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Annual Review of Genetics

Volume 50, 2016

Functions, Regulation, and Therapeutic Implications of the ATR Checkpoint Pathway

Abstract

The ATR (ATM and rad3-related) pathway is crucial for proliferation, responding to DNA replication stress and DNA damage. This critical signaling pathway is carefully orchestrated through a multistep process requiring initial priming of ATR prior to damage, recruitment of ATR to DNA damage lesions, activation of ATR signaling, and, finally, modulation of ATR activity through a variety of post-translational modifications. Following activation, ATR functions in several vital cellular processes, including suppression of replication origin firing, promotion of deoxynucleotide synthesis and replication fork restart, prevention of double-stranded DNA break formation, and avoidance of replication catastrophe and mitotic catastrophe. In many cancers, tumor cells have increased dependence on ATR signaling for survival, making ATR a promising target for cancer therapy. Tumor cells compromised in DNA repair pathways or DNA damage checkpoints, cells reliant on homologous recombination, and cells with increased replication stress are particularly sensitive to ATR inhibition. Understanding ATR signaling and modulation is essential to unraveling which tumors have increased dependence on ATR signaling as well as how the ATR pathway can best be exploited for targeted cancer therapy.

Keyword(s): ATR, cancer therapy, checkpoint, Chk1, DNA damage, DNA repair, genomic instability, replication stress
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/content/journals/10.1146/annurev-genet-121415-121658
2016-11-23
2024-04-19
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Literature Cited

  1. Abbas R, McColl KS, Kresak A, Yang M, Chen Y. 1.  et al. 2015. PIAS3 expression in squamous cell lung cancer is low and predicts overall survival. Cancer Med. 4:325–32 [Google Scholar]
  2. Adamson B, Smogorzewska A, Sigoillot FD, King RW, Elledge SJ. 2.  2012. A genome-wide homologous recombination screen identifies the RNA-binding protein RBMX as a component of the DNA-damage response. Nat. Cell Biol. 14:318–28 [Google Scholar]
  3. Ammazzalorso F, Pirzio LM, Bignami M, Franchitto A, Pichierri P. 3.  2010. ATR and ATM differently regulate WRN to prevent DSBs at stalled replication forks and promote replication fork recovery. EMBO J. 29:3156–69 [Google Scholar]
  4. Besse B, Olaussen KA, Soria JC. 4.  2013. ERCC1 and RRM1: ready for prime time?. J. Clin. Oncol. 31:1050–60 [Google Scholar]
  5. Boos D, Sanchez-Pulido L, Rappas M, Pearl LH, Oliver AW. 5.  et al. 2011. Regulation of DNA replication through Sld3-Dpb11 interaction is conserved from yeast to humans. Curr. Biol. 21:1152–57 [Google Scholar]
  6. Brantley EC, Nabors LB, Gillespie GY, Choi YH, Palmer CA. 6.  et al. 2008. Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: implications for STAT-3 activation and gene expression. Clin. Cancer Res. 14:4694–704 [Google Scholar]
  7. Brown EJ, Baltimore D. 7.  2000. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14:397–402 [Google Scholar]
  8. Buisson R, Boisvert JL, Benes CH, Zou L. 8.  2015. Distinct but concerted roles of ATR, DNA-PK, and Chk1 in countering replication stress during S phase. Mol. Cell 59:1011–24 [Google Scholar]
  9. Burdova K, Mihaljevic B, Sturzenegger A, Chappidi N, Janscak P. 9.  2015. The mismatch-binding factor MutSβ can mediate ATR activation in response to DNA double-strand breaks. Mol. Cell 59:603–14 [Google Scholar]
  10. Busino L, Donzelli M, Chiesa M, Guardavaccaro D, Ganoth D. 10.  et al. 2003. Degradation of Cdc25A by β-TrCP during S phase and in response to DNA damage. Nature 426:87–91 [Google Scholar]
  11. Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA. 11.  2005. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 19:1040–52 [Google Scholar]
  12. Calzada A, Hodgson B, Kanemaki M, Bueno A, Labib K. 12.  2005. Molecular anatomy and regulation of a stable replisome at a paused eukaryotic DNA replication fork. Genes Dev. 19:1905–19 [Google Scholar]
  13. Casper AM, Nghiem P, Arlt MF, Glover TW. 13.  2002. ATR regulates fragile site stability. Cell 111:779–89 [Google Scholar]
  14. Chen H, Lisby M, Symington LS. 14.  2013. RPA coordinates DNA end resection and prevents formation of DNA hairpins. Mol. Cell 50:589–600 [Google Scholar]
  15. Chen YH, Jones MJ, Yin Y, Crist SB, Colnaghi L. 15.  et al. 2015. ATR-mediated phosphorylation of FANCI regulates dormant origin firing in response to replication stress. Mol. Cell 58:323–38 [Google Scholar]
  16. Ciccia A, Elledge SJ. 16.  2010. The DNA damage response: making it safe to play with knives. Mol. Cell 40:179–204 [Google Scholar]
  17. Cimprich KA, Cortez D. 17.  2008. ATR: an essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 9:616–27 [Google Scholar]
  18. Collis SJ, Ciccia A, Deans AJ, Horejsi Z, Martin JS. 18.  et al. 2008. FANCM and FAAP24 function in ATR-mediated checkpoint signaling independently of the Fanconi anemia core complex. Mol. Cell 32:313–24 [Google Scholar]
  19. Cortez D, Glick G, Elledge SJ. 19.  2004. Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. PNAS 101:10078–83 [Google Scholar]
  20. Cortez D, Guntuku S, Qin J, Elledge SJ. 20.  2001. ATR and ATRIP: partners in checkpoint signaling. Science 294:1713–16 [Google Scholar]
  21. Cotta-Ramusino C, McDonald ER 3rd, Hurov K, Sowa ME, Harper JW, Elledge SJ. 21.  2011. A DNA damage response screen identifies RHINO, a 9-1-1 and TopBP1 interacting protein required for ATR signaling. Science 332:1313–17 [Google Scholar]
  22. Couch FB, Bansbach CE, Driscoll R, Luzwick JW, Glick GG. 22.  et al. 2013. ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev. 27:1610–23 [Google Scholar]
  23. Dabir S, Kluge A, Kresak A, Yang M, Fu P. 23.  et al. 2014. Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival. Clin. Cancer Res. 20:5124–32 [Google Scholar]
  24. Delacroix S, Wagner JM, Kobayashi M, Yamamoto K, Karnitz LM. 24.  2007. The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1. Genes Dev. 21:1472–77 [Google Scholar]
  25. Denchi EL, de Lange T. 25.  2007. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448:1068–71 [Google Scholar]
  26. Deng SK, Yin Y, Petes TD, Symington LS. 26.  2015. Mre11-Sae2 and RPA collaborate to prevent palindromic gene amplification. Mol. Cell 60:500–8 [Google Scholar]
  27. Dungrawala H, Rose KL, Bhat KP, Mohni KN, Glick GG. 27.  et al. 2015. The replication checkpoint prevents two types of fork collapse without regulating replisome stability. Mol. Cell 59:998–1010 [Google Scholar]
  28. Duursma AM, Driscoll R, Elias JE, Cimprich KA. 28.  2013. A role for the MRN complex in ATR activation via TOPBP1 recruitment. Mol. Cell 50:116–22 [Google Scholar]
  29. Elia AE, Wang DC, Willis NA, Boardman AP, Hajdu I. 29.  et al. 2015. RFWD3-dependent ubiquitination of RPA regulates repair at stalled replication forks. Mol. Cell 60:280–93 [Google Scholar]
  30. Ellison V, Stillman B. 30.  2003. Biochemical characterization of DNA damage checkpoint complexes: clamp loader and clamp complexes with specificity for 5′ recessed DNA. PLOS Biol. 1:E33 [Google Scholar]
  31. Eykelenboom JK, Harte EC, Canavan L, Pastor-Peidro A, Calvo-Asensio I. 31.  et al. 2013. ATR activates the S-M checkpoint during unperturbed growth to ensure sufficient replication prior to mitotic onset. Cell Rep. 5:1095–107 [Google Scholar]
  32. Flynn RL, Cox KE, Jeitany M, Wakimoto H, Bryll AR. 32.  et al. 2015. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 347:273–77 [Google Scholar]
  33. Flynn RL, Zou L. 33.  2011. ATR: a master conductor of cellular responses to DNA replication stress. Trends Biochem. Sci. 36:133–40 [Google Scholar]
  34. Gilad O, Nabet BY, Ragland RL, Schoppy DW, Smith KD. 34.  et al. 2010. Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner. Cancer Res. 70:9693–702 [Google Scholar]
  35. Gohler T, Sabbioneda S, Green CM, Lehmann AR. 35.  2011. ATR-mediated phosphorylation of DNA polymerase eta is needed for efficient recovery from UV damage. J. Cell Biol. 192:219–27 [Google Scholar]
  36. Gong Z, Chen J. 36.  2011. E3 ligase RFWD3 participates in replication checkpoint control. J. Biol. Chem. 286:22308–13 [Google Scholar]
  37. Gravel S, Chapman JR, Magill C, Jackson SP. 37.  2008. DNA helicases Sgs1 and BLM promote DNA double-strand break resection. Genes Dev. 22:2767–72 [Google Scholar]
  38. Guo C, Kumagai A, Schlacher K, Shevchenko A, Shevchenko A, Dunphy WG. 38.  2015. Interaction of Chk1 with Treslin negatively regulates the initiation of chromosomal DNA replication. Mol. Cell 57:492–505 [Google Scholar]
  39. Hakin-Smith V, Jellinek DA, Levy D, Carroll T, Teo M. 39.  et al. 2003. Alternative lengthening of telomeres and survival in patients with glioblastoma multiforme. Lancet 361:836–38 [Google Scholar]
  40. Hao J, de Renty C, Li Y, Xiao H, Kemp MG. 40.  et al. 2015. And-1 coordinates with Claspin for efficient Chk1 activation in response to replication stress. EMBO J. 34:2096–110 [Google Scholar]
  41. Harrigan JA, Belotserkovskaya R, Coates J, Dimitrova DS, Polo SE. 41.  et al. 2011. Replication stress induces 53BP1-containing OPT domains in G1 cells. J. Cell Biol. 193:97–108 [Google Scholar]
  42. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH. 42.  et al. 2011. Altered telomeres in tumors with ATRX and DAXX mutations. Science 333:425 [Google Scholar]
  43. Heffernan TP, Unsal-Kacmaz K, Heinloth AN, Simpson DA, Paules RS. 43.  et al. 2007. Cdc7-Dbf4 and the human S checkpoint response to UVC. J. Biol. Chem. 282:9458–68 [Google Scholar]
  44. Hoffmann S, Smedegaard S, Nakamura K, Mortuza GB, Raschle M. 44.  et al. 2016. TRAIP is a PCNA-binding ubiquitin ligase that protects genome stability after replication stress. J. Cell Biol. 212:63–75 [Google Scholar]
  45. Huang M, Kim JM, Shiotani B, Yang K, Zou L, D'Andrea AD. 45.  2010. The FANCM/FAAP24 complex is required for the DNA interstrand crosslink-induced checkpoint response. Mol. Cell 39:259–68 [Google Scholar]
  46. Hurov KE, Cotta-Ramusino C, Elledge SJ. 46.  2010. A genetic screen identifies the Triple T complex required for DNA damage signaling and ATM and ATR stability. Genes Dev. 24:1939–50 [Google Scholar]
  47. Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A. 47.  et al. 2008. FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat. Struct. Mol. Biol. 15:1138–46 [Google Scholar]
  48. Jackson PK. 48.  2013. Nek8 couples renal ciliopathies to DNA damage and checkpoint control. Mol. Cell 51:407–8 [Google Scholar]
  49. Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC. 49.  et al. 2006. ATM- and cell cycle–dependent regulation of ATR in response to DNA double-strand breaks. Nat. Cell Biol. 8:37–45 [Google Scholar]
  50. Jin J, Shirogane T, Xu L, Nalepa G, Qin J. 50.  et al. 2003. SCFβ-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Genes Dev 17:3062–74 [Google Scholar]
  51. Karnitz LM, Zou L. 51.  2015. Molecular pathways: targeting ATR in cancer therapy. Clin. Cancer Res. 21:4780–85 [Google Scholar]
  52. Kousholt AN, Fugger K, Hoffmann S, Larsen BD, Menzel T. 52.  et al. 2012. CtIP-dependent DNA resection is required for DNA damage checkpoint maintenance but not initiation. J. Cell Biol. 197:869–76 [Google Scholar]
  53. Kumagai A, Lee J, Yoo HY, Dunphy WG. 53.  2006. TopBP1 activates the ATR-ATRIP complex. Cell 124:943–55 [Google Scholar]
  54. Kumar A, Mazzanti M, Mistrik M, Kosar M, Beznoussenko G. 54.  et al. 2014. ATR mediates a checkpoint at the nuclear envelope in response to mechanical stress. Cell 158:633–46 [Google Scholar]
  55. Kwok M, Davies N, Agathanggelou A, Smith E, Petermann E. 55.  et al. 2015. Synthetic lethality in chronic lymphocytic leukaemia with DNA damage response defects by targeting the ATR pathway. Lancet 385:Suppl. 1S58 [Google Scholar]
  56. Lee J, Dunphy WG. 56.  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 21:926–35 [Google Scholar]
  57. Lee J, Dunphy WG. 57.  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 24:1343–53 [Google Scholar]
  58. Lee J, Kumagai A, Dunphy WG. 58.  2007. The Rad9-Hus1-Rad1 checkpoint clamp regulates interaction of TopBP1 with ATR. J. Biol. Chem. 282:28036–44 [Google Scholar]
  59. Li J, Cui J, Zhang J, Liu Y, Han L. 59.  et al. 2015. PIAS3, an inhibitor of STAT3, has intensively negative association with the survival of gastric cancer. Int. J. Clin. Exp. Med. 8:682–89 [Google Scholar]
  60. Lin SY, Li K, Stewart GS, Elledge SJ. 60.  2004. Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation. PNAS 101:6484–89 [Google Scholar]
  61. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D. 61.  et al. 2000. Chk1 is an essential kinase that is regulated by Atr and required for the G2/M DNA damage checkpoint. Genes Dev. 14:1448–59 [Google Scholar]
  62. Liu S, Chu J, Yucer N, Leng M, Wang SY. 62.  et al. 2011. RING finger and WD repeat domain 3 (RFWD3) associates with replication protein A (RPA) and facilitates RPA-mediated DNA damage response. J. Biol. Chem. 286:22314–22 [Google Scholar]
  63. Liu S, Ho CK, Ouyang J, Zou L. 63.  2013. Nek1 kinase associates with ATR-ATRIP and primes ATR for efficient DNA damage signaling. PNAS 110:2175–80 [Google Scholar]
  64. Liu S, Shiotani B, Lahiri M, Marechal A, Tse A. 64.  et al. 2011. ATR autophosphorylation as a molecular switch for checkpoint activation. Mol. Cell 43:192–202 [Google Scholar]
  65. Lopez-Contreras AJ, Specks J, Barlow JH, Ambrogio C, Desler C. 65.  et al. 2015. Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice. Genes Dev. 29:690–95 [Google Scholar]
  66. Lovejoy CA, Li W, Reisenweber S, Thongthip S, Bruno J. 66.  et al. 2012. Loss of ATRX, genome instability, and an altered DNA damage response are hallmarks of the alternative lengthening of telomeres pathway. PLOS Genet. 8:e1002772 [Google Scholar]
  67. Lukas C, Savic V, Bekker-Jensen S, Doil C, Neumann B. 67.  et al. 2011. 53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress. Nat. Cell Biol. 13:243–53 [Google Scholar]
  68. Mailand N, Falck J, Lukas C, Syljuasen RG, Welcker M. 68.  et al. 2000. Rapid destruction of human Cdc25A in response to DNA damage. Science 288:1425–29 [Google Scholar]
  69. Marechal A, Li JM, Ji XY, Wu CS, Yazinski SA. 69.  et al. 2014. PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Mol. Cell 53:235–46 [Google Scholar]
  70. Marechal A, Zou L. 70.  2013. DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol. 5:pii:012716 [Google Scholar]
  71. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE. 71.  et al. 2007. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316:1160–66 [Google Scholar]
  72. McNees CJ, Tejera AM, Martinez P, Murga M, Mulero F. 72.  et al. 2010. ATR suppresses telomere fragility and recombination but is dispensable for elongation of short telomeres by telomerase. J. Cell Biol. 188:639–52 [Google Scholar]
  73. Mohni KN, Kavanaugh GM, Cortez D. 73.  2014. ATR pathway inhibition is synthetically lethal in cancer cells with ERCC1 deficiency. Cancer Res. 74:2835–45 [Google Scholar]
  74. Mordes DA, Glick GG, Zhao R, Cortez D. 74.  2008. TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Genes Dev. 22:1478–89 [Google Scholar]
  75. Mu Y, Lou J, Srivastava M, Zhao B, Feng XH. 75.  et al. 2016. SLFN11 inhibits checkpoint maintenance and homologous recombination repair. EMBO Rep. 17:94–109 [Google Scholar]
  76. Murga M, Bunting S, Montana MF, Soria R, Mulero F. 76.  et al. 2009. A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging. Nat. Genet. 41:891–98 [Google Scholar]
  77. Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R. 77.  et al. 2011. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat. Struct. Mol. Biol. 18:1331–35 [Google Scholar]
  78. Murphy AK, Fitzgerald M, Ro T, Kim JH, Rabinowitsch AI. 78.  et al. 2014. Phosphorylated RPA recruits PALB2 to stalled DNA replication forks to facilitate fork recovery. J. Cell Biol. 206:493–507 [Google Scholar]
  79. Myers JS, Cortez D. 79.  2006. Rapid activation of ATR by ionizing radiation requires ATM and Mre11. J. Biol. Chem. 281:9346–50 [Google Scholar]
  80. Nam EA, Zhao R, Cortez D. 80.  2011. Analysis of mutations that dissociate G2 and essential S phase functions of human ataxia telangiectasia–mutated and Rad3-related (ATR) protein kinase. J. Biol. Chem. 286:37320–27 [Google Scholar]
  81. Nghiem P, Park PK, Kim Y, Vaziri C, Schreiber SL. 81.  2001. ATR inhibition selectively sensitizes G1 checkpoint–deficient cells to lethal premature chromatin condensation. PNAS 98:9092–97 [Google Scholar]
  82. Ohashi E, Takeishi Y, Ueda S, Tsurimoto T. 82.  2014. Interaction between Rad9-Hus1-Rad1 and TopBP1 activates ATR-ATRIP and promotes TopBP1 recruitment to sites of UV-damage. DNA Repair 21:1–11 [Google Scholar]
  83. Pabla N, Ma Z, McIlhatton MA, Fishel R, Dong Z. 83.  2011. hMSH2 recruits ATR to DNA damage sites for activation during DNA damage-induced apoptosis. J. Biol. Chem. 286:10411–18 [Google Scholar]
  84. Petermann E, Maya-Mendoza A, Zachos G, Gillespie DA, Jackson DA, Caldecott KW. 84.  2006. Chk1 requirement for high global rates of replication fork progression during normal vertebrate S phase. Mol. Cell. Biol. 26:3319–26 [Google Scholar]
  85. Petermann E, Woodcock M, Helleday T. 85.  2010. Chk1 promotes replication fork progression by controlling replication initiation. PNAS 107:16090–95 [Google Scholar]
  86. Pickett HA, Reddel RR. 86.  2015. Molecular mechanisms of activity and derepression of alternative lengthening of telomeres. Nat. Struct. Mol. Biol. 22:875–80 [Google Scholar]
  87. Psakhye I, Jentsch S. 87.  2012. Protein group modification and synergy in the SUMO pathway as exemplified in DNA repair. Cell 151:807–20 [Google Scholar]
  88. Ragland RL, Patel S, Rivard RS, Smith K, Peters AA. 88.  et al. 2013. RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells. Genes Dev. 27:2259–73 [Google Scholar]
  89. Reaper PM, Griffiths MR, Long JM, Charrier JD, Maccormick S. 89.  et al. 2011. Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR. Nat. Chem. Biol. 7:428–30 [Google Scholar]
  90. Sanjiv K, Hagenkort A, Calderon-Montano JM, Koolmeister T, Reaper PM. 90.  et al. 2016. Cancer-specific synthetic lethality between ATR and CHK1 kinase activities. Cell Rep 14:298–309 [Google Scholar]
  91. Sartori AA, Lukas C, Coates J, Mistrik M, Fu S. 91.  et al. 2007. Human CtIP promotes DNA end resection. Nature 450:509–14 [Google Scholar]
  92. Scheel C, Schaefer KL, Jauch A, Keller M, Wai D. 92.  et al. 2001. Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas. Oncogene 20:3835–44 [Google Scholar]
  93. Schoppy DW, Ragland RL, Gilad O, Shastri N, Peters AA. 93.  et al. 2012. Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR. J. Clin. Investig. 122:241–52 [Google Scholar]
  94. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E. 94.  et al. 2012. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–31 [Google Scholar]
  95. Shiloh Y, Ziv Y. 95.  2013. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol. 14:197–210 [Google Scholar]
  96. Shiotani B, Nguyen HD, Hakansson P, Marechal A, Tse A. 96.  et al. 2013. Two distinct modes of ATR activation orchestrated by Rad17 and Nbs1. Cell Rep. 3:1651–62 [Google Scholar]
  97. Stiff T, Cerosaletti K, Concannon P, O'Driscoll M, Jeggo PA. 97.  2008. Replication independent ATR signalling leads to G2/M arrest requiring Nbs1, 53BP1 and MDC1. Hum. Mol. Genet. 17:3247–53 [Google Scholar]
  98. Sultana R, Abdel-Fatah T, Perry C, Moseley P, Albarakti N. 98.  et al. 2013. Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells. PLOS ONE 8:e57098 [Google Scholar]
  99. Syljuasen RG, Sorensen CS, Hansen LT, Fugger K, Lundin C. 99.  et al. 2005. Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage. Mol. Cell. Biol. 25:3553–62 [Google Scholar]
  100. Takai H, Xie Y, de Lange T, Pavletich NP. 100.  2010. Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes. Genes Dev. 24:2019–30 [Google Scholar]
  101. Takeishi Y, Ohashi E, Ogawa K, Masai H, Obuse C, Tsurimoto T. 101.  2010. Casein kinase 2-dependent phosphorylation of human Rad9 mediates the interaction between human Rad9-Hus1-Rad1 complex and TopBP1. Genes Cells 15:761–71 [Google Scholar]
  102. Techer H, Koundrioukoff S, Carignon S, Wilhelm T, Millot GA. 102.  et al. 2016. Signaling from Mus81-Eme2-dependent DNA damage elicited by Chk1 deficiency modulates replication fork speed and origin usage. Cell Rep. 5:1114–27 [Google Scholar]
  103. Toledo LI, Altmeyer M, Rask MB, Lukas C, Larsen DH. 103.  et al. 2013. ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell 155:1088–103 [Google Scholar]
  104. Toledo LI, Murga M, Zur R, Soria R, Rodriguez A. 104.  et al. 2011. A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations. Nat. Struct. Mol. Biol. 18:721–27 [Google Scholar]
  105. Tomimatsu N, Mukherjee B, Deland K, Kurimasa A, Bolderson E. 105.  et al. 2012. Exo1 plays a major role in DNA end resection in humans and influences double-strand break repair and damage signaling decisions. DNA Repair 11:441–48 [Google Scholar]
  106. Tong AS, Stern JL, Sfeir A, Kartawinata M, de Lange T. 106.  et al. 2015. ATM and ATR signaling regulate the recruitment of human telomerase to telomeres. Cell Rep. 13:1633–46 [Google Scholar]
  107. Vassin VM, Anantha RW, Sokolova E, Kanner S, Borowiec JA. 107.  2009. Human RPA phosphorylation by ATR stimulates DNA synthesis and prevents ssDNA accumulation during DNA-replication stress. J. Cell Sci. 122:4070–80 [Google Scholar]
  108. Vrouwe MG, Pines A, Overmeer RM, Hanada K, Mullenders LH. 108.  2011. UV-induced photolesions elicit ATR-kinase-dependent signaling in non-cycling cells through nucleotide excision repair–dependent and –independent pathways. J. Cell Sci. 124:435–46 [Google Scholar]
  109. Wan L, Huang J. 109.  2014. The PSO4 protein complex associates with replication protein A (RPA) and modulates the activation of ataxia telangiectasia–mutated and Rad3-related (ATR). J. Biol. Chem. 289:6619–26 [Google Scholar]
  110. Wang H, Wang H, Powell SN, Iliakis G, Wang Y. 110.  2004. ATR affecting cell radiosensitivity is dependent on homologous recombination repair but independent of nonhomologous end joining. Cancer Res. 64:7139–43 [Google Scholar]
  111. Wang J, Gong Z, Chen J. 111.  2011. MDC1 collaborates with TopBP1 in DNA replication checkpoint control. J. Cell Biol. 193:267–73 [Google Scholar]
  112. Wang X, Zou L, Lu T, Bao S, Hurov KE. 112.  et al. 2006. Rad17 phosphorylation is required for claspin recruitment and Chk1 activation in response to replication stress. Mol. Cell 23:331–41 [Google Scholar]
  113. Wang Y, Qin J. 113.  2003. MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation. PNAS 100:15387–92 [Google Scholar]
  114. Weiss RS, Matsuoka S, Elledge SJ, Leder P. 114.  2002. Hus1 acts upstream of Chk1 in a mammalian DNA damage response pathway. Curr. Biol. 12:73–77 [Google Scholar]
  115. Wu CS, Ouyang J, Mori E, Nguyen HD, Marechal A. 115.  et al. 2014. SUMOylation of ATRIP potentiates DNA damage signaling by boosting multiple protein interactions in the ATR pathway. Genes Dev. 28:1472–84 [Google Scholar]
  116. Wu CS, Zou L. 116.  2016. The SUMO (small ubiquitin-like modifier) ligase PIAS3 primes ATR for checkpoint activation. J. Biol. Chem. 291:279–90 [Google Scholar]
  117. Yang XH, Shiotani B, Classon M, Zou L. 117.  2008. Chk1 and Claspin potentiate PCNA ubiquitination. Genes Dev. 22:1147–52 [Google Scholar]
  118. Yoo HY, Shevchenko A, Shevchenko A, Dunphy WG. 118.  2004. Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses. J. Biol. Chem. 279:53353–64 [Google Scholar]
  119. Yoshioka K, Yoshioka Y, Hsieh P. 119.  2006. ATR kinase activation mediated by MutSα and MutLα in response to cytotoxic O6-methylguanine adducts. Mol. Cell 22:501–10 [Google Scholar]
  120. Zellweger R, Dalcher D, Mutreja K, Berti M, Schmid JA. 120.  et al. 2015. Rad51-mediated replication fork reversal is a global response to genotoxic treatments in human cells. J. Cell Biol. 208:563–79 [Google Scholar]
  121. Zhang J, Walter JC. 121.  2014. Mechanism and regulation of incisions during DNA interstrand cross-link repair. DNA Repair 19:135–42 [Google Scholar]
  122. Zhao H, Piwnica-Worms H. 122.  2001. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Mol. Cell. Biol. 21:4129–39 [Google Scholar]
  123. Zou L, Cortez D, Elledge SJ. 123.  2002. Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Genes Dev. 16:198–208 [Google Scholar]
  124. Zou L, Elledge SJ. 124.  2003. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300:1542–48 [Google Scholar]
  125. Zou L, Liu D, Elledge SJ. 125.  2003. Replication protein A-mediated recruitment and activation of Rad17 complexes. PNAS 100:13827–32 [Google Scholar]
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Functions, Regulation, and Therapeutic Implications of the ATR Checkpoint Pathway
Annual Review of Genetics 50, 155 (2016); https://doi.org/10.1146/annurev-genet-121415-121658
/content/journals/10.1146/annurev-genet-121415-121658
/content/journals/10.1146/annurev-genet-121415-121658
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  • Article Type: Review Article

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