1932

Abstract

Germ-line and somatic mutations in genes that promote homology-directed repair (HDR), especially and , are frequently observed in several cancers, in particular, breast and ovary but also prostate and other cancers. HDR is critical for the error-free repair of DNA double-strand breaks and other lesions, and HDR factors also protect stalled replication forks. As a result, loss of BRCA1 or BRCA2 poses significant risks to genome integrity, leading not only to cancer predisposition but also to sensitivity to DNA-damaging agents, affecting therapeutic approaches. Here we review recent advances in our understanding of BRCA1 and BRCA2, including how they genetically interact with other repair factors, how they protect stalled replication forks, how they affect the response to aldehydes, and how loss of their functions links to mutation signatures. Importantly, given the recent advances with poly(ADP-ribose) polymerase inhibitors (PARPi) for the treatment of HDR-deficient tumors, we discuss mechanisms by which BRCA-deficient tumors acquire resistance to PARPi and other agents.

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2018-03-04
2024-12-07
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Literature Cited

  1. Afghahi A, Timms KM, Vinayak S, Jensen KC, Kurian AW. et al. 2017. Tumor BRCA1 reversion mutation arising during neoadjuvant platinum-based chemotherapy in triple-negative breast cancer is associated with therapy resistance. Clin. Cancer Res. 23:3365–70 [Google Scholar]
  2. Ahlskog JK, Larsen BD, Achanta K, Sorensen CS. 2016. ATM/ATR-mediated phosphorylation of PALB2 promotes RAD51 function. EMBO Rep 17:671–81 [Google Scholar]
  3. Alvarez-Quilon A, Serrano-Benitez A, Lieberman JA, Quintero C, Sanchez-Gutierrez D. et al. 2014. ATM specifically mediates repair of double-strand breaks with blocked DNA ends. Nat. Commun. 5:3347 [Google Scholar]
  4. Anantha RW, Simhadri S, Foo TK, Miao S, Liu J. et al. 2017. Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance. eLife 6:e21350 [Google Scholar]
  5. Bakr A, Oing C, Kocher S, Borgmann K, Dornreiter I. et al. 2015. Involvement of ATM in homologous recombination after end resection and RAD51 nucleofilament formation. Nucleic Acids Res 43:3154–66 [Google Scholar]
  6. Beucher A, Birraux J, Tchouandong L, Barton O, Shibata A. et al. 2009. ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2. EMBO J 28:3413–27 [Google Scholar]
  7. Bhatia V, Barroso SI, Garcia-Rubio ML, Tumini E, Herrera-Moyano E, Aguilera A. 2014. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511:362–65 [Google Scholar]
  8. Bhowmick R, Minocherhomji S, Hickson ID. 2016. RAD52 facilitates mitotic DNA synthesis following replication stress. Mol. Cell 64:1117–26 [Google Scholar]
  9. Boersma V, Moatti N, Segura-Bayona S, Peuscher MH, van der Torre J. et al. 2015. MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection. Nature 521:537–40 [Google Scholar]
  10. Bolderson E, Tomimatsu N, Richard DJ, Boucher D, Kumar R. et al. 2010. Phosphorylation of Exo1 modulates homologous recombination repair of DNA double-strand breaks. Nucleic Acids Res 38:1821–31 [Google Scholar]
  11. Bothmer A, Robbiani DF, Feldhahn N, Gazumyan A, Nussenzweig A, Nussenzweig MC. 2010. 53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination. J. Exp. Med. 207:855–65 [Google Scholar]
  12. Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR. et al. 2006. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127:1361–73 [Google Scholar]
  13. Bouffet E, Larouche V, Campbell BB, Merico D, de Borja R. et al. 2016. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J. Clin. Oncol. 34:2206–11 [Google Scholar]
  14. Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J. et al. 2010. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17:688–95 [Google Scholar]
  15. Bouwman P, van der Gulden H, van der Heijden I, Drost R, Klijn CN. et al. 2013. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov 3:1142–55 [Google Scholar]
  16. Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ. et al. 2014. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res 24:743–50 [Google Scholar]
  17. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D. et al. 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–17 [Google Scholar]
  18. Buisson R, Dion-Côté AM, Coulombe Y, Launay H, Cai H. et al. 2010. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat. Struct. Mol. Biol. 17:1247–54 [Google Scholar]
  19. Bunting SF, Callen E, Kozak ML, Kim JM, Wong N. et al. 2012. BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol. Cell 46:125–35 [Google Scholar]
  20. Bunting SF, Callen E, Wong N, Chen HT, Polato F. et al. 2010. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141:243–54 [Google Scholar]
  21. Caldon CE. 2014. Estrogen signaling and the DNA damage response in hormone dependent breast cancers. Front. Oncol. 4:106 [Google Scholar]
  22. Callen E, Di Virgilio M, Kruhlak MJ, Nieto-Soler M, Wong N. et al. 2013. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 153:1266–80 [Google Scholar]
  23. Cao L, Xu X, Bunting SF, Liu J, Wang RH. et al. 2009. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol. Cell 35:534–41 [Google Scholar]
  24. Ceccaldi R, Liu JC, Amunugama R, Hajdu I, Primack B. et al. 2015. Homologous-recombination-deficient tumours are dependent on Polθ-mediated repair. Nature 518:258–62 [Google Scholar]
  25. Ceccaldi R, Sarangi P, D'Andrea AD. 2016. The Fanconi anaemia pathway: new players and new functions. Nat. Rev. Mol. Cell Biol. 17:337–49 [Google Scholar]
  26. Chang S, Biswas K, Martin BK, Stauffer S, Sharan SK. 2009. Expression of human BRCA1 variants in mouse ES cells allows functional analysis of BRCA1 mutations. J. Clin. Investig. 119:3160–71 [Google Scholar]
  27. Chanut P, Britton S, Coates J, Jackson SP, Calsou P. 2016. Coordinated nuclease activities counteract Ku at single-ended DNA double-strand breaks. Nat. Commun. 7:12889 [Google Scholar]
  28. Chapman JR, Barral P, Vannier JB, Borel V, Steger M. et al. 2013. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol. Cell 49:858–71 [Google Scholar]
  29. Chapman JR, Sossick AJ, Boulton SJ, Jackson SP. 2012.a BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J. Cell Sci. 125:3529–34 [Google Scholar]
  30. Chapman JR, Taylor MR, Boulton SJ. 2012.b Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell 47:497–510 [Google Scholar]
  31. Chen CC, Kass EM, Yen WF, Ludwig T, Moynahan ME. et al. 2017. ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair. PNAS 114:7665–70 [Google Scholar]
  32. Choi E, Park PG, Lee HO, Lee YK, Kang GH. et al. 2012. BRCA2 fine-tunes the spindle assembly checkpoint through reinforcement of BubR1 acetylation. Dev. Cell 22:295–308 [Google Scholar]
  33. Christie EL, Fereday S, Doig K, Pattnaik S, Dawson SJ, Bowtell DDL. 2017. Reversion of BRCA1/2 germline mutations detected in circulating tumor DNA from patients with high-grade serous ovarian cancer. J. Clin. Oncol. 35:1274–80 [Google Scholar]
  34. 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 286:1162–66 [Google Scholar]
  35. D'Andrea AD. 2013. BRCA1: a missing link in the Fanconi anemia/BRCA pathway. Cancer Discov 3:376–78 [Google Scholar]
  36. Daniel JA, Pellegrini M, Lee BS, Guo Z, Filsuf D. et al. 2012. Loss of ATM kinase activity leads to embryonic lethality in mice. J. Cell Biol. 198:295–304 [Google Scholar]
  37. Daniels MJ, Wang Y, Lee M, Venkitaraman AR. 2004. Abnormal cytokinesis in cells deficient in the breast cancer susceptibility protein BRCA2. Science 306:876–79 [Google Scholar]
  38. Davies H, Glodzik D, Morganella S, Yates LR, Staaf J. et al. 2017. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23:517–25 [Google Scholar]
  39. Degorce SL, Barlaam B, Cadogan E, Dishington A, Ducray R. et al. 2016. Discovery of novel 3-quinoline carboxamides as potent, selective, and orally bioavailable inhibitors of ataxia telangiectasia mutated (ATM) kinase. J. Med. Chem. 59:6281–92 [Google Scholar]
  40. Densham RM, Garvin AJ, Stone HR, Strachan J, Baldock RA. et al. 2016. Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat. Struct. Mol. Biol. 23:647–55 [Google Scholar]
  41. Di Virgilio M, Callen E, Yamane A, Zhang W, Jankovic M. et al. 2013. Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Science 339:711–15 [Google Scholar]
  42. Difilippantonio S, Gapud E, Wong N, Huang CY, Mahowald G. et al. 2008. 53BP1 facilitates long-range DNA end-joining during V(D)J recombination. Nature 456:529–33 [Google Scholar]
  43. Ding X, Ray Chaudhuri A, Callen E, Pang Y, Biswas K. et al. 2016. Synthetic viability by BRCA2 and PARP1/ARTD1 deficiencies. Nat. Commun. 7:12425 [Google Scholar]
  44. Dray E, Etchin J, Wiese C, Saro D, Williams GJ. et al. 2010. Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nat. Struct. Mol. Biol. 17:1255–59 [Google Scholar]
  45. Drost R, Bouwman P, Rottenberg S, Boon U, Schut E. et al. 2011. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell 20:797–809 [Google Scholar]
  46. Drost R, Dhillon KK, van der Gulden H, van der Heijden I, Brandsma I. et al. 2016. BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1. J. Clin. Investig. 126:2903–18 [Google Scholar]
  47. Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R. et al. 2008. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111–15 [Google Scholar]
  48. Escribano-Diaz C, Orthwein A, Fradet-Turcotte A, Xing M, Young JT. et al. 2013. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol. Cell 49:872–83 [Google Scholar]
  49. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA. et al. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–21 [Google Scholar]
  50. Feng L, Fong KW, Wang J, Wang W, Chen J. 2013. RIF1 counteracts BRCA1-mediated end resection during DNA repair. J. Biol. Chem. 288:11135–43 [Google Scholar]
  51. Feng W, Jasin M. 2017. BRCA2 suppresses replication stress-induced mitotic and G1 abnormalities through homologous recombination. Nat. Commun. 8:525 [Google Scholar]
  52. Feng Z, Scott SP, Bussen W, Sharma GG, Guo G. et al. 2011. Rad52 inactivation is synthetically lethal with BRCA2 deficiency. PNAS 108:686–91 [Google Scholar]
  53. Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA. et al. 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 [Google Scholar]
  54. Foulkes WD, Stefansson IM, Chappuis PO, Begin LR, Goffin JR. et al. 2003. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J. Natl. Cancer Inst. 95:1482–85 [Google Scholar]
  55. Fradet-Turcotte A, Canny MD, Escribano-Diaz C, Orthwein A, Leung CC. et al. 2013. 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499:50–54 [Google Scholar]
  56. Garaycoechea JI, Crossan GP, Langevin F, Daly M, Arends MJ, Patel KJ. 2012. Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function. Nature 489:571–75 [Google Scholar]
  57. Gatei M, Scott SP, Filippovitch I, Soronika N, Lavin MF. et al. 2000. Role for ATM in DNA damage-induced phosphorylation of BRCA1. Cancer Res 60:3299–304 [Google Scholar]
  58. Goodall J, Mateo J, Yuan W, Mossop H, Porta N. et al. 2017. Circulating free DNA to guide prostate cancer treatment with PARP inhibition. Cancer Discov 7:1–12 [Google Scholar]
  59. Goodarzi AA, Jeggo PA. 2012. The heterochromatic barrier to DNA double strand break repair: how to get the entry visa. Int. J. Mol. Sci. 13:11844–60 [Google Scholar]
  60. Guillemette S, Serra RW, Peng M, Hayes JA, Konstantinopoulos PA. et al. 2015. Resistance to therapy in BRCA2 mutant cells due to loss of the nucleosome remodeling factor CHD4. Genes Dev 29:489–94 [Google Scholar]
  61. Gupta A, Hunt CR, Hegde ML, Chakraborty S, Chakraborty S. et al. 2014. MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice. Cell Rep 8:177–89 [Google Scholar]
  62. Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D. et al. 2001. The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J. Biol. Chem. 276:14537–40 [Google Scholar]
  63. Helleday T, Eshtad S, Nik-Zainal S. 2014. Mechanisms underlying mutational signatures in human cancers. Nat. Rev. Genet. 15:585–98 [Google Scholar]
  64. Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH. et al. 2016. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165:35–44 [Google Scholar]
  65. Huyen Y, Zgheib O, Ditullio RA Jr., Gorgoulis VG, Zacharatos P. et al. 2004. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432:406–11 [Google Scholar]
  66. Isono M, Niimi A, Oike T, Hagiwara Y, Sato H. et al. 2017. BRCA1 directs the repair pathway to homologous recombination by promoting 53BP1 dephosphorylation. Cell Rep 18:520–32 [Google Scholar]
  67. Jankovic M, Feldhahn N, Oliveira TY, Silva IT, Kieffer-Kwon KR. et al. 2013. 53BP1 alters the landscape of DNA rearrangements and suppresses AID-induced B cell lymphoma. Mol. Cell 49:623–31 [Google Scholar]
  68. Jasin M, Rothstein R. 2013. Repair of strand breaks by homologous recombination. Cold Spring Harb. Perspect. Biol. 5:a012740 [Google Scholar]
  69. Jaspers JE, Kersbergen A, Boon U, Sol W, van Deemter L. et al. 2013. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov 3:68–81 [Google Scholar]
  70. Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC. 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]
  71. Jensen RB, Carreira A, Kowalczykowski SC. 2010. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 467:678–83 [Google Scholar]
  72. Johnson N, Johnson SF, Yao W, Li YC, Choi YE. et al. 2013. Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance. PNAS 110:17041–46 [Google Scholar]
  73. Jonsson G, Staaf J, Vallon-Christersson J, Ringner M, Holm K. et al. 2010. Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics. Breast Cancer Res 12:R42 [Google Scholar]
  74. Kakarougkas A, Ismail A, Katsuki Y, Freire R, Shibata A, Jeggo PA. 2013. Co-operation of BRCA1 and POH1 relieves the barriers posed by 53BP1 and RAP80 to resection. Nucleic Acids Res 41:10298–311 [Google Scholar]
  75. Kass EM, Helgadottir HR, Chen CC, Barbera M, Wang R. et al. 2013. Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase. PNAS 110:5564–69 [Google Scholar]
  76. Kass EM, Lim PX, Helgadottir HR, Moynahan ME, Jasin M. 2016.a Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation. Nat. Commun. 7:13241 [Google Scholar]
  77. Kass EM, Moynahan ME, Jasin M. 2016.b When genome maintenance goes badly awry. Mol. Cell 62:777–87 [Google Scholar]
  78. Kijas AW, Lim YC, Bolderson E, Cerosaletti K, Gatei M. et al. 2015. ATM-dependent phosphorylation of MRE11 controls extent of resection during homology directed repair by signalling through Exonuclease 1. Nucleic Acids Res 43:8352–67 [Google Scholar]
  79. Kolinjivadi AM, Sannino V, de Antoni A, Techer H, Baldi G, Costanzo V. 2017. Moonlighting at replication forks—a new life for homologous recombination proteins BRCA1, BRCA2 and RAD51. FEBS Lett 591:1083–100 [Google Scholar]
  80. Kondrashova O, Nguyen M, Shield-Artin K, Tinker AV, Teng N. et al. 2017. Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma. Cancer Discov. 7:984–98 [Google Scholar]
  81. Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC. et al. 2012. Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol. Rev. 64:520–39 [Google Scholar]
  82. Krawczyk PM, Eppink B, Essers J, Stap J, Rodermond H. et al. 2011. Mild hypertermia inhibits homologous recombination, induces BRCA2 degradation and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. PNAS 108:9851–56 [Google Scholar]
  83. Kuznetsov SG, Liu P, Sharan SK. 2008. Mouse embryonic stem cell–based functional assay to evaluate mutations in BRCA2. Nat. Med. 14:875–81 [Google Scholar]
  84. Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ. 2011. Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice. Nature 475:53–58 [Google Scholar]
  85. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR. et al. 2017. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357:409–13 [Google Scholar]
  86. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H. et al. 2015. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372:2509–20 [Google Scholar]
  87. Lee MS, Green R, Marsillac SM, Coquelle N, Williams RS. et al. 2010. Comprehensive analysis of missense variations in the BRCT domain of BRCA1 by structural and functional assays. Cancer Res 70:4880–90 [Google Scholar]
  88. Li M, Cole F, Patel DS, Misenko SM, Her J. et al. 2016. 53BP1 ablation rescues genomic instability in mice expressing ‘RING-less’ BRCA1. EMBO Rep 17:1532–41 [Google Scholar]
  89. Li M, Yu X. 2013. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell 23:693–704 [Google Scholar]
  90. Lim E, Vaillant F, Wu D, Forrest NC, Pal B. et al. 2009. Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat. Med. 15:907–13 [Google Scholar]
  91. Liu J, Doty T, Gibson B, Heyer WD. 2010. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat. Struct. Mol. Biol. 17:1260–62 [Google Scholar]
  92. Lok BH, Carley AC, Tchang B, Powell SN. 2013. RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination. Oncogene 32:3552–58 [Google Scholar]
  93. Long DT, Joukov V, Budzowska M, Walter JC. 2014. BRCA1 promotes unloading of the CMG helicase from a stalled DNA replication fork. Mol. Cell 56:174–85 [Google Scholar]
  94. Lord CJ, Ashworth A. 2016. BRCAness revisited. Nat. Rev. Cancer 16:110–20 [Google Scholar]
  95. Lord CJ, Ashworth A. 2017. PARP inhibitors: synthetic lethality in the clinic. Science 355:1152–58 [Google Scholar]
  96. Mandriota SJ, Buser R, Lesne L, Stouder C, Favaudon V. et al. 2010. Ataxia telangiectasia mutated (ATM) inhibition transforms human mammary gland epithelial cells. J. Biol. Chem. 285:13092–106 [Google Scholar]
  97. Mateos-Gomez PA, Gong F, Nair N, Miller KM, Lazzerini-Denchi E, Sfeir A. 2015. Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature 518:254–57 [Google Scholar]
  98. McCarthy EE, Celebi JT, Baer R, Ludwig T. 2003. Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. Mol. Cell Biol. 23:5056–63 [Google Scholar]
  99. Menzel T, Nahse-Kumpf V, Kousholt AN, Klein DK, Lund-Andersen C. et al. 2011. A genetic screen identifies BRCA2 and PALB2 as key regulators of G2 checkpoint maintenance. EMBO Rep 12:705–12 [Google Scholar]
  100. Meyer S, Tischkowitz M, Chandler K, Gillespie A, Birch JM, Evans DG. 2014. Fanconi anaemia, BRCA2 mutations and childhood cancer: a developmental perspective from clinical and epidemiological observations with implications for genetic counselling. J. Med. Genet. 51:71–75 [Google Scholar]
  101. Millot GA, Carvalho MA, Caputo SM, Vreeswijk MP, Brown MA. et al. 2012. A guide for functional analysis of BRCA1 variants of uncertain significance. Hum. Mutat. 33:1526–37 [Google Scholar]
  102. Mimitou EP, Symington LS. 2010. Ku prevents Exo1 and Sgs1-dependent resection of DNA ends in the absence of a functional MRX complex or Sae2. EMBO J 29:3358–69 [Google Scholar]
  103. Molyneux G, Geyer FC, Magnay FA, McCarthy A, Kendrick H. et al. 2010. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7:403–17 [Google Scholar]
  104. Mondal G, Rowley M, Guidugli L, Wu J, Pankratz VS, Couch FJ. 2012. BRCA2 localization to the midbody by Filamin A regulates CEP55 signaling and completion of cytokinesis. Dev. Cell 23:137–52 [Google Scholar]
  105. Morrison C, Sonoda E, Takao N, Shinohara A, Yamamoto K, Takeda S. 2000. The controlling role of ATM in homologous recombinational repair of DNA damage. EMBO J 19:463–71 [Google Scholar]
  106. Mouw KW, Goldberg MS, Konstantinopoulos PA, D'Andrea AD. 2017. DNA damage and repair biomarkers of immunotherapy response. Cancer Discov. 7:675–93 [Google Scholar]
  107. Moynahan ME, Chiu JW, Koller BH, Jasin M. 1999. Brca1 controls homology-directed DNA repair. Mol. Cell 4:511–18 [Google Scholar]
  108. Moynahan ME, Cui TY, Jasin M. 2001.a Homology-directed DNA repair, mitomycin-C resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 61:4842–50 [Google Scholar]
  109. Moynahan ME, Jasin M. 2010. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat. Rev. Mol. Cell Biol. 11:196–207 [Google Scholar]
  110. Moynahan ME, Pierce AJ, Jasin M. 2001.b BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7:263–72 [Google Scholar]
  111. Nakanishi K, Cavallo F, Perrouault L, Giovannangeli C, Moynahan ME. et al. 2011. Homology-directed Fanconi anemia pathway cross-link repair is dependent on DNA replication. Nat. Struct. Mol. Biol. 18:500–3 [Google Scholar]
  112. Nakanishi K, Yang YG, Pierce AJ, Taniguchi T, Digweed M. et al. 2005. Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. PNAS 102:1110–15 [Google Scholar]
  113. Nelson AC, Holt JT. 2010. Impact of RING and BRCT domain mutations on BRCA1 protein stability, localization and recruitment to DNA damage. Radiat. Res. 174:1–13 [Google Scholar]
  114. Nik-Zainal S, Alexandrov LB, Wedge DC, Van Loo P, Greenman CD. et al. 2012. Mutational processes molding the genomes of 21 breast cancers. Cell 149:979–93 [Google Scholar]
  115. Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D. et al. 2016. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534:47–54 [Google Scholar]
  116. Nolan E, Savas P, Policheni AN, Darcy PK, Vaillant F. et al. 2017. Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer. Sci. Transl. Med. 9:eaal4992 [Google Scholar]
  117. Nolan E, Vaillant F, Branstetter D, Pal B, Giner G. et al. 2016. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat. Med. 22:933–39 [Google Scholar]
  118. Norquist B, Wurz KA, Pennil CC, Garcia R, Gross J. et al. 2011. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J. Clin. Oncol. 29:3008–15 [Google Scholar]
  119. Panier S, Boulton SJ. 2014. Double-strand break repair: 53BP1 comes into focus. Nat. Rev. Mol. Cell Biol. 15:7–18 [Google Scholar]
  120. Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J. et al. 2015. Whole-genome characterization of chemoresistant ovarian cancer. Nature 521:489–94 [Google Scholar]
  121. Patel AG, Sarkaria JN, Kaufmann SH. 2011. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. PNAS 108:3406–11 [Google Scholar]
  122. Pathania S, Bade S, Le Guillou M, Burke K, Reed R. et al. 2014. BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat. Commun. 5:5496 [Google Scholar]
  123. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC. et al. 2014. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin. Cancer Res. 20:764–75 [Google Scholar]
  124. Pishvaian MJ, Biankin AV, Bailey P, Chang DK, Laheru D. et al. 2017. BRCA2 secondary mutation-mediated resistance to platinum and PARP inhibitor-based therapy in pancreatic cancer. Br. J. Cancer 116:1021–26 [Google Scholar]
  125. Polato F, Callen E, Wong N, Faryabi R, Bunting S. et al. 2014. CtIP-mediated resection is essential for viability and can operate independently of BRCA1. J. Exp. Med. 211:1027–36 [Google Scholar]
  126. Pontel LB, Rosado IV, Burgos-Barragan G, Garaycoechea JI, Yu R. et al. 2015. Endogenous formaldehyde is a hematopoietic stem cell genotoxin and metabolic carcinogen. Mol. Cell 60:177–88 [Google Scholar]
  127. Prakash R, Zhang Y, Feng W, Jasin M. 2015. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb. Perspect. Biol. 7:a016600 [Google Scholar]
  128. Proia TA, Keller PJ, Gupta PB, Klebba I, Jones AD. et al. 2011. Genetic predisposition directs breast cancer phenotype by dictating progenitor cell fate. Cell Stem Cell 8:149–63 [Google Scholar]
  129. Quigley D, Alumkal JJ, Wyatt AW, Kothari V, Foye A. et al. 2017. Analysis of circulating cell-free DNA identifies multi-clonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors. Cancer Discov. 7:999–1005 [Google Scholar]
  130. Rass E, Chandramouly G, Zha S, Alt FW, Xie A. 2013. Ataxia telangiectasia mutated (ATM) is dispensable for endonuclease I-SceI-induced homologous recombination in mouse embryonic stem cells. J. Biol. Chem. 288:7086–95 [Google Scholar]
  131. Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte AA. et al. 2016. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535:382–87 [Google Scholar]
  132. Reiman A, Srinivasan V, Barone G, Last JI, Wootton LL. et al. 2011. Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours. Br. J. Cancer 105:586–91 [Google Scholar]
  133. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T. et al. 2006. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat. Genet. 38:873–75 [Google Scholar]
  134. Reuter M, Zelensky A, Smal I, Meijering E, van Cappellen WA. et al. 2014. BRCA2 diffuses as oligomeric clusters with RAD51 and changes mobility after DNA damage in live cells. J. Cell Biol. 207:599–613 [Google Scholar]
  135. Ridpath JR, Nakamura A, Tano K, Luke AM, Sonoda E. et al. 2007. Cells deficient in the FANC/BRCA pathway are hypersensitive to plasma levels of formaldehyde. Cancer Res 67:11117–22 [Google Scholar]
  136. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V. et al. 2015. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348:124–28 [Google Scholar]
  137. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ. et al. 2015. Integrative clinical genomics of advanced prostate cancer. Cell 161:1215–28 [Google Scholar]
  138. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. 2015. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160:48–61 [Google Scholar]
  139. Ross WE, Shipley N. 1980. Relationship between DNA damage and survival in formaldehyde-treated mouse cells. Mutat. Res. 79:277–83 [Google Scholar]
  140. Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J. et al. 2008. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451:1116–20 [Google Scholar]
  141. Sanchez H, Paul MW, Grosbart M, van Rossum-Fikkert SE, Lebbink JHG. et al. 2017. Architectural plasticity of human BRCA2-RAD51 complexes in DNA break repair. Nucleic Acids Res 45:4507–18 [Google Scholar]
  142. Sartori AA, Lukas C, Coates J, Mistrik M, Fu S. et al. 2007. Human CtIP promotes DNA end resection. Nature 450:509–14 [Google Scholar]
  143. Sau A, Lau R, Cabrita MA, Nolan E, Crooks PA. et al. 2016. Persistent activation of NF-κB in BRCA1-deficient mammary progenitors drives aberrant proliferation and accumulation of DNA damage. Cell Stem Cell 19:52–65 [Google Scholar]
  144. Sawyer SL, Tian L, Kahkonen M, Schwartzentruber J, Kircher M. et al. 2015. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov 5:135–42 [Google Scholar]
  145. 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 145:529–42 [Google Scholar]
  146. Schlacher K, Wu H, Jasin M. 2012. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22:106–16 [Google Scholar]
  147. Schumacher TN, Schreiber RD. 2015. Neoantigens in cancer immunotherapy. Science 348:69–74 [Google Scholar]
  148. Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF. 2002. Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. PNAS 99:925–30 [Google Scholar]
  149. Sedic M, Skibinski A, Brown N, Gallardo M, Mulligan P. et al. 2015. Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nat. Commun. 6:7505 [Google Scholar]
  150. Sfeir A, Symington LS. 2015. Microhomology-mediated end joining: a back-up survival mechanism or dedicated pathway?. Trends Biochem. Sci. 40:701–14 [Google Scholar]
  151. Shahid T, Soroka J, Kong EH, Malivert L, McIlwraith MJ. et al. 2014. Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor. Nat. Struct. Mol. Biol. 21:962–68 [Google Scholar]
  152. Shakya R, Reid LJ, Reczek CR, Cole F, Egli D. et al. 2011. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334:525–28 [Google Scholar]
  153. Shakya R, Szabolcs M, McCarthy E, Ospina E, Basso K. et al. 2008. The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. PNAS 105:7040–45 [Google Scholar]
  154. Sharma P, Allison JP. 2015. The future of immune checkpoint therapy. Science 348:56–61 [Google Scholar]
  155. Shiloh Y, Ziv Y. 2013. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat. Rev. Mol. Cell Biol. 14:197–210 [Google Scholar]
  156. Siaud N, Barbera MA, Egashira A, Lam I, Christ N. et al. 2011. Plasticity of BRCA2 function in homologous recombination: genetic interactions of the PALB2 and DNA binding domains. PLOS Genet 7:e1002409 [Google Scholar]
  157. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM. et al. 2014. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371:2189–99 [Google Scholar]
  158. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS. et al. 2003. Repeated observation of breast tumor subtypes in independent gene expression data sets. PNAS 100:8418–23 [Google Scholar]
  159. Stark JM, Pierce AJ, Oh J, Pastink A, Jasin M. 2004. Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Mol. Cell Biol. 24:9305–16 [Google Scholar]
  160. Stecklein SR, Kumaraswamy E, Behbod F, Wang W, Chaguturu V. et al. 2012. BRCA1 and HSP90 cooperate in homologous and non-homologous DNA double-strand-break repair and G2/M checkpoint activation. PNAS 109:13650–55 [Google Scholar]
  161. Stork CT, Bocek M, Crossley MP, Sollier J, Sanz LA. et al. 2016. Co-transcriptional R-loops are the main cause of estrogen-induced DNA damage. eLife 5:e17548 [Google Scholar]
  162. Swisher EM, Sakai W, Karlan BY, Wurz K, Urban N, Taniguchi T. 2008. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res 68:2581–86 [Google Scholar]
  163. Sy SM, Huen MS, Chen J. 2009. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. PNAS 106:7155–60 [Google Scholar]
  164. Tacconi EM, Lai X, Folio C, Porru M, Zonderland G. et al. 2017. BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. EMBO Mol. Med. 9:1398–414 [Google Scholar]
  165. Tan SLW, Chadha S, Liu Y, Gabasova E, Perera D. et al. 2017. A class of environmental and endogenous toxins induces BRCA2 haploinsufficiency and genome instability. Cell 169:1105–18.e15 [Google Scholar]
  166. Tang J, Cho NW, Cui G, Manion EM, Shanbhag NM. et al. 2013. Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nat. Struct. Mol. Biol. 20:317–25 [Google Scholar]
  167. Tarsounas M, Davies D, West SC. 2003. BRCA2-dependent and independent formation of RAD51 nuclear foci. Oncogene 22:1115–23 [Google Scholar]
  168. Thangavel S, Berti M, Levikova M, Pinto C, Gomathinayagam S. et al. 2015. DNA2 drives processing and restart of reversed replication forks in human cells. J. Cell Biol. 208:545–62 [Google Scholar]
  169. Thompson D, Duedal S, Kirner J, McGuffog L, Last J. et al. 2005. Cancer risks and mortality in heterozygous ATM mutation carriers. J. Natl. Cancer Inst. 97:813–22 [Google Scholar]
  170. Thorslund T, McIlwraith MJ, Compton SA, Lekomtsev S, Petronczki M. et al. 2010. The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat. Struct. Mol. Biol. 17:1263–65 [Google Scholar]
  171. Tkac J, Xu G, Adhikary H, Young JT, Gallo D. et al. 2016. HELB is a feedback inhibitor of DNA end resection. Mol. Cell 61:405–18 [Google Scholar]
  172. Tomimatsu N, Mukherjee B, Burma S. 2009. Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM-deficient cells. EMBO Rep 10:629–35 [Google Scholar]
  173. Tubbs AT, Dorsett Y, Chan E, Helmink B, Lee BS. et al. 2014. KAP-1 promotes resection of broken DNA ends not protected by gamma-H2AX and 53BP1 in G1-phase lymphocytes. Mol. Cell. Biol. 34:2811–21 [Google Scholar]
  174. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C. et al. 2015. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350:207–11 [Google Scholar]
  175. Vendetti FP, Lau A, Schamus S, Conrads TP, O'Connor MJ, Bakkenist CJ. 2015. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo. Oncotarget 6:44289–305 [Google Scholar]
  176. Vendetti FP, Leibowitz BJ, Barnes J, Schamus S, Kiesel BF. et al. 2017. Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation. Sci. Rep. 7:41892 [Google Scholar]
  177. Verhagen MM, Last JI, Hogervorst FB, Smeets DF, Roeleveld N. et al. 2012. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype–phenotype study. Hum. Mutat. 33:561–71 [Google Scholar]
  178. Waddell N, Arnold J, Cocciardi S, da Silva L, Marsh A. et al. 2010. Subtypes of familial breast tumours revealed by expression and copy number profiling. Breast Cancer Res. Treat. 123:661–77 [Google Scholar]
  179. Walker JR, Corpina RA, Goldberg J. 2001. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412:607–14 [Google Scholar]
  180. Wang H, Shi LZ, Wong CC, Han X, Hwang PY. et al. 2013. The interaction of CtIP and Nbs1 connects CDK and ATM to regulate HR–mediated double-strand break repair. PLOS Genet 9:e1003277 [Google Scholar]
  181. Wang J, Aroumougame A, Lobrich M, Li Y, Chen D. et al. 2014. PTIP associates with Artemis to dictate DNA repair pathway choice. Genes Dev 28:2693–98 [Google Scholar]
  182. Wang Y, Bernhardy AJ, Cruz C, Krais JJ, Nacson J. et al. 2016.a The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP inhibition and cisplatin. Cancer Res 76:2778–90 [Google Scholar]
  183. Wang Y, Krais JJ, Bernhardy AJ, Nicolas E, Cai KQ. et al. 2016.b RING domain–deficient BRCA1 promotes PARP inhibitor and platinum resistance. J. Clin. Investig. 126:3145–57 [Google Scholar]
  184. Westermark UK, Reyngold M, Olshen AB, Baer R, Jasin M, Moynahan ME. 2003. BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks. Mol. Cell Biol 23:7926–36 [Google Scholar]
  185. Weston VJ, Oldreive CE, Skowronska A, Oscier DG, Pratt G. et al. 2010. The PARP inhibitor olaparib induces significant killing of ATM-deficient lymphoid tumor cells in vitro and in vivo. Blood 116:4578–87 [Google Scholar]
  186. White JS, Choi S, Bakkenist CJ. 2010. Transient ATM kinase inhibition disrupts DNA damage–induced sister chromatid exchange. Sci. Signal. 3:ra44 [Google Scholar]
  187. Williams RS, Lee MS, Hau DD, Glover JN. 2004. Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. Nat. Struct. Mol. Biol. 11:519–25 [Google Scholar]
  188. Williamson CT, Muzik H, Turhan AG, Zamò A, O'Connor MJ. et al. 2010. ATM deficiency sensitizes Mantle Cell Lymphoma cells to PARP-1 inhibitors. Mol. Cancer Ther. 9:347–57 [Google Scholar]
  189. Willis NA, Chandramouly G, Huang B, Kwok A, Follonier C. et al. 2014. BRCA1 controls homologous recombination at Tus/Ter-stalled mammalian replication forks. Nature 510:556–59 [Google Scholar]
  190. Wu Q, Jubb H, Blundell TL. 2015. Phosphopeptide interactions with BRCA1 BRCT domains: more than just a motif. Prog. Biophys. Mol. Biol. 117:143–48 [Google Scholar]
  191. Xu B, O'Donnell AH, Kim ST, Kastan MB. 2002. Phosphorylation of serine 1387 in Brca1 is specifically required for the Atm-mediated S-phase checkpoint after ionizing irradiation. Cancer Res 62:4588–91 [Google Scholar]
  192. Xu G, Chapman JR, Brandsma I, Yuan J, Mistrik M. et al. 2015. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 521:541–44 [Google Scholar]
  193. Xu X, Qiao W, Linke SP, Cao L, Li WM. et al. 2001. Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat. Genet. 28:266–71 [Google Scholar]
  194. Yamamoto K, Wang J, Sprinzen L, Xu J, Haddock CJ. et al. 2016. Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors. eLife 5:e14709 [Google Scholar]
  195. Yamamoto K, Wang Y, Jiang W, Liu X, Dubois RL. et al. 2012. Kinase-dead ATM protein causes genomic instability and early embryonic lethality in mice. J. Cell Biol. 198:305–13 [Google Scholar]
  196. Yamane A, Robbiani DF, Resch W, Bothmer A, Nakahashi H. et al. 2013. RPA accumulation during class switch recombination represents 5′–3′ DNA-end resection during the S–G2/M phase of the cell cycle. Cell Rep 3:138–47 [Google Scholar]
  197. Yazinski SA, Comaills V, Buisson R, Genois MM, Nguyen HD. et al. 2017. ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev 31:318–32 [Google Scholar]
  198. Ying S, Hamdy FC, Helleday T. 2012. Mre11-dependent degradation of stalled DNA replication forks is prevented by BRCA2 and PARP1. Cancer Res 72:2814–21 [Google Scholar]
  199. You Z, Shi LZ, Zhu Q, Wu P, Zhang YW. et al. 2009. CtIP links DNA double-strand break sensing to resection. Mol. Cell 36:954–69 [Google Scholar]
  200. Yu HS, Oyama T, Isse T, Kitagawa K, Pham TT. et al. 2010. Formation of acetaldehyde-derived DNA adducts due to alcohol exposure. Chem. Biol. Interact. 188:367–75 [Google Scholar]
  201. Yuan SS, Lee SY, Chen G, Song M, Tomlinson GE, Lee EY. 1999. BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res 59:3547–51 [Google Scholar]
  202. Zellweger R, Dalcher D, Mutreja K, Berti M, Schmid JA. 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]
  203. Zhang F, Ma J, Wu J, Ye L, Cai H. et al. 2009. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19:524–29 [Google Scholar]
  204. Zhang H, Liu H, Chen Y, Yang X, Wang P. et al. 2016. A cell cycle-dependent BRCA1–UHRF1 cascade regulates DNA double-strand break repair pathway choice. Nat. Commun. 7:10201 [Google Scholar]
  205. Zimmermann M, de Lange T. 2014. 53BP1: pro choice in DNA repair. Trends Cell Biol 24:108–17 [Google Scholar]
  206. Zimmermann M, Lottersberger F, Buonomo SB, Sfeir A, de Lange T. 2013. 53BP1 regulates DSB repair using Rif1 to control 5′ end resection. Science 339:700–4 [Google Scholar]
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