Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches

Reinhardt, 2013, Phospho-Ser/Thr-binding domains: navigating the cell cycle and DNA damage response, Nat. Rev. Mol. Cell Biol., 14, 563, 10.1038/nrm3640 Jackson, 2009, The DNA-damage response in human biology and disease, Nature, 461, 1071, 10.1038/nature08467 Reinhardt, 2012, The p53 network: cellular and systemic DNA damage responses in aging and cancer, Trends Genet., 28, 128, 10.1016/j.tig.2011.12.002 Harper, 2007, The DNA damage response: ten years after, Mol. Cell, 28, 739, 10.1016/j.molcel.2007.11.015 Reinhardt, 2011, Is post-transcriptional stabilization, splicing and translation of selective mRNAs a key to the DNA damage response?, Cell Cycle, 10, 23, 10.4161/cc.10.1.14351 Hoeijmakers, 2009, DNA damage, aging, and cancer, N. Engl. J. Med., 361, 1475, 10.1056/NEJMra0804615 Ciriello, 2013, Emerging landscape of oncogenic signatures across human cancers, Nat. Genet., 45, 1127, 10.1038/ng.2762 Reinhardt, 2009, Exploiting synthetic lethal interactions for targeted cancer therapy, Cell Cycle, 8, 3112, 10.4161/cc.8.19.9626 Lord, 2012, The DNA damage response and cancer therapy, Nature, 481, 287, 10.1038/nature10760 Loeb, 2003, Multiple mutations and cancer, Proc. Natl. Acad. Sci. U.S.A., 100, 776, 10.1073/pnas.0334858100 Loeb, 2008, Cancers exhibit a mutator phenotype: clinical implications, Cancer Res., 68, 3551, 10.1158/0008-5472.CAN-07-5835 Jiricny, 2006, The multifaceted mismatch-repair system, Nat. Rev. Mol. Cell Biol., 7, 335, 10.1038/nrm1907 Bartkova, 2005, DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis, Nature, 434, 864, 10.1038/nature03482 Bartkova, 2006, Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints, Nature, 444, 633, 10.1038/nature05268 Di Micco, 2006, Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication, Nature, 444, 638, 10.1038/nature05327 Gorgoulis, 2005, Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions, Nature, 434, 907, 10.1038/nature03485 Halazonetis, 2008, An oncogene-induced DNA damage model for cancer development, Science, 319, 1352, 10.1126/science.1140735 Negrini, 2010, Genomic instability – an evolving hallmark of cancer, Nat. Rev. Mol. Cell Biol., 11, 220, 10.1038/nrm2858 Prakash, 2005, Eukaryotic translesion synthesis DNA polymerases: specificity of structure and function, Annu. Rev. Biochem., 74, 317, 10.1146/annurev.biochem.74.082803.133250 Hegde, 2008, Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells, Cell Res., 18, 27, 10.1038/cr.2008.8 David, 2007, Base-excision repair of oxidative DNA damage, Nature, 447, 941, 10.1038/nature05978 Hoeijmakers, 2001, Genome maintenance mechanisms for preventing cancer, Nature, 411, 366, 10.1038/35077232 Iyama, 2013, DNA repair mechanisms in dividing and non-dividing cells, DNA Repair (Amst.), 12, 620, 10.1016/j.dnarep.2013.04.015 Li, 2008, Mechanisms and functions of DNA mismatch repair, Cell Res., 18, 85, 10.1038/cr.2007.115 Kunkel, 2005, DNA mismatch repair, Annu. Rev. Biochem., 74, 681, 10.1146/annurev.biochem.74.082803.133243 Gerson, 2004, MGMT: its role in cancer aetiology and cancer therapeutics, Nat. Rev. Cancer, 4, 296, 10.1038/nrc1319 Pegg, 2000, Repair of O(6)-alkylguanine by alkyltransferases, Mutat. Res., 462, 83, 10.1016/S1383-5742(00)00017-X Weller, 2010, MGMT promoter methylation in malignant gliomas: ready for personalized medicine?, Nat. Rev. Neurol., 6, 39, 10.1038/nrneurol.2009.197 Weterings, 2008, The endless tale of non-homologous end-joining, Cell Res., 18, 114, 10.1038/cr.2008.3 Chiruvella, 2013, Repair of double-strand breaks by end joining, Cold Spring Harb. Perspect. Biol., 5, a012757, 10.1101/cshperspect.a012757 Lieber, 2010, The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway, Annu. Rev. Biochem., 79, 181, 10.1146/annurev.biochem.052308.093131 van Gent, 2007, Non-homologous end-joining, a sticky affair, Oncogene, 26, 7731, 10.1038/sj.onc.1210871 McCulloch, 2008, The fidelity of DNA synthesis by eukaryotic replicative and translesion synthesis polymerases, Cell Res., 18, 148, 10.1038/cr.2008.4 Andersen, 2008, Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA, Cell Res., 18, 162, 10.1038/cr.2007.114 Kim, 2012, Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway, Genes Dev., 26, 1393, 10.1101/gad.195248.112 Kottemann, 2013, Fanconi anaemia and the repair of Watson and Crick DNA crosslinks, Nature, 493, 356, 10.1038/nature11863 Li, 2008, Homologous recombination in DNA repair and DNA damage tolerance, Cell Res., 18, 99, 10.1038/cr.2008.1 Sung, 2006, Mechanism of homologous recombination: mediators and helicases take on regulatory functions, Nat. Rev. Mol. Cell Biol., 7, 739, 10.1038/nrm2008 Moynahan, 2010, Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis, Nat. Rev. Mol. Cell Biol., 11, 196, 10.1038/nrm2851 Shuck, 2008, Eukaryotic nucleotide excision repair: from understanding mechanisms to influencing biology, Cell Res., 18, 64, 10.1038/cr.2008.2 Fousteri, 2008, Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects, Cell Res., 18, 73, 10.1038/cr.2008.6 Warren, 2007, Structure of the human MutSalpha DNA lesion recognition complex, Mol. Cell, 26, 579, 10.1016/j.molcel.2007.04.018 Surtees, 2006, Mismatch repair factor MSH2-MSH3 binds and alters the conformation of branched DNA structures predicted to form during genetic recombination, J. Mol. Biol., 360, 523, 10.1016/j.jmb.2006.05.032 Pluciennik, 2010, PCNA function in the activation and strand direction of MutLalpha endonuclease in mismatch repair, Proc. Natl. Acad. Sci. U.S.A., 107, 16066, 10.1073/pnas.1010662107 Kadyrov, 2006, Endonucleolytic function of MutLalpha in human mismatch repair, Cell, 126, 297, 10.1016/j.cell.2006.05.039 Campalans, 2013, Distinct spatiotemporal patterns and PARP dependence of XRCC1 recruitment to single-strand break and base excision repair, Nucleic Acids Res., 41, 3115, 10.1093/nar/gkt025 Friedberg, 2001, How nucleotide excision repair protects against cancer, Nat. Rev. Cancer, 1, 22, 10.1038/35094000 Cleaver, 2005, Cancer in xeroderma pigmentosum and related disorders of DNA repair, Nat. Rev. Cancer, 5, 564, 10.1038/nrc1652 Moser, 2007, Sealing of chromosomal DNA nicks during nucleotide excision repair requires XRCC1 and DNA ligase III alpha in a cell-cycle-specific manner, Mol. Cell, 27, 311, 10.1016/j.molcel.2007.06.014 Chapman, 2012, Playing the end game: DNA double-strand break repair pathway choice, Mol. Cell, 47, 497, 10.1016/j.molcel.2012.07.029 Lyndaker, 2009, A tale of tails: insights into the coordination of 3′ end processing during homologous recombination, Bioessays, 31, 315, 10.1002/bies.200800195 Cimprich, 2008, ATR: an essential regulator of genome integrity, Nat. Rev. Mol. Cell Biol., 9, 616, 10.1038/nrm2450 Krejci, 2012, Homologous recombination and its regulation, Nucleic Acids Res., 40, 5795, 10.1093/nar/gks270 San Filippo, 2008, Mechanism of eukaryotic homologous recombination, Annu. Rev. Biochem., 77, 229, 10.1146/annurev.biochem.77.061306.125255 Heyer, 2010, Regulation of homologous recombination in eukaryotes, Annu. Rev. Genet., 44, 113, 10.1146/annurev-genet-051710-150955 Venkitaraman, 2004, Tracing the network connecting BRCA and Fanconi anaemia proteins, Nat. Rev. Cancer, 4, 266, 10.1038/nrc1321 Meindl, 2010, Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene, Nat. Genet., 42, 410, 10.1038/ng.569 Al-Sukhni, 2008, Germline BRCA1 mutations predispose to pancreatic adenocarcinoma, Hum. Genet., 124, 271, 10.1007/s00439-008-0554-0 Bartsch, 2012, Familial pancreatic cancer – current knowledge, Nat. Rev. Gastroenterol. Hepatol., 9, 445, 10.1038/nrgastro.2012.111 Greer, 2007, Role of BRCA1 and BRCA2 mutations in pancreatic cancer, Gut, 56, 601, 10.1136/gut.2006.101220 Biankin, 2012, Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes, Nature, 491, 399, 10.1038/nature11547 Ding, 2008, Somatic mutations affect key pathways in lung adenocarcinoma, Nature, 455, 1069, 10.1038/nature07423 2011, Integrated genomic analyses of ovarian carcinoma, Nature, 474, 609, 10.1038/nature10166 Puente, 2011, Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia, Nature, 465, 101, 10.1038/nature10113 Quesada, 2011, Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia, Nat. Genet., 44, 47, 10.1038/ng.1032 Hartlerode, 2009, Mechanisms of double-strand break repair in somatic mammalian cells, Biochem. J., 423, 157, 10.1042/BJ20090942 Lees-Miller, 2003, Repair of DNA double strand breaks by non-homologous end joining, Biochimie, 85, 1161, 10.1016/j.biochi.2003.10.011 McVey, 2008, MMEJ repair of double-strand breaks (director's cut): deleted sequences and alternative endings, Trends Genet., 24, 529, 10.1016/j.tig.2008.08.007 Deriano, 2013, Modernizing the nonhomologous end-joining repertoire: alternative and classical NHEJ share the stage, Annu. Rev. Genet., 47, 433, 10.1146/annurev-genet-110711-155540 Frit, 2014, Alternative end-joining pathway(s): Bricolage at DNA breaks, DNA Repair (Amst.), 17, 81, 10.1016/j.dnarep.2014.02.007 Boveri, 1914 2012, Comprehensive molecular portraits of human breast tumours, Nature, 490, 61, 10.1038/nature11412 2012, Comprehensive molecular characterization of human colon and rectal cancer, Nature, 487, 330, 10.1038/nature11252 2011, Integrated genomic analyses of ovarian carcinoma, Nature, 474, 609, 10.1038/nature10166 Grasso, 2012, The mutational landscape of lethal castration-resistant prostate cancer, Nature, 487, 239, 10.1038/nature11125 Kandoth, 2013, Integrated genomic characterization of endometrial carcinoma, Nature, 497, 67, 10.1038/nature12113 Puente, 2011, Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia, Nature, 475, 101, 10.1038/nature10113 Quesada, 2012, Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia, Nat. Genet., 44, 47, 10.1038/ng.1032 Stratton, 2009, The cancer genome, Nature, 458, 719, 10.1038/nature07943 Weinstein, 2002, Cancer. Addiction to oncogenes – the Achilles heal of cancer, Science, 297, 63, 10.1126/science.1073096 Weinstein, 2008, Oncogene addiction, Cancer Res., 68, 3077, 10.1158/0008-5472.CAN-07-3293 Weinstein, 2006, Mechanisms of disease: oncogene addiction – a rationale for molecular targeting in cancer therapy, Nat. Clin. Pract. Oncol., 3, 448, 10.1038/ncponc0558 Sharma, 2006, ‘Oncogenic shock’: explaining oncogene addiction through differential signal attenuation, Clin. Cancer Res., 12, 4392s, 10.1158/1078-0432.CCR-06-0096 Druker, 1996, Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells, Nat. Med., 2, 561, 10.1038/nm0596-561 Kwak, 2010, Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer, N. Engl. J. Med., 363, 1693, 10.1056/NEJMoa1006448 Sharma, 2007, Epidermal growth factor receptor mutations in lung cancer, Nat. Rev. Cancer, 7, 169, 10.1038/nrc2088 Felsher, 1999, Reversible tumorigenesis by MYC in hematopoietic lineages, Mol. Cell, 4, 199, 10.1016/S1097-2765(00)80367-6 Jain, 2002, Sustained loss of a neoplastic phenotype by brief inactivation of MYC, Science, 297, 102, 10.1126/science.1071489 Pelengaris, 1999, Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion, Mol. Cell, 3, 565, 10.1016/S1097-2765(00)80350-0 Brough, 2011, Searching for synthetic lethality in cancer, Curr. Opin. Genet. Dev., 21, 34, 10.1016/j.gde.2010.10.009 Kaelin, 2005, The concept of synthetic lethality in the context of anticancer therapy, Nat. Rev. Cancer, 5, 689, 10.1038/nrc1691 Kroll, 1996, Establishing genetic interactions by a synthetic dosage lethality phenotype, Genetics, 143, 95, 10.1093/genetics/143.1.95 Li, 1993, Isolation of ORC6, a component of the yeast origin recognition complex by a one-hybrid system, Science, 262, 1870, 10.1126/science.8266075 Measday, 2002, Synthetic dosage lethality, Methods Enzymol., 350, 316, 10.1016/S0076-6879(02)50971-X Rouleau, 2010, PARP inhibition: PARP1 and beyond, Nat. Rev. Cancer, 10, 293, 10.1038/nrc2812 Masson, 1998, XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage, Mol. Cell. Biol., 18, 3563, 10.1128/MCB.18.6.3563 El-Khamisy, 2003, A requirement for PARP-1 for the assembly or stability of XRCC1 nuclear foci at sites of oxidative DNA damage, Nucleic Acids Res., 31, 5526, 10.1093/nar/gkg761 Strom, 2011, Poly (ADP-ribose) polymerase (PARP) is not involved in base excision repair but PARP inhibition traps a single-strand intermediate, Nucleic Acids Res., 39, 3166, 10.1093/nar/gkq1241 Helleday, 2011, The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings, Mol. Oncol., 5, 387, 10.1016/j.molonc.2011.07.001 Bryant, 2009, PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination, EMBO J., 28, 2601, 10.1038/emboj.2009.206 De Vos, 2012, The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art, Biochem. Pharmacol., 84, 137, 10.1016/j.bcp.2012.03.018 Wang, 2006, PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways, Nucleic Acids Res., 34, 6170, 10.1093/nar/gkl840 Audebert, 2004, Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining, J. Biol. Chem., 279, 55117, 10.1074/jbc.M404524200 Bryant, 2005, Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase, Nature, 434, 913, 10.1038/nature03443 Farmer, 2005, Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, Nature, 434, 917, 10.1038/nature03445 De Lorenzo, 2013, The elephant and the blind men: making sense of PARP inhibitors in homologous recombination deficient tumor cells, Front. Oncol., 3, 228, 10.3389/fonc.2013.00228 Gurley, 2001, Synthetic lethality between mutation in Atm and DNA-PK(cs) during murine embryogenesis, Curr. Biol., 11, 191, 10.1016/S0960-9822(01)00048-3 Xu, 1996, Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma, Genes Dev., 10, 2411, 10.1101/gad.10.19.2411 Gao, 1998, A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination, Immunity, 9, 367, 10.1016/S1074-7613(00)80619-6 Heyer, 2000, Hypersensitivity to DNA damage leads to increased apoptosis during early mouse development, Genes Dev., 14, 2072, 10.1101/gad.14.16.2072 Snow, 1977, Gastrulation in the mouse: growth and regionalization of the epiblast, J. Embryol. Exp. Morphol., 42, 293 Austen, 2007, Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion, J. Clin. Oncol., 25, 5448, 10.1200/JCO.2007.11.2649 Haidar, 2000, ATM gene deletion in patients with adult acute lymphoblastic leukemia, Cancer, 88, 1057, 10.1002/(SICI)1097-0142(20000301)88:5<1057::AID-CNCR16>3.0.CO;2-6 Ripolles, 2006, Genetic abnormalities and clinical outcome in chronic lymphocytic leukemia, Cancer Genet. Cytogenet., 171, 57, 10.1016/j.cancergencyto.2006.07.006 Skowronska, 2012, Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 Trial, J. Clin. Oncol., 30, 4525, 10.1200/JCO.2011.41.0852 Dohner, 2000, Genomic aberrations and survival in chronic lymphocytic leukemia, N. Engl. J. Med., 343, 1910, 10.1056/NEJM200012283432602 Riabinska, 2013, Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors, Sci Transl. Med., 5, 189ra178, 10.1126/scitranslmed.3005814 Barretina, 2012, The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity, Nature, 483, 603, 10.1038/nature11003 Forbes, 2008, The catalogue of somatic mutations in cancer (COSMIC), Curr. Protoc. Hum. Genet., 10.1002/0471142905.hg1011s57 Garnett, 2012, Systematic identification of genomic markers of drug sensitivity in cancer cells, Nature, 483, 570, 10.1038/nature11005 Dietlein, 2014, A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC, Cancer Discov., 4, 592, 10.1158/2159-8290.CD-13-0907 Risinger, 1996, Mutation of MSH3 in endometrial cancer and evidence for its functional role in heteroduplex repair, Nat. Genet., 14, 102, 10.1038/ng0996-102 Park, 2013, MSH3 mismatch repair protein regulates sensitivity to cytotoxic drugs and a histone deacetylase inhibitor in human colon carcinoma cells, PLoS ONE, 8, e65369, 10.1371/journal.pone.0065369 Haugen, 2008, Genetic instability caused by loss of MutS homologue 3 in human colorectal cancer, Cancer Res., 68, 8465, 10.1158/0008-5472.CAN-08-0002 Plaschke, 2004, Loss of MSH3 protein expression is frequent in MLH1-deficient colorectal cancer and is associated with disease progression, Cancer Res., 64, 864, 10.1158/0008-5472.CAN-03-2807 Guerrette, 1998, Interactions of human hMSH2 with hMSH3 and hMSH2 with hMSH6: examination of mutations found in hereditary nonpolyposis colorectal cancer, Mol. Cell. Biol., 18, 6616, 10.1128/MCB.18.11.6616 Kleczkowska, 2001, hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci, Genes Dev., 15, 724, 10.1101/gad.191201 Sugawara, 2000, DNA length dependence of the single-strand annealing pathway and the role of Saccharomyces cerevisiae RAD59 in double-strand break repair, Mol. Cell. Biol., 20, 5300, 10.1128/MCB.20.14.5300-5309.2000 Sugawara, 1997, Role of Saccharomyces cerevisiae Msh2 and Msh3 repair proteins in double-strand break-induced recombination, Proc. Natl. Acad. Sci. U.S.A., 94, 9214, 10.1073/pnas.94.17.9214 Zhang, 2009, Involvement of nucleotide excision and mismatch repair mechanisms in double strand break repair, Curr. Genomics, 10, 250, 10.2174/138920209788488544 van Oers, 2013, The MutSbeta complex is a modulator of p53-driven tumorigenesis through its functions in both DNA double-strand break repair and mismatch repair, Oncogene Takahashi, 2011, MSH3 mediates sensitization of colorectal cancer cells to cisplatin, oxaliplatin, and a poly(ADP-ribose) polymerase inhibitor, J. Biol. Chem., 286, 12157, 10.1074/jbc.M110.198804 Ivanov, 1996, Genetic requirements for the single-strand annealing pathway of double-strand break repair in Saccharomyces cerevisiae, Genetics, 142, 693, 10.1093/genetics/142.3.693 Evans, 2000, The Saccharomyces cerevisiae Msh2 mismatch repair protein localizes to recombination intermediates in vivo, Mol. Cell, 5, 789, 10.1016/S1097-2765(00)80319-6 Saparbaev, 1996, Requirement of mismatch repair genes MSH2 and MSH3 in the RAD1–RAD10 pathway of mitotic recombination in Saccharomyces cerevisiae, Genetics, 142, 727, 10.1093/genetics/142.3.727 Kirkpatrick, 1997, Repair of DNA loops involves DNA-mismatch and nucleotide-excision repair proteins, Nature, 387, 929, 10.1038/43225 Surtees, 2006, Mismatch repair factor MSH2–MSH3 binds and alters the conformation of branched DNA structures predicted to form during genetic recombination, J. Mol. Biol., 360, 523, 10.1016/j.jmb.2006.05.032 Gupta, 2012, Mechanism of mismatch recognition revealed by human MutSbeta bound to unpaired DNA loops, Nat. Struct. Mol. Biol., 19, 72, 10.1038/nsmb.2175 Wang, 2010, PTIP promotes DNA double-strand break repair through homologous recombination, Genes Cells, 15, 243, 10.1111/j.1365-2443.2009.01379.x Callen, 2013, 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions, Cell, 153, 1266, 10.1016/j.cell.2013.05.023 Ogi, 2010, Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells, Mol. Cell, 37, 714, 10.1016/j.molcel.2010.02.009 Almeida, 2007, A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification, DNA Repair (Amst.), 6, 695, 10.1016/j.dnarep.2007.01.009 Stoimenov, 2009, PCNA on the crossroad of cancer, Biochem. Soc. Trans., 37, 605, 10.1042/BST0370605 Bunting, 2012, BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair, Mol. Cell, 46, 125, 10.1016/j.molcel.2012.02.015 Schlacher, 2012, A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51–BRCA1/2, Cancer Cell, 22, 106, 10.1016/j.ccr.2012.05.015 Schlacher, 2011, Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11, Cell, 145, 529, 10.1016/j.cell.2011.03.041 Scully, 2013, Double strand break repair functions of histone H2AX, Mutat. Res., 750, 5, 10.1016/j.mrfmmm.2013.07.007 Bouwman, 2010, 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers, Nat. Struct. Mol. Biol., 17, 688, 10.1038/nsmb.1831 Bunting, 2010, 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks, Cell, 141, 243, 10.1016/j.cell.2010.03.012 Cao, 2009, A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency, Mol. Cell, 35, 534, 10.1016/j.molcel.2009.06.037 Hashimoto, 2010, Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis, Nat. Struct. Mol. Biol., 17, 1305, 10.1038/nsmb.1927 Lord, 2008, Targeted therapy for cancer using PARP inhibitors, Curr. Opin. Pharmacol., 8, 363, 10.1016/j.coph.2008.06.016 de Bono, 2010, Translating cancer research into targeted therapeutics, Nature, 467, 543, 10.1038/nature09339 Patel, 2011, Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells, Proc. Natl. Acad. Sci. U.S.A., 108, 3406, 10.1073/pnas.1013715108 Riabinska, 2013, Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors, Sci. Transl. Med., 5, 189ra178, 10.1126/scitranslmed.3005814 Srivastava, 2012, An inhibitor of nonhomologous end-joining abrogates double-strand break repair and impedes cancer progression, Cell, 151, 1474, 10.1016/j.cell.2012.11.054 Muggia, 2014, ‘BRCAness’ and its implications for platinum action in gynecologic cancer, Anticancer Res., 34, 551 Narod, 2010, BRCA mutations in the management of breast cancer: the state of the art, Nat. Rev. Clin. Oncol., 7, 702, 10.1038/nrclinonc.2010.166 Edwards, 2008, Resistance to therapy caused by intragenic deletion in BRCA2, Nature, 451, 1111, 10.1038/nature06548 Sakai, 2008, Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers, Nature, 451, 1116, 10.1038/nature06633 Rottenberg, 2008, High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs, Proc. Natl. Acad. Sci. U.S.A., 105, 17079, 10.1073/pnas.0806092105 Evers, 2008, Selective inhibition of BRCA2-deficient mammary tumor cell growth by AZD2281 and cisplatin, Clin. Cancer Res., 14, 3916, 10.1158/1078-0432.CCR-07-4953