Cellular responses to DNA damage are important determinants of both cancer development and cancer outcome following radiation therapy and chemotherapy. Identification of molecular pathways governing DNA damage signaling and DNA repair in response to different types of DNA lesions allows for a better understanding of the effects of radiation and chemotherapy on normal and tumor cells. Although dysregulation of the DNA damage response (DDR) is associated with predisposition to cancer development, it can also result in hypersensitivity or resistance of tumors to therapy and can be exploited for improvement of cancer treatment. We highlight the DDR pathways that are activated after treatment with radiation and different classes of chemotherapeutic drugs and describe mechanisms determining tumor sensitivity and resistance to these agents. Further, we discuss approaches to enhance tumor sensitivity to radiation and chemotherapy by modulating the DDR with a goal of enhancing the effectiveness of cancer therapies.


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Literature Cited

  1. Shiloh Y.1.  1997. Ataxia-telangiectasia and the Nijmegen breakage syndrome: related disorders but genes apart. Annu. Rev. Genet. 31:635–62 [Google Scholar]
  2. Huen MS, Sy SM, Chen J. 2.  2010. BRCA1 and its toolbox for the maintenance of genome integrity. Nat. Rev. Mol. Cell Biol. 11:138–48 [Google Scholar]
  3. Modrich P, Lahue R. 3.  1996. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu. Rev. Biochem. 65:101–33 [Google Scholar]
  4. Luch A.4.  2005. Nature and nurture—lessons from chemical carcinogenesis. Nat. Rev. Cancer 5:113–25 [Google Scholar]
  5. Ciccia A, Elledge SJ. 5.  2010. The DNA damage response: making it safe to play with knives. Mol. Cell 40:179–204 [Google Scholar]
  6. Bakkenist CJ, Kastan MB. 6.  2003. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421:499–506 [Google Scholar]
  7. Kitagawa R, Bakkenist CJ, McKinnon PJ, Kastan MB. 7.  2004. Phosphorylation of SMC1 is a critical downstream event in the ATM-NBS1-BRCA1 pathway. Genes Dev. 18:1423–38 [Google Scholar]
  8. Kastan MB, Bartek J. 8.  2004. Cell-cycle checkpoints and cancer. Nature 432:316–23 [Google Scholar]
  9. Byun TS, Pacek M, Yee MC. 9.  et al. 2005. Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev. 19:1040–52 [Google Scholar]
  10. Brown EJ, Baltimore D. 10.  2000. ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev. 14:397–402 [Google Scholar]
  11. Brown EJ, Baltimore D. 11.  2003. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 17:615–28 [Google Scholar]
  12. Cromie GA, Connelly JC, Leach DR. 12.  2001. Recombination at double-strand breaks and DNA ends: conserved mechanisms from phage to humans. Mol. Cell 8:1163–74 [Google Scholar]
  13. Leber R, Wise TW, Mizuta R, Meek K. 13.  1998. The XRCC4 gene product is a target for and interacts with the DNA-dependent protein kinase. J. Biol. Chem. 273:1794–801 [Google Scholar]
  14. Christmann M, Tomicic MT, Roos WP, Kaina B. 14.  2003. Mechanisms of human DNA repair: an update. Toxicology 193:3–34 [Google Scholar]
  15. Goldstein M, Derheimer FA, Tait-Mulder J, Kastan MB. 15.  2013. Nucleolin mediates nucleosome disruption critical for DNA double-strand break repair. Proc. Natl. Acad. Sci. USA 110:16874–79 [Google Scholar]
  16. Mimitou EP, Symington LS. 16.  2008. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455:770–74 [Google Scholar]
  17. Cadet J, Delatour T, Douki T. 17.  et al. 1999. Hydroxyl radicals and DNA base damage. Mutat. Res. 424:9–21 [Google Scholar]
  18. Nikjoo H, Uehara S, Wilson WE. 18.  et al. 1998. Track structure in radiation biology: theory and applications. Int. J. Radiat. Biol. 73:355–64 [Google Scholar]
  19. Rothkamm K, Lobrich M. 19.  2003. Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses. Proc. Natl. Acad. Sci. USA 100:5057–62 [Google Scholar]
  20. Willems P, Claes K, Baeyens A. 20.  et al. 2008. Polymorphisms in nonhomologous end-joining genes associated with breast cancer risk and chromosomal radiosensitivity. Genes Chromosomes Cancer 47:137–48 [Google Scholar]
  21. Lee MN, Tseng RC, Hsu HS. 21.  et al. 2007. Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer. Clin. Cancer Res. 13:832–38 [Google Scholar]
  22. Esteller M, Silva JM, Dominguez G. 22.  et al. 2000. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl. Cancer Inst. 92:564–69 [Google Scholar]
  23. Ernestos B, Nikolaos P, Koulis G. 23.  et al. 2010. Increased chromosomal radiosensitivity in women carrying BRCA1/BRCA2 mutations assessed with the G2 assay. Int. J. Radiat. Oncol. Biol. Phys. 76:1199–205 [Google Scholar]
  24. Fourquet A, Stoppa-Lyonnet D, Kirova YM. 24.  et al. 2009. Familial breast cancer: clinical response to induction chemotherapy or radiotherapy related to BRCA1/2 mutations status. Am. J. Clin. Oncol. 32:127–31 [Google Scholar]
  25. Jazayeri A, Falck J, Lukas C. 25.  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]
  26. Rainey MD, Charlton ME, Stanton RV, Kastan MB. 26.  2008. Transient inhibition of ATM kinase is sufficient to enhance cellular sensitivity to ionizing radiation. Cancer Res. 68:7466–74 [Google Scholar]
  27. Biddlestone-Thorpe L, Sajjad M, Rosenberg E. 27.  et al. 2013. ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation. Clin. Cancer Res. 19:3189–200 [Google Scholar]
  28. Hickson I, Zhao Y, Richardson CJ. 28.  et al. 2004. Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM. Cancer Res. 64:9152–59 [Google Scholar]
  29. Westphal CH, Hoyes KP, Canman CE. 29.  et al. 1998. Loss of ATM radiosensitizes multiple p53 null tissues. Cancer Res. 58:5637–39 [Google Scholar]
  30. Veuger SJ, Curtin NJ, Richardson CJ. 30.  et al. 2003. Radiosensitization and DNA repair inhibition by the combined use of novel inhibitors of DNA-dependent protein kinase and poly(ADP-ribose) polymerase-1. Cancer Res. 63:6008–15 [Google Scholar]
  31. Takata M, Sasaki MS, Sonoda E. 31.  et al. 1998. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 17:5497–508 [Google Scholar]
  32. Konstantinidou G, Bey EA, Rabellino A. 32.  et al. 2009. Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations. Cancer Res. 69:7644–52 [Google Scholar]
  33. Mukherjee B, Tomimatsu N, Amancherla K. 33.  et al. 2012. The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia 14:34–43 [Google Scholar]
  34. Toledo LI, Murga M, Zur R. 34.  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]
  35. Tao Y, Leteur C, Yang C. 35.  et al. 2009. Radiosensitization by Chir-124, a selective CHK1 inhibitor: effects of p53 and cell cycle checkpoints. Cell Cycle 8:1196–205 [Google Scholar]
  36. Shao RG, Cao CX, Shimizu T. 36.  et al. 1997. Abrogation of an S-phase checkpoint and potentiation of camptothecin cytotoxicity by 7-hydroxystaurosporine (UCN-01) in human cancer cell lines, possibly influenced by p53 function. Cancer Res. 57:4029–35 [Google Scholar]
  37. Takai H, Naka K, Okada Y. 37.  et al. 2002. Chk2-deficient mice exhibit radioresistance and defective p53-mediated transcription. EMBO J. 21:5195–205 [Google Scholar]
  38. Engelke CG, Parsels LA, Qian Y. 38.  et al. 2013. Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776. Clin. Cancer Res. 19:4412–21 [Google Scholar]
  39. Herring CJ, West CM, Wilks DP. 39.  et al. 1998. Levels of the DNA repair enzyme human apurinic/apyrimidinic endonuclease (APE1, APEX, Ref-1) are associated with the intrinsic radiosensitivity of cervical cancers. Br. J. Cancer 78:1128–33 [Google Scholar]
  40. Robertson KA, Bullock HA, Xu Y. 40.  et al. 2001. Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation. Cancer Res. 61:2220–25 [Google Scholar]
  41. Taverna P, Hwang HS, Schupp JE. 41.  et al. 2003. Inhibition of base excision repair potentiates iododeoxyuridine-induced cytotoxicity and radiosensitization. Cancer Res. 63:838–46 [Google Scholar]
  42. Liu SK, Coackley C, Krause M. 42.  et al. 2008. A novel poly(ADP-ribose) polymerase inhibitor, ABT-888, radiosensitizes malignant human cell lines under hypoxia. Radiother. Oncol. 88:258–68 [Google Scholar]
  43. Dungey FA, Loser DA, Chalmers AJ. 43.  2008. Replication-dependent radiosensitization of human glioma cells by inhibition of poly(ADP-Ribose) polymerase: mechanisms and therapeutic potential. Int. J. Radiat. Oncol. Biol. Phys. 72:1188–97 [Google Scholar]
  44. Powell C, Mikropoulos C, Kaye SB. 44.  et al. 2010. Pre-clinical and clinical evaluation of PARP inhibitors as tumour-specific radiosensitisers. Cancer Treat. Rev. 36:566–75 [Google Scholar]
  45. Hickman MJ, Samson LD. 45.  1999. Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents. Proc. Natl. Acad. Sci. USA 96:10764–69 [Google Scholar]
  46. Roos W, Baumgartner M, Kaina B. 46.  2004. Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1. Oncogene 23:359–67 [Google Scholar]
  47. Karran P, Stephenson C. 47.  1990. Mismatch binding proteins and tolerance to alkylating agents in human cells. Mutat. Res. 236:269–75 [Google Scholar]
  48. Pepponi R, Marra G, Fuggetta MP. 48.  et al. 2003. The effect of O6-alkylguanine-DNA alkyltransferase and mismatch repair activities on the sensitivity of human melanoma cells to temozolomide, 1,3-bis(2-chloroethyl)1-nitrosourea, and cisplatin. J. Pharmacol. Exp. Ther. 304:661–68 [Google Scholar]
  49. Shinsato Y, Furukawa T, Yunoue S. 49.  et al. 2013. Reduction of MLH1 and PMS2 confers temozolomide resistance and is associated with recurrence of glioblastoma. Oncotarget 4:2261–70 [Google Scholar]
  50. von Bueren AO, Bacolod MD, Hagel C. 50.  et al. 2012. Mismatch repair deficiency: a temozolomide resistance factor in medulloblastoma cell lines that is uncommon in primary medulloblastoma tumours. Br. J. Cancer 107:1399–408 [Google Scholar]
  51. Pegg AE, Dolan ME, Moschel RC. 51.  1995. Structure, function, and inhibition of O6-alkylguanine-DNA alkyltransferase. Prog. Nucleic Acid. Res. Mol. Biol. 51:167–223 [Google Scholar]
  52. Pegg AE.52.  1990. Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res. 50:6119–29 [Google Scholar]
  53. Zaidi NH, Liu L, Gerson SL. 53.  1996. Quantitative immunohistochemical estimates of O6-alkylguanine-DNA alkyltransferase expression in normal and malignant human colon. Clin. Cancer Res. 2:577–84 [Google Scholar]
  54. Esteller M, Hamilton SR, Burger PC. 54.  et al. 1999. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 59:793–97 [Google Scholar]
  55. Hegi ME, Diserens AC, Gorlia T. 55.  et al. 2005. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352:997–1003 [Google Scholar]
  56. Kaina B, Margison GP, Christmann M. 56.  2010. Targeting O6-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy. Cell. Mol. Life Sci. 67:3663–81 [Google Scholar]
  57. Friedman HS, Kokkinakis DM, Pluda J. 57.  et al. 1998. Phase I trial of O6-benzylguanine for patients undergoing surgery for malignant glioma. J. Clin. Oncol. 16:3570–75 [Google Scholar]
  58. Rabik CA, Njoku MC, Dolan ME. 58.  2006. Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy. Cancer Treat. Rev. 32:261–76 [Google Scholar]
  59. Cerchia L, de Franciscis V. 59.  2010. Targeting cancer cells with nucleic acid aptamers. Trends Biotechnol. 28:517–25 [Google Scholar]
  60. Trivedi RN, Wang XH, Jelezcova E. 60.  et al. 2008. Human methyl purine DNA glycosylase and DNA polymerase beta expression collectively predict sensitivity to temozolomide. Mol. Pharmacol. 74:505–16 [Google Scholar]
  61. Cerda SR, Turk PW, Thor AD, Weitzman SA. 61.  1998. Altered expression of the DNA repair protein, N-methylpurine-DNA glycosylase (MPG) in breast cancer. FEBS Lett. 431:12–18 [Google Scholar]
  62. Kim NK, Ahn JY, Song J. 62.  et al. 2003. Expression of the DNA repair enzyme, N-methylpurine-DNA glycosylase (MPG) in astrocytic tumors. Anticancer Res. 23:1417–23 [Google Scholar]
  63. Abbotts R, Madhusudan S. 63.  2010. Human AP endonuclease 1 (APE1): from mechanistic insights to druggable target in cancer. Cancer Treat. Rev. 36:425–35 [Google Scholar]
  64. Al-Attar A, Gossage L, Fareed KR. 64.  et al. 2010. Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers. Br. J. Cancer 102:704–9 [Google Scholar]
  65. Zaremba T, Ketzer P, Cole M. 65.  et al. 2009. Poly(ADP-ribose) polymerase-1 polymorphisms, expression and activity in selected human tumour cell lines. Br. J. Cancer 101:256–62 [Google Scholar]
  66. Bauer M, Goldstein M, Heylmann D, Kaina B. 66.  2012. Human monocytes undergo excessive apoptosis following temozolomide activating the ATM/ATR pathway while dendritic cells and macrophages are resistant. PLOS ONE 7:e39956 [Google Scholar]
  67. Tentori L, Ricci-Vitiani L, Muzi A. 67.  et al. 2014. Pharmacological inhibition of poly(ADP-ribose) polymerase-1 modulates resistance of human glioblastoma stem cells to temozolomide. BMC Cancer 14:151 [Google Scholar]
  68. Taverna P, Liu L, Hwang HS. 68.  et al. 2001. Methoxyamine potentiates DNA single strand breaks and double strand breaks induced by temozolomide in colon cancer cells. Mutat. Res. 485:269–81 [Google Scholar]
  69. Gordon MS, Rosen LS, Mendelson D. 69.  et al. 2013. A phase 1 study of TRC102, an inhibitor of base excision repair, and pemetrexed in patients with advanced solid tumors. Invest. New Drugs 31:714–23 [Google Scholar]
  70. Del Rowe JD, Bello J, Mitnick R. 70.  et al. 1999. Accelerated regression of brain metastases in patients receiving whole brain radiation and the topoisomerase II inhibitor, lucanthone. Int. J. Radiat. Oncol. Biol. Phys. 43:89–93 [Google Scholar]
  71. Plummer R, Jones C, Middleton M. 71.  et al. 2008. Phase I study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors. Clin. Cancer Res. 14:7917–23 [Google Scholar]
  72. Plo I, Liao ZY, Barcelo JM. 72.  et al. 2003. Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA Repair 2:1087–100 [Google Scholar]
  73. Smith LM, Willmore E, Austin CA, Curtin NJ. 73.  2005. The novel poly(ADP-ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clin. Cancer Res. 11:8449–57 [Google Scholar]
  74. Kummar S, Chen A, Ji J. 74.  et al. 2011. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res. 71:5626–34 [Google Scholar]
  75. Holm C, Covey JM, Kerrigan D, Pommier Y. 75.  1989. Differential requirement of DNA replication for the cytotoxicity of DNA topoisomerase I and II inhibitors in Chinese hamster DC3F cells. Cancer Res. 49:6365–68 [Google Scholar]
  76. Strumberg D, Pilon AA, Smith M. 76.  et al. 2000. Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5′-phosphorylated DNA double-strand breaks by replication runoff. Mol. Cell. Biol. 20:3977–87 [Google Scholar]
  77. Fedier A, Steiner RA, Schwarz VA. 77.  et al. 2003. The effect of loss of Brca1 on the sensitivity to anticancer agents in p53-deficient cells. Int. J. Oncol. 22:1169–73 [Google Scholar]
  78. Davidson D, Coulombe Y, Martinez-Marignac VL. 78.  et al. 2012. Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells. Invest. New Drugs 30:1248–56 [Google Scholar]
  79. Ma CX, Ellis MJ, Petroni GR. 79.  et al. 2013. A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer. Breast Cancer Res. Treat. 137:483–92 [Google Scholar]
  80. Willmore E, de Caux S, Sunter NJ. 80.  et al. 2004. A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia. Blood 103:4659–65 [Google Scholar]
  81. Tamaichi H, Sato M, Porter AC. 81.  et al. 2013. Ataxia telangiectasia mutated-dependent regulation of topoisomerase II alpha expression and sensitivity to topoisomerase II inhibitor. Cancer Sci. 104:178–84 [Google Scholar]
  82. Goldstein M, Roos WP, Kaina B. 82.  2008. Apoptotic death induced by the cyclophosphamide analogue mafosfamide in human lymphoblastoid cells: contribution of DNA replication, transcription inhibition and Chk/p53 signaling. Toxicol. Appl. Pharmacol. 229:20–32 [Google Scholar]
  83. Tong WP, Kirk MC, Ludlum DB. 83.  1982. Formation of the cross-link 1-[N3-deoxycytidyl],2-[N1-deoxyguanosinyl]-ethane in DNA treated with N,N′-bis(2-chloroethyl)-N-nitrosourea. Cancer Res. 42:3102–5 [Google Scholar]
  84. Fichtinger-Schepman AM, van der Veer JL, den Hartog JH. 84.  et al. 1985. Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: formation, identification, and quantitation. Biochemistry 24:707–13 [Google Scholar]
  85. Damia G, Imperatori L, Stefanini M, D'Incalci M. 85.  1996. Sensitivity of CHO mutant cell lines with specific defects in nucleotide excision repair to different anti-cancer agents. Int. J. Cancer 66:779–83 [Google Scholar]
  86. Usanova S, Piee-Staffa A, Sied U. 86.  et al. 2010. Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression. Mol. Cancer 9:248 [Google Scholar]
  87. Horwich A, Shipley J, Huddart R. 87.  2006. Testicular germ-cell cancer. Lancet 367:754–65 [Google Scholar]
  88. Kuschal C, Thoms KM, Boeckmann L. 88.  et al. 2011. Cyclosporin A inhibits nucleotide excision repair via downregulation of the xeroderma pigmentosum group A and G proteins, which is mediated by calcineurin inhibition. Exp. Dermatol. 20:795–99 [Google Scholar]
  89. Prewett M, Deevi DS, Bassi R. 89.  et al. 2007. Tumors established with cell lines selected for oxaliplatin resistance respond to oxaliplatin if combined with cetuximab. Clin. Cancer Res. 13:7432–40 [Google Scholar]
  90. Alekseev S, Ayadi M, Brino L. 90.  et al. 2014. A small molecule screen identifies an inhibitor of DNA repair inducing the degradation of TFIIH and the chemosensitization of tumor cells to platinum. Chem. Biol. 21:3398–407 [Google Scholar]
  91. Vollebergh MA, Lips EH, Nederlof PM. 91.  et al. 2011. An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients. Ann. Oncol. 22:1561–70 [Google Scholar]
  92. Swisher EM, Sakai W, Karlan BY. 92.  et al. 2008. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 68:2581–86 [Google Scholar]
  93. Kim H, D'Andrea AD. 93.  2012. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev. 26:1393–408 [Google Scholar]
  94. Taniguchi T, Tischkowitz M, Ameziane N. 94.  et al. 2003. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Nat. Med. 9:568–74 [Google Scholar]
  95. Marsit CJ, Liu M, Nelson HH. 95.  et al. 2004. Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. Oncogene 23:1000–4 [Google Scholar]
  96. Farmer H, McCabe N, Lord CJ. 96.  et al. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–21 [Google Scholar]
  97. Bryant HE, Schultz N, Thomas HD. 97.  et al. 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–17 [Google Scholar]
  98. Edwards SL, Brough R, Lord CJ. 98.  et al. 2008. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111–15 [Google Scholar]
  99. Bouwman P, Aly A, Escandell JM. 99.  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]
  100. Patel AG, Sarkaria JN, Kaufmann SH. 100.  2011. Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc. Natl. Acad. Sci. USA 108:3406–11 [Google Scholar]

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