases by HPLC with electrochemical detection. Biochem J 318(Pt 1):21–23
Kim H, D’Andrea AD (2012) Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev 26(13):1393–1408
Knipscheer P, Raschle M, Smogorzewska A, Enoiu M, Ho TV, Scharer OD, Elledge SJ, Walter JC (2009) The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science 326(5960):1698–1701
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(5543):867–870
Kousholt AN, Fugger K, Hoffmann S, Larsen BD, Menzel T, Sartori AA, Sorensen CS (2012) CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation. J Cell Biol 197(7):869–876
Kratz K, Schopf B, Kaden S, Sendoel A, Eberhard R, Lademann C, Cannavo E, Sartori AA, Hengartner MO, Jiricny J (2010) Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand cross-linking agents. Cell 142(1):77–88
Kumagai A, Dunphy WG (2003) Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1. Nat Cell Biol 5(2):161–165
Kumagai A, Lee J, Yoo HY, Dunphy WG (2006) TopBP1 activates the ATR-ATRIP complex. Cell 124(5):943–955
Kumar S, Burgers PM (2013) Lagging strand maturation factor Dna2 is a component of the replication checkpoint initiation machinery. Genes Dev 27(3):313–321
Lee J, Dunphy WG (2010) Rad17 plays a central role in establishment of the interaction between TopBP1 and the Rad9-Hus1-Rad1 complex at stalled replication forks. Mol Biol Cell 21(6):926–935
Lee J, Dunphy WG (2013) The Mre11-Rad50-Nbs1 (MRN) complex has a specific role in the activation of Chk1 in response to stalled replication forks. Mol Biol Cell 24(9):1343–1353
Lee J, Kumagai A, Dunphy WG (2007) The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. J Biol Chem 282(38):28036–28044
Lehmann AR (2005) Replication of damaged DNA by translesion synthesis in human cells. FEBS Lett 579(4):873–876
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 G(2)/M DNA damage checkpoint. Genes Dev 14(12):1448–1459
Liu S, Shiotani B, Lahiri M, Marechal A, Tse A, Leung CC, Glover JN, Yang XH, Zou L (2011) ATR autophosphorylation as a molecular switch for checkpoint activation. Mol Cell 43(2):192–202
Liu S, Song N, Zou L (2012) The conserved C-terminus of Claspin interacts with Rad9 and promotes rapid activation of Chk1. Cell Cycle 11(14):2711–2716
Lopes M, Foiani M, Sogo JM (2006) Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions. Mol Cell 21(1):15–27
Lossaint G, Larroque M, Ribeyre C, Bec N, Larroque C, Decaillet C, Gari K, Constantinou A (2013) FANCD2 binds MCM proteins and controls replisome function upon activation of s phase checkpoint signaling. Mol Cell 51(5):678–690
Luke-Glaser S, Luke B, Grossi S, Constantinou A (2010) FANCM regulates DNA chain elongation and is stabilized by S-phase checkpoint signaling. EMBO J 29(4):795–805
MacDougall CA, Byun TS, Van C, Yee MC, Cimprich KA (2007) The structural determinants of checkpoint activation. Genes Dev 21(8):898–903
MacKay C, Declais AC, Lundin C, Agostinho A, Deans AJ, MacArtney TJ, Hofmann K, Gartner A, West SC, Helleday T, Lilley DM, Rouse J (2010) Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell 142(1):65–76
Majka J, Binz SK, Wold MS, Burgers PM (2006a) Replication protein A directs loading of the DNA damage checkpoint clamp to 5′-DNA junctions. J Biol Chem 281(38):27855–27861
Majka J, Niedziela-Majka A, Burgers PM (2006b) The checkpoint clamp activates Mec1 kinase during initiation of the DNA damage checkpoint. Mol Cell 24(6):891–901
Marechal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol 5(9). doi: 10.1101/cshperspect.a012716
Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316(5828):1160–1166
Maugeri-Sacca M, Bartucci M, De Maria R (2013) Checkpoint kinase 1 inhibitors for potentiating systemic anticancer therapy. Cancer Treat Rev 39(5):525–533
McNees CJ, Tejera AM, Martinez P, Murga M, Mulero F, Fernandez-Capetillo O, Blasco MA (2010) ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase. J Cell Biol 188(5):639–652
Melo JA, Cohen J, Toczyski DP (2001) Two checkpoint complexes are independently recruited to sites of DNA damage in vivo. Genes Dev 15(21):2809–2821
Mordes DA, Glick GG, Zhao R, Cortez D (2008a) TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes Dev 22(11):1478–1489
Mordes DA, Nam EA, Cortez D (2008b) Dpb11 activates the Mec1-Ddc2 complex. Proc Natl Acad Sci USA 105(48):18730–18734
Mouron S, Rodriguez-Acebes S, Martinez-Jimenez MI, Garcia-Gomez S, Chocron S, Blanco L, Mendez J (2013) Repriming of DNA synthesis at stalled replication forks by human PrimPol. Nat Struct Mol Biol 20(12):1383–1389
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(24):17330–17334
Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montana MF, D’Artista L, Schleker T, Guerra C, Garcia E, Barbacid M, Hidalgo M, Amati B, Fernandez-Capetillo O (2011) Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol 18(12):1331–1335
Myers JS, Cortez D (2006) Rapid activation of ATR by ionizing radiation requires ATM and Mre11. J Biol Chem 281(14):9346–9350
Namiki Y, Zou L (2006) ATRIP associates with replication protein A-coated ssDNA through multiple interactions. Proc Natl Acad Sci USA 103(3):580–585
Navadgi-Patil VM, Burgers PM (2009) The unstructured C-terminal tail of the 9-1-1 clamp subunit Ddc1 activates Mec1/ATR via two distinct mechanisms. Mol Cell 36(5):743–753
Navadgi-Patil VM, Kumar S, Burgers PM (2011) The unstructured C-terminal tail of yeast Dpb11 (human TopBP1) protein is dispensable for DNA replication and the S phase checkpoint but required for the G2/M checkpoint. J Biol Chem 286(47):40999–41007
Neelsen KJ, Zanini IM, Herrador R, Lopes M (2013) Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates. J Cell Biol 200(6):699–708
Negishi M, Chiba T, Saraya A, Miyagi S, Iwama A (2009) Dmap1 plays an essential role in the maintenance of genome integrity through the DNA repair process. Genes Cells 14(11):1347–1357
Nghiem P, Park PK, Kim Y, Vaziri C, Schreiber SL (2001) ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation. Proc Natl Acad Sci USA 98(16):9092–9097
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(4):497–501
Oakley GG, Tillison K, Opiyo SA, Glanzer JG, Horn JM, Patrick SM (2009) Physical interaction between replication protein A (RPA) and MRN: involvement of RPA2 phosphorylation and the N-terminus of RPA1. Biochemistry 48(31):7473–7481
Olson E, Nievera CJ, Lee AY, Chen L, Wu X (2007a) 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(31):22939–22952
Olson E, Nievera CJ, Liu E, Lee AY, Chen L, Wu X (2007b) The Mre11 complex mediates the S-phase checkpoint through an interaction with replication protein A. Mol Cell Biol 27(17):6053–6067
Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H (1997) Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216. Science 277(5331):1501–1505
Peterson SE, Li Y, Wu-Baer F, Chait BT, Baer R, Yan H, Gottesman ME, Gautier J (2013) Activation of DSB processing requires phosphorylation of CtIP by ATR. Mol Cell 49(4):657–667
Pommier Y, Cherfils J (2005) Interfacial inhibition of macromolecular interactions: nature’s paradigm for drug discovery. Trends Pharmacol Sci 26(3):138–145
Postow L, Woo EM, Chait BT, Funabiki H (2009) Identification of SMARCAL1 as a component of the DNA damage response. J Biol Chem 284(51):35951–35961
Prevo R, Fokas E, Reaper PM, Charlton PA, Pollard JR, McKenna WG, Muschel RJ, Brunner TB (2012) The novel ATR inhibitor VE-821 increases sensitivity of pancreatic cancer cells to radiation and chemotherapy. Cancer Biol Ther 13(11):1072–1081
Ragland RL, Patel S, Rivard RS, Smith K, Peters AA, Bielinsky AK, Brown EJ (2013) RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells. Genes Dev 27(20):2259–2273
Reaper PM, Griffiths MR, Long JM, Charrier JD, Maccormick S, Charlton PA, Golec JM, Pollard JR (2011) Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat Chem Biol 7(7):428–430
Regairaz M, Zhang YW, Fu H, Agama KK, Tata N, Agrawal S, Aladjem MI, Pommier Y (2011) Mus81-mediated DNA cleavage resolves replication forks stalled by topoisomerase I-DNA complexes. J Cell Biol 195(5):739–749
Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ (1997) Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science 277(5331):1497–1501
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(7169):509–514
Schlacher K, Christ N, Siaud N, Egashira A, Wu H, Jasin M (2011) Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145(4):529–542
Schlacher K, Wu H, Jasin M (2012) A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22(1):106–116
Schoppy DW, Ragland RL, Gilad O, Shastri N, Peters AA, Murga M, Fernandez-Capetillo O, Diehl JA, Brown EJ (2012) Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J Clin Invest 122(1):241–252
Schwab RA, Blackford AN, Niedzwiedz W (2010) ATR activation and replication fork restart are defective in FANCM-deficient cells. EMBO J 29(4):806–818
Shell SM, Li Z, Shkriabai N, Kvaratskhelia M, Brosey C, Serrano MA, Chazin WJ, Musich PR, Zou Y (2009) Checkpoint kinase ATR promotes nucleotide excision repair of UV-induced DNA damage via physical interaction with xeroderma pigmentosum group A. J Biol Chem 284(36):24213–24222
Shen X, Do H, Li Y, Chung WH, Tomasz M, de Winter JP, **a B, Elledge SJ, Wang W, Li L (2009) Recruitment of Fanconi anemia and breast cancer proteins to DNA damage sites is differentially governed by replication. Mol Cell 35(5):716–723
Shigechi T, Tomida J, Sato K, Kobayashi M, Eykelenboom JK, Pessina F, Zhang Y, Uchida E, Ishiai M, Lowndes NF, Yamamoto K, Kurumizaka H, Maehara Y, Takata M (2012) ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway. Cancer Res 72(5):1149–1156
Shiloh Y, Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14(4):197–210
Shimada M, Niida H, Zineldeen DH, Tagami H, Tanaka M, Saito H, Nakanishi M (2008) Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression. Cell 132(2):221–232
Shiotani B, Nguyen HD, Hakansson P, Marechal A, Tse A, Tahara H, Zou L (2013) Two distinct modes of ATR activation orchestrated by Rad17 and Nbs1. Cell Rep 3(5):1651–1662
Singh TR, Ali AM, Paramasivam M, Pradhan A, Wahengbam K, Seidman MM, Meetei AR (2013) ATR-dependent phosphorylation of FANCM at serine 1045 is essential for FANCM functions. Cancer Res 73(14):4300–4310
Smogorzewska A, Matsuoka S, Vinciguerra P, McDonald ER 3rd, Hurov KE, Luo J, Ballif BA, Gygi SP, Hofmann K, D’Andrea AD, Elledge SJ (2007) Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. Cell 129(2):289–301
Smogorzewska A, Desetty R, Saito TT, Schlabach M, Lach FP, Sowa ME, Clark AB, Kunkel TA, Harper JW, Colaiacovo MP, Elledge SJ (2010) A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand cross-link repair. Mol Cell 39(1):36–47
Sogo JM, Lopes M, Foiani M (2002) Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297(5581):599–602
Sorensen CS, Hansen LT, Dziegielewski J, Syljuasen RG, Lundin C, Bartek J, Helleday T (2005) The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol 7(2):195–201
Srinivasan SV, Dominguez-Sola D, Wang LC, Hyrien O, Gautier J (2013) Cdc45 is a critical effector of myc-dependent DNA replication stress. Cell Rep 3(5):1629–1639
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(1):199–208
Stokes MP, Rush J, Macneill J, Ren JM, Sprott K, Nardone J, Yang V, Beausoleil SA, Gygi SP, Livingstone M, Zhang H, Polakiewicz RD, Comb MJ (2007) Profiling of UV-induced ATM/ATR signaling pathways. Proc Natl Acad Sci USA 104(50):19855–19860
Symington LS, Gautier J (2011) Double-strand break end resection and repair pathway choice. Annu Rev Genet 45:247–271
Tanaka S, Araki H (2013) Helicase activation and establishment of replication forks at chromosomal origins of replication. Cold Spring Harb Perspect Biol. doi: 10.1101/cshperspect.a010371
Terret ME, Sherwood R, Rahman S, Qin J, Jallepalli PV (2009) Cohesin acetylation speeds the replication fork. Nature 462(7270):231–234
Toledo LI, Altmeyer M, Rask MB, Lukas C, Larsen DH, Povlsen LK, Bekker-Jensen S, Mailand N, Bartek J, Lukas J (2013) ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 155(5):1088–1103
Van C, Yan S, Michael WM, Waga S, Cimprich KA (2010) Continued primer synthesis at stalled replication forks contributes to checkpoint activation. J Cell Biol 189(2):233–246
Vavrova J, Zarybnicka L, Lukasova E, Rezacova M, Novotna E, Sinkorova Z, Tichy A, Pejchal J, Durisova K (2013) Inhibition of ATR kinase with the selective inhibitor VE-821 results in radiosensitization of cells of promyelocytic leukemia (HL-60). Radiat Environ Biophys 52(4):471–479
Waga S, Stillman B (1998) The DNA replication fork in eukaryotic cells. Annu Rev Biochem 67:721–751
Walter J, Newport J (2000) Initiation of eukaryotic DNA replication: origin unwinding and sequential chromatin association of Cdc45, RPA, and DNA polymerase alpha. Mol Cell 5(4):617–627
Wan L, Lou J, **a Y, Su B, Liu T, Cui J, Sun Y, Lou H, Huang J (2013) hPrimpol1/CCDC111 is a human DNA primase-polymerase required for the maintenance of genome integrity. EMBO Rep 14(12):1104–1112
Wang W (2007) Emergence of a DNA-damage response network consisting of Fanconi anemia and BRCA proteins. Nat Rev Genet 8(10):735–748
Wang X, Zou L, Lu T, Bao S, Hurov KE, Hittelman WN, Elledge SJ, Li L (2006) Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress. Mol Cell 23(3):331–341
Wang J, Gong Z, Chen J (2011) MDC1 collaborates with TopBP1 in DNA replication checkpoint control. J Cell Biol 193(2):267–273
Wang Y, Leung JW, Jiang Y, Lowery MG, Do H, Vasquez KM, Chen J, Wang W, Li L (2013) FANCM and FAAP24 maintain genome stability via cooperative as well as unique functions. Mol Cell 49(5):997–1009
Yamamoto KN, Kobayashi S, Tsuda M, Kurumizaka H, Takata M, Kono K, Jiricny J, Takeda S, Hirota K (2011) Involvement of SLX4 in interstrand cross-link repair is regulated by the Fanconi anemia pathway. Proc Natl Acad Sci USA 108(16):6492–6496
Yoo HY, Kumagai A, Shevchenko A, Dunphy WG (2009) The Mre11-Rad50-Nbs1 complex mediates activation of TopBP1 by ATM. Mol Biol Cell 20(9):2351–2360
Yu X, Wu LC, Bowcock AM, Aronheim A, Baer R (1998) The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J Biol Chem 273(39):25388–25392
Yuan J, Ghosal G, Chen J (2009) The annealing helicase HARP protects stalled replication forks. Genes Dev 23(20):2394–2399
Yusufzai T, Kadonaga JT (2008) HARP is an ATP-driven annealing helicase. Science 322(5902):748–750
Yusufzai T, Kong X, Yokomori K, Kadonaga JT (2009) The annealing helicase HARP is recruited to DNA repair sites via an interaction with RPA. Genes Dev 23(20):2400–2404
Zhou ZW, Liu C, Li TL, Bruhn C, Krueger A, Min W, Wang ZQ, Carr AM (2013) An essential function for the ATR-activation-domain (AAD) of TopBP1 in mouse development and cellular senescence. PLoS Genet 9(8), e1003702
Zou L, Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300(5625):1542–1548
Zou L, Cortez D, Elledge SJ (2002) Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes Dev 16(2):198–208
Zou L, Liu D, Elledge SJ (2003) Replication protein A-mediated recruitment and activation of Rad17 complexes. Proc Natl Acad Sci USA 100(24):13827–13832
Acknowledgment
We apologize to the colleagues whose work is not cited in this article due to space limitation. B. S. is supported by a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology (KAKENHI, 25701005). L. Z. is a Jim & Ann Orr Massachusetts General Hospital Research Scholar and is supported by grants from NIH (GM076388) and the Federal Share of MGH Proton Program.
Author information
Authors and Affiliations
Corresponding authors
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Japan
About this chapter
Cite this chapter
Shiotani, B., Zou, L. (2016). Signaling of DNA Replication Stress Through the ATR Checkpoint. In: Hanaoka, F., Sugasawa, K. (eds) DNA Replication, Recombination, and Repair. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55873-6_16
Download citation
DOI: https://doi.org/10.1007/978-4-431-55873-6_16
Published:
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-55871-2
Online ISBN: 978-4-431-55873-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)