DNA Double Strand Break Repair - Related Synthetic Lethality

doi:10.2174/0929867325666180201114306
摘要

癌症是一种异质性疾病，肿瘤之间和肿瘤内部具有高度多样性。我们对其生物学的有限知识导致无效治疗。然而，个性化方法可能是抗癌治疗领域的里程碑。它可以增加对肿瘤起始癌症干细胞（CSC）和癌症祖细胞（CPC）的治疗的特异性，对正常细胞和组织的影响最小。癌细胞携带多种遗传和表观遗传畸变，这可能破坏细胞存活所必需的途径。合成杀伤力的发现为创造有效和个性化的抗肿瘤治疗带来了新的希望。当两个基因或其产物的同时失活导致细胞死亡而任一基因的个体失活不致死时，发生合成致死。许多抗肿瘤疗法的有效性取决于DNA损伤的诱导，因此表达产物对DNA修复途径至关重要的基因异常的肿瘤细胞是合成致死性的有希望的靶标。在这里，我们讨论了DNA双链断裂修复途径缺陷背景下合成致死性的机制方面。此外，我们回顾了利用合成致死性相互作用的临床试验，并讨论了耐药机制。
关键词: DNA修复，双链断裂（DSB），合成致死率，抗癌疗法，放射疗法，PARP。
« Previous Next »
[1] 
Kaelin, W.G., Jr The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer,  2005, 5(9), 689-698.
[2] 
Chan, D.A.; Giaccia, A.J. Targeting cancer cells by synthetic lethality: Autophagy and VHL in cancer therapeutics. Cell Cycle,  2008, 7(19), 2987-2990.
[3] 
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell,  2011, 144(5), 646-674.
[4] 
Weidle, U.H.; Maisel, D.; Eick, D. Synthetic lethality-based targets for discovery of new cancer therapeutics. Cancer Genomics Proteomics,  2011, 8(4), 159-171.
[5] 
Thompson, N.; Adams, D.J.; Ranzani, M. Synthetic lethality: Emerging targets and opportunities in melanoma. Pigment Cell Melanoma Res.,  2017, 30(2), 183-193.
[6] 
Curtin, N.J. DNA repair dysregulation from cancer driver to therapeutic target. Nat. Rev. Cancer,  2012, 12(12), 801-817.
[7] 
Gibson, G. Decanalization and the origin of complex disease. Nat. Rev. Genet.,  2009, 10(2), 134-140.
[8] 
Kirschner, M.; Gerhart, J. Evolvability. Proc. Natl. Acad. Sci. USA,  1998, 95(15), 8420-8427.
[9] 
Kamb, A. Mutation load, functional overlap, and synthetic lethality in the evolution and treatment of cancer. J. Theor. Biol.,  2003, 223(2), 205-213.
[10] 
Yates, L.R.; Campbell, P.J. Evolution of the cancer genome. Nat. Rev. Genet.,  2012, 13(11), 795-806.
[11] 
Dean, M.; Fojo, T.; Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer,  2005, 5(4), 275-284.
[12] 
Frame, F.M.; Maitland, N.J. Cancer stem cells, models of study and implications of therapy resistance mechanisms. Adv. Exp. Med. Biol.,  2011, 720, 105-118.
[13] 
Lutz, C.; Woll, P.S.; Hall, G.; Castor, A.; Dreau, H.; Cazzaniga, G.; Zuna, J.; Jensen, C.; Clark, S.A.; Biondi, A.; Mitchell, C.; Ferry, H.; Schuh, A.; Buckle, V.; Jacobsen, S.W.; Enver, T. Quiescent leukaemic cells account for minimal residual disease in childhood lymphoblastic leukaemia. Leukemia,  2013, 27(5), 1204-1207.
[14] 
Crews, L.A.; Jamieson, C.H. Selective elimination of leukemia stem cells: Hitting a moving target. Cancer Lett.,  2013, 338(1), 15-22.
[15] 
Gasch, C.; Ffrench, B.; O’Leary, J.J.; Gallagher, M.F. Catching moving targets: Cancer stem cell hierarchies, therapy-resistance & considerations for clinical intervention. Mol. Cancer,  2017, 16(1), 43.
[16] 
Sallmyr, A.; Fan, J.; Rassool, F.V. Genomic instability in myeloid malignancies: Increased Reactive Oxygen Species (ROS), DNA Double Strand Breaks (DSBs) and error-prone repair. Cancer Lett.,  2008, 270(1), 1-9.
[17] 
Wang, T.; Birsoy, K.; Hughes, N.W.; Krupczak, K.M.; Post, Y.; Wei, J.J.; Lander, E.S.; Sabatini, D.M. Identification and characterization of essential genes in the human genome. Science,  2015, 350(6264), 1096-1101.
[18] 
Chan, D.A.; Giaccia, A.J. Harnessing synthetic lethal interactions in anticancer drug discovery. Nat. Rev. Drug Discov.,  2011, 10(5), 351-364.
[19] 
Scholl, C.; Fröhling, S.; Dunn, I.F.; Schinzel, A.C.; Barbie, D.A.; Kim, S.Y.; Silver, S.J.; Tamayo, P.; Wadlow, R.C.; Ramaswamy, S.; Döhner, K.; Bullinger, L.; Sandy, P.; Boehm, J.S.; Root, D.E.; Jacks, T.; Hahn, W.C.; Gilliland, D.G. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell,  2009, 137(5), 821-834.
[20] 
Chan, D.A.; Sutphin, P.D.; Nguyen, P.; Turcotte, S.; Lai, E.W.; Banh, A.; Reynolds, G.E.; Chi, J.T.; Wu, J.; Solow-Cordero, D.E.; Bonnet, M.; Flanagan, J.U.; Bouley, D.M.; Graves, E.E.; Denny, W.A.; Hay, M.P.; Giaccia, A.J. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Transl. Med.,  2011, 3(94), 94ra70.
[21] 
Sinha, S.; Thomas, D.; Chan, S.; Gao, Y.; Brunen, D.; Torabi, D.; Reinisch, A.; Hernandez, D.; Chan, A.; Rankin, E.B.; Bernards, R.; Majeti, R.; Dill, D.L. Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data. Nat. Commun.,  2017, 8, 15580.
[22] 
Mateo, J.; Carreira, S.; Sandhu, S.; Miranda, S.; Mossop, H.; Perez-Lopez, R.; Nava Rodrigues, D.; Robinson, D.; Omlin, A.; Tunariu, N.; Boysen, G.; Porta, N.; Flohr, P.; Gillman, A.; Figueiredo, I.; Paulding, C.; Seed, G.; Jain, S.; Ralph, C.; Protheroe, A.; Hussain, S.; Jones, R.; Elliott, T.; McGovern, U.; Bianchini, D.; Goodall, J.; Zafeiriou, Z.; Williamson, C.T.; Ferraldeschi, R.; Riisnaes, R.; Ebbs, B.; Fowler, G.; Roda, D.; Yuan, W.; Wu, Y.M.; Cao, X.; Brough, R.; Pemberton, H.; A’Hern, R.; Swain, A.; Kunju, L.P.; Eeles, R.; Attard, G.; Lord, C.J.; Ashworth, A.; Rubin, M.A.; Knudsen, K.E.; Feng, F.Y.; Chinnaiyan, A.M.; Hall, E.; De Bono, J.S. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med.,  2015, 373(18), 1697-1708.
[23] 
Telli, M.L.; Timms, K.M.; Reid, J.; Hennessy, B.; Mills, G.B.; Jensen, K.C.; Szallasi, Z.; Barry, W.T.; Winer, E.P.; Tung, N.M.; Isakoff, S.J.; Ryan, P.D.; Greene-Colozzi, A.; Gutin, A.; Sangale, Z.; Iliev, D.; Neff, C.; Abkevich, V.; Jones, J.T.; Lanchbury, J.S.; Hartman, A.R.; Garber, J.E.; Ford, J.M.; Silver, D.P.; Richardson, A.L. Homologous Recombination Deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res.,  2016, 22(15), 3764-3773.
[24] 
Nieborowska-Skorska, M.; Sullivan, K.; Dasgupta, Y. Podszywalow-Bartnicka, P.; Hoser, G.; Maifrede, S.;
Martinez, E.; Di Marcantonio, D.; Bolton-Gillespie, E.;
Cramer-Morales, K.; Lee, J.; Li, M.; Slupianek, A.;
Gritsyuk, D.; Cerny-Reiterer, S.; Seferynska, I.; Stoklosa,
T.; Bullinger, L.; Zhao, H.; Gorbunova, V.; Piwocka, K.;
Valent, P.; Civin, C.I.; Muschen, M.; Dick, J.E.; Wang,
J.C.; Bhatia, S.; Bhatia, R.; Eppert, K.; Minden, M.D.;
Sykes, S.M.; Skorski, T. Gene expression and mutationguided
synthetic lethality eradicates proliferating and
quiescent leukemia cells. J. Clin. Invest,  2017, 127(6), 2392-2406.
[25] 
Guo, J.; Liu, H.; Zheng, J. SynLethDB: Synthetic lethality database toward discovery of selective and sensitive anti-cancer drug targets. Nucleic Acids Res.,  2016, 44(D1), D1011-D1017.
[26] 
Kim, G.; Ison, G.; McKee, A.E.; Zhang, H.; Tang, S.; Gwise, T.; Sridhara, R.; Lee, E.; Tzou, A.; Philip, R.; Chiu, H.J.; Ricks, T.K.; Palmby, T.; Russell, A.M.; Ladouceur, G.; Pfuma, E.; Li, H.; Zhao, L.; Liu, Q.; Venugopal, R.; Ibrahim, A.; Pazdur, R. FDA approval summary: Olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin. Cancer Res.,  2015, 21(19), 4257-4261.
[27] 
Bridges, C.B. The origin of variations in sexual and sex-limited characters. Am. Nat.,  1922, 56(642), 51-63.
[28] 
Dobzhansky, T. Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura. Genetics,  1946, 31, 269-290.
[29] 
Simon, J.A.; Szankasi, P.; Nguyen, D.K.; Ludlow, C.; Dunstan, H.M.; Roberts, C.J.; Jensen, E.L.; Hartwell, L.H.; Friend, S.H. Differential toxicities of anticancer agents among DNA repair and checkpoint mutants of Saccharomyces cerevisiae. Cancer Res.,  2000, 60(2), 328-333.
[30] 
Wong, S.L.; Zhang, L.V.; Tong, A.H.; Li, Z.; Goldberg, D.S.; King, O.D.; Lesage, G.; Vidal, M.; Andrews, B.; Bussey, H.; Boone, C.; Roth, F.P. Combining biological networks to predict genetic interactions. Proc. Natl. Acad. Sci. USA,  2004, 101(44), 15682-15687.
[31] 
Nijman, S.M. Synthetic lethality: General principles, utility and detection using genetic screens in human cells. FEBS Lett.,  2011, 585(1), 1-6.
[32] 
Hartwell, L.H.; Szankasi, P.; Roberts, C.J.; Murray, A.W.; Friend, S.H. Integrating genetic approaches into the discovery of anticancer drugs. Science,  1997, 278(5340), 1064-1068.
[33] 
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell,  2000, 100(1), 57-70.
[34] 
Jackson, S.P.; Bartek, J. The DNA-damage response in human biology and disease. Nature,  2009, 461(7267), 1071-1078.
[35] 
Jackson, R.A.; Chen, E.S. Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs. Pharmacol. Ther.,  2016, 162, 69-85.
[36] 
Pawson, T.; Warner, N. Oncogenic re-wiring of cellular signaling pathways. Oncogene,  2007, 26(9), 1268-1275.
[37] 
Kandoth, C.; McLellan, M.D.; Vandin, F.; Ye, K.; Niu, B.; Lu, C.; Xie, M.; Zhang, Q.; McMichael, J.F.; Wyczalkowski, M.A.; Leiserson, M.D.; Miller, C.A.; Welch, J.S.; Walter, M.J.; Wendl, M.C.; Ley, T.J.; Wilson, R.K.; Raphael, B.J.; Ding, L. Mutational landscape and significance across 12 major cancer types. Nature,  2013, 502(7471), 333-339.
[38] 
Vogelstein, B.; Papadopoulos, N.; Velculescu, V.E.; Zhou, S.; Diaz, L.A., Jr; Kinzler, K.W. Cancer genome landscapes. Science,  2013, 339(6127), 1546-1558.
[39] 
Wood, L.D.; Parsons, D.W.; Jones, S.; Lin, J.; Sjöblom, T.; Leary, R.J.; Shen, D.; Boca, S.M.; Barber, T.; Ptak, J.; Silliman, N.; Szabo, S.; Dezso, Z.; Ustyanksky, V.; Nikolskaya, T.; Nikolsky, Y.; Karchin, R.; Wilson, P.A.; Kaminker, J.S.; Zhang, Z.; Croshaw, R.; Willis, J.; Dawson, D.; Shipitsin, M.; Willson, J.K.; Sukumar, S.; Polyak, K.; Park, B.H.; Pethiyagoda, C.L.; Pant, P.V.; Ballinger, D.G.; Sparks, A.B.; Hartigan, J.; Smith, D.R.; Suh, E.; Papadopoulos, N.; Buckhaults, P.; Markowitz, S.D.; Parmigiani, G.; Kinzler, K.W.; Velculescu, V.E.; Vogelstein, B. The genomic landscapes of human breast and colorectal cancers. Science,  2007, 318(5853), 1108-1113.
[40] 
Luo, J.; Solimini, N.L.; Elledge, S.J. Principles of cancer therapy: Oncogene and non-oncogene addiction. Cell,  2009, 136(5), 823-837.
[41] 
Nagel, R.; Semenova, E.A.; Berns, A. Drugging the addict: Non-oncogene addiction as a target for cancer therapy. EMBO Rep.,  2016, 17(11), 1516-1531.
[42] 
Solimini, N.L.; Luo, J.; Elledge, S.J. Non-oncogene addiction and the stress phenotype of cancer cells. Cell,  2007, 130(6), 986-988.
[43] 
Weinstein, I.B. Cancer. Addiction to oncogenes-The Achilles heal of cancer. Science,  2002, 297(5578), 63-64.
[44] 
Zecchini, V.; Frezza, C. Metabolic synthetic lethality in cancer therapy. Biochim. Biophys. Acta. Bioenerg.,  2017, 1858(8), 723-731.
[45] 
Neshat, M.S.; Mellinghoff, I.K.; Tran, C.; Stiles, B.; Thomas, G.; Petersen, R.; Frost, P.; Gibbons, J.J.; Wu, H.; Sawyers, C.L. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl. Acad. Sci. USA,  2001, 98(18), 10314-10319.
[46] 
Kwon, C.H.; Zhu, X.; Zhang, J.; Baker, S.J. mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc. Natl. Acad. Sci. USA,  2003, 100(22), 12923-12928.
[47] 
Dong, Y.; Li, A.; Wang, J.; Weber, J.D.; Michel, L.S. Synthetic lethality through combined notch-epidermal growth factor receptor pathway inhibition in basal-like breast cancer. Cancer Res.,  2010, 70(13), 5465-5474.
[48] 
Puyol, M.; Martín, A.; Dubus, P.; Mulero, F.; Pizcueta, P.; Khan, G.; Guerra, C.; Santamaría, D.; Barbacid, M. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell,  2010, 18(1), 63-73.
[49] 
Yim, H.; Erikson, R.L. Plk1-targeted therapies in TP53- or RAS-mutated cancer. Mutat. Res. Rev. Mutat. Res.,  2014, 761, 31-39.
[50] 
Iliakis, G.; Murmann, T.; Soni, A. Alternative end-joining repair pathways are the ultimate backup for abrogated classical non-homologous end-joining and homologous recombination repair: Implications for the formation of chromosome translocations. Mutat. Res. Genet. Toxicol. Environ. Mutagen.,  2015, 793, 166-175.
[51] 
Nickoloff, J.A.; Jones, D.; Lee, S.H.; Williamson, E.A.; Hromas, R. Drugging the cancers addicted to DNA repair. J. Natl. Cancer Inst.,  2017, 109(11), djx059.
[52] 
Aguilera, A.; Gaillard, H. Transcription and recombination: When RNA meets DNA. Cold Spring Harb. Perspect. Biol.,  2014, 6(8), a016543.
[53] 
Mehta, A.; Haber, J.E. Sources of DNA double-strand breaks and models of recombinational DNA repair. Cold Spring Harb. Perspect. Biol.,  2014, 6(9), a016428.
[54] 
Zeman, M.K.; Cimprich, K.A. Causes and consequences of replication stress. Nat. Cell Biol.,  2014, 16(1), 2-9.
[55] 
Panich, U.; Sittithumcharee, G.; Rathviboon, N.; Jirawatnotai, S. Ultraviolet radiation-induced skin aging: The role of DNA damage and oxidative stress in epidermal stem cell damage mediated skin aging. Stem Cells Int.,  2016, 2016, 7370642.
[56] 
Hoeijmakers, J.H. DNA damage, aging, and cancer. N. Engl. J. Med.,  2009, 361(15), 1475-1485.
[57] 
Gavande, N.S.; Vander Vere-Carozza, P.S.; Hinshaw, H.D.; Jalal, S.I.; Sears, C.R.; Pawelczak, K.S.; Turchi, J.J. DNA repair targeted therapy: The past or future of cancer treatment? Pharmacol. Ther.,  2016, 160, 65-83.
[58] 
Ciccia, A.; Elledge, S.J. The DNA damage response: Making it safe to play with knives. Mol. Cell,  2010, 40(2), 179-204.
[59] 
Begg, A.C.; Stewart, F.A.; Vens, C. Strategies to improve radiotherapy with targeted drugs. Nat. Rev. Cancer,  2011, 11(4), 239-253.
[60] 
Chapman, J.R.; Taylor, M.R.; Boulton, S.J. Playing the end game: DNA double-strand break repair pathway choice. Mol. Cell,  2012, 47(4), 497-510.
[61] 
Cannan, W.J.; Pederson, D.S. Mechanisms and consequences of double-strand DNA break formation in chromatin. J. Cell. Physiol.,  2016, 231(1), 3-14.
[62] 
Daley, J.M.; Kwon, Y.; Niu, H.; Sung, P. Investigations of homologous recombination pathways and their regulation. Yale J. Biol. Med.,  2013, 86(4), 453-461.
[63] 
Ma, Y.; Lu, H.; Tippin, B.; Goodman, M.F.; Shimazaki, N.; Koiwai, O.; Hsieh, C.L.; Schwarz, K.; Lieber, M.R. A biochemically defined system for mammalian nonhomologous DNA end joining. Mol. Cell,  2004, 16(5), 701-713.
[64] 
Lieber, M.R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu. Rev. Biochem.,  2010, 79, 181-211.
[65] 
Chang, H.H.; Watanabe, G.; Lieber, M.R. Unifying the DNA end-processing roles of the artemis nuclease: Ku-dependent artemis resection at blunt DNA ends. J. Biol. Chem.,  2015, 290(40), 24036-24050.
[66] 
Aparicio, T.; Baer, R.; Gautier, J. DNA double-strand break repair pathway choice and cancer. DNA Repair (Amst.),  2014, 19, 169-175.
[67] 
Ceccaldi, R.; Rondinelli, B.; D’Andrea, A.D. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol.,  2016, 26(1), 52-64.
[68] 
Botuyan, M.V.; Lee, J.; Ward, I.M.; Kim, J.E.; Thompson, J.R.; Chen, J.; Mer, G. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell,  2006, 127(7), 1361-1373.
[69] 
Hustedt, N.; Durocher, D. The control of DNA repair by the cell cycle. Nat. Cell Biol.,  2016, 19(1), 1-9.
[70] 
Li, J.; Xu, X. DNA double-strand break repair: A tale of pathway choices. Acta Biochim. Biophys. Sin. (Shanghai),  2016, 48(7), 641-646.
[71] 
Saredi, G.; Huang, H.; Hammond, C.M.; Alabert, C.; Bekker-Jensen, S.; Forne, I.; Reverón-Gómez, N.; Foster, B.M.; Mlejnkova, L.; Bartke, T.; Cejka, P.; Mailand, N.; Imhof, A.; Patel, D.J.; Groth, A. H4K20me0 marks post-replicative chromatin and recruits the TONSL-MMS22L DNA repair complex. Nature,  2016, 534(7609), 714-718.
[72] 
Escribano-Díaz, C.; Orthwein, A.; Fradet-Turcotte, A.; Xing, M.; Young, J.T.; Tkáč, J.; Cook, M.A.; Rosebrock, A.P.; Munro, M.; Canny, M.D.; Xu, D.; Durocher, D. A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. Mol. Cell,  2013, 49(5), 872-883.
[73] 
Saha, J.; Davis, A.J. Unsolved mystery: The role of BRCA1 in DNA end-joining. J. Radiat. Res. (Tokyo),  2016, 57(Suppl. 1), i18-i24.
[74] 
Durdikova, K.; Chovanec, M. Regulation of non-homologous end joining via post-translational modifications of components of the ligation step. Curr. Genet.,  2016, 63(4), 591-605.
[75] 
Lieber, M.R.; Ma, Y.; Pannicke, U.; Schwarz, K. Mechanism and regulation of human non-homologous DNA end-joining. Nat. Rev. Mol. Cell Biol.,  2003, 4(9), 712-720.
[76] 
Lieber, M.R. The mechanism of human nonhomologous DNA end joining. J. Biol. Chem.,  2008, 283(1), 1-5.
[77] 
Walker, J.R.; Corpina, R.A.; Goldberg, J. Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature,  2001, 412(6847), 607-614.
[78] 
Grundy, G.J.; Moulding, H.A.; Caldecott, K.W.; Rulten, S.L. One ring to bring them all-the role of Ku in mammalian non-homologous end joining. DNA Repair (Amst.),  2014, 17, 30-38.
[79] 
Roberts, S.A.; Strande, N.; Burkhalter, M.D.; Strom, C.; Havener, J.M.; Hasty, P.; Ramsden, D.A. Ku is a 5′-dRP/AP lyase that excises nucleotide damage near broken ends. Nature,  2010, 464(7292), 1214-1217.
[80] 
Strande, N.; Roberts, S.A.; Oh, S.; Hendrickson, E.A.; Ramsden, D.A. Specificity of the dRP/AP lyase of Ku promotes Non-homologous End Joining (NHEJ) fidelity at damaged ends. J. Biol. Chem.,  2012, 287(17), 13686-13693.
[81] 
Strande, N.T.; Carvajal-Garcia, J.; Hallett, R.A.; Waters, C.A.; Roberts, S.A.; Strom, C.; Kuhlman, B.; Ramsden, D.A. Requirements for 5'dRP/AP lyase activity in Ku. Nucleic Acids Res.,  2014, 42(17), 11136-11143.
[82] 
Chang, H.H.; Pannunzio, N.R.; Adachi, N.; Lieber, M.R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat. Rev. Mol. Cell Biol.,  2017, 18(8), 495-506.
[83] 
Uematsu, N.; Weterings, E.; Yano, K.; Morotomi-Yano, K.; Jakob, B.; Taucher-Scholz, G.; Mari, P.O.; Van Gent, D.C.; Chen, B.P.; Chen, D.J. Autophosphorylation of DNA-PKCS regulates its dynamics at DNA double-strand breaks. J. Cell Biol.,  2007, 177(2), 219-229.
[84] 
Gottlieb, T.M.; Jackson, S.P. The DNA-dependent protein kinase: Requirement for DNA ends and association with Ku antigen. Cell,  1993, 72(1), 131-142.
[85] 
Meek, K.; Dang, V.; Lees-Miller, S.P. DNA-PK: The means to justify the ends? Adv. Immunol.,  2008, 99, 33-58.
[86] 
Jovanovic, M.; Dynan, W.S. Terminal DNA structure and ATP influence binding parameters of the DNA-dependent protein kinase at an early step prior to DNA synapsis. Nucleic Acids Res.,  2006, 34(4), 1112-1120.
[87] 
Ma, Y.; Pannicke, U.; Schwarz, K.; Lieber, M.R. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell,  2002, 108(6), 781-794.
[88] 
Li, S.; Kanno, S.; Watanabe, R.; Ogiwara, H.; Kohno, T.; Watanabe, G.; Yasui, A.; Lieber, M.R. Polynucleotide kinase and aprataxin-like forkhead-associated protein (PALF) acts as both a single-stranded DNA endonuclease and a single-stranded DNA 3′ exonuclease and can participate in DNA end joining in a biochemical system. J. Biol. Chem.,  2011, 286(42), 36368-36377.
[89] 
Rass, E.; Grabarz, A.; Plo, I.; Gautier, J.; Bertrand, P.; Lopez, B.S. Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells. Nat. Struct. Mol. Biol.,  2009, 16(8), 819-824.
[90] 
Quennet, V.; Beucher, A.; Barton, O.; Takeda, S.; Löbrich, M. CtIP and MRN promote non-homologous end-joining of etoposide-induced DNA double-strand breaks in G1. Nucleic Acids Res.,  2011, 39(6), 2144-2152.
[91] 
Mahajan, K.N.; Nick McElhinny, S.A.; Mitchell, B.S.; Ramsden, D.A. Association of DNA polymerase μ (pol μ) with Ku and ligase IV: Role for pol μ in end-joining double-strand break repair. Mol. Cell. Biol.,  2002, 22(14), 5194-5202.
[92] 
Ramsden, D.A.; Asagoshi, K. DNA polymerases in nonhomologous end joining: Are there any benefits to standing out from the crowd? Environ. Mol. Mutagen.,  2012, 53(9), 741-751.
[93] 
Radhakrishnan, S.K.; Jette, N.; Lees-Miller, S.P. Non-homologous end joining: Emerging themes and unanswered questions. DNA Repair (Amst.),  2014, 17, 2-8.
[94] 
Ochi, T.; Blackford, A.N.; Coates, J.; Jhujh, S.; Mehmood, S.; Tamura, N.; Travers, J.; Wu, Q.; Draviam, V.M.; Robinson, C.V.; Blundell, T.L.; Jackson, S.P. DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote DNA double-strand break repair. Science,  2015, 347(6218), 185-188.
[95] 
Wu, P.Y.; Frit, P.; Meesala, S.; Dauvillier, S.; Modesti, M.; Andres, S.N.; Huang, Y.; Sekiguchi, J.; Calsou, P.; Salles, B.; Junop, M.S. Structural and functional interaction between the human DNA repair proteins DNA ligase IV and XRCC4. Mol. Cell. Biol.,  2009, 29(11), 3163-3172.
[96] 
Truong, L.N.; Li, Y.; Shi, L.Z.; Hwang, P.Y.; He, J.; Wang, H.; Razavian, N.; Berns, M.W.; Wu, X. Microhomology-mediated end joining and homologous recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells. Proc. Natl. Acad. Sci. USA,  2013, 110(19), 7720-7725.
[97] 
Zhang, Y.; Jasin, M. An essential role for CtIP in chromosomal translocation formation through an alternative end-joining pathway. Nat. Struct. Mol. Biol.,  2011, 18(1), 80-84.
[98] 
Soni, A.; Siemann, M.; Pantelias, G.E.; Iliakis, G. Marked contribution of alternative end-joining to chromosome-translocation-formation by stochastically induced DNA double-strand-breaks in G2-phase human cells. Mutat. Res. Genet. Toxicol. Environ. Mutagen.,  2015, 793, 2-8.
[99] 
Ottaviani, D.; LeCain, M.; Sheer, D. The role of microhomology in genomic structural variation. Trends Genet.,  2014, 30(3), 85-94.
[100] 
Frit, P.; Barboule, N.; Yuan, Y.; Gomez, D.; Calsou, P. Alternative end-joining pathway(s): Bricolage at DNA breaks. DNA Repair (Amst.),  2014, 17, 81-97.
[101] 
De Vos, M.; Schreiber, V.; Dantzer, F. The diverse roles and clinical relevance of PARPs in DNA damage repair: Current state of the art. Biochem. Pharmacol.,  2012, 84(2), 137-146.
[102] 
Wang, M.; Wu, W.; Wu, W.; Rosidi, B.; Zhang, L.; Wang, H.; Iliakis, G. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res.,  2006, 34(21), 6170-6182.
[103] 
Audebert, M.; Salles, B.; Calsou, P. 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.,  2004, 279(53), 55117-55126.
[104] 
Williams, G.J.; Lees-Miller, S.P.; Tainer, J.A. Mre11-Rad50-Nbs1 conformations and the control of sensing, signaling, and effector responses at DNA double-strand breaks. DNA Repair (Amst.),  2010, 9(12), 1299-1306.
[105] 
Williams, R.S.; Moncalian, G.; Williams, J.S.; Yamada, Y.; Limbo, O.; Shin, D.S.; Groocock, L.M.; Cahill, D.; Hitomi, C.; Guenther, G.; Moiani, D.; Carney, J.P.; Russell, P.; Tainer, J.A. Mre11 dimers coordinate DNA end bridging and nuclease processing in double-strand-break repair. Cell,  2008, 135(1), 97-109.
[106] 
Sartori, A.A.; Lukas, C.; Coates, J.; Mistrik, M.; Fu, S.; Bartek, J.; Baer, R.; Lukas, J.; Jackson, S.P. Human CtIP promotes DNA end resection. Nature,  2007, 450(7169), 509-514.
[107] 
Makharashvili, N.; Tubbs, A.T.; Yang, S.H.; Wang, H.; Barton, O.; Zhou, Y.; Deshpande, R.A.; Lee, J.H.; Lobrich, M.; Sleckman, B.P.; Wu, X.; Paull, T.T. Catalytic and noncatalytic roles of the CtIP endonuclease in double-strand break end resection. Mol. Cell,  2014, 54(6), 1022-1033.
[108] 
Mateos-Gomez, P.A.; Gong, F.; Nair, N.; Miller, K.M.; Lazzerini-Denchi, E.; Sfeir, A. Mammalian polymerase θ promotes alternative NHEJ and suppresses recombination. Nature,  2015, 518(7538), 254-257.
[109] 
Zahn, K.E.; Averill, A.M.; Aller, P.; Wood, R.D.; Doublié, S. Human DNA polymerase θ grasps the primer terminus to mediate DNA repair. Nat. Struct. Mol. Biol.,  2015, 22(4), 304-311.
[110] 
Kent, T.; Mateos-Gomez, P.A.; Sfeir, A.; Pomerantz, R.T. Polymerase θ is a robust terminal transferase that oscillates between three different mechanisms during end-joining. eLife,  2016, 5, 5.
[111] 
Kent, T.; Chandramouly, G.; McDevitt, S.M.; Ozdemir, A.Y.; Pomerantz, R.T. Mechanism of microhomology-mediated end-joining promoted by human DNA polymerase θ. Nat. Struct. Mol. Biol.,  2015, 22(3), 230-237.
[112] 
Wyatt, D.W.; Feng, W.; Conlin, M.P.; Yousefzadeh, M.J.; Roberts, S.A.; Mieczkowski, P.; Wood, R.D.; Gupta, G.P.; Ramsden, D.A. Essential roles for polymerase θ-mediated end joining in the repair of chromosome breaks. Mol. Cell,  2016, 63(4), 662-673.
[113] 
Wood, R.D.; Doublié, S. DNA polymerase θ (POLQ), double-strand break repair, and cancer. DNA Repair (Amst.),  2016, 44, 22-32.
[114] 
Newman, J.A.; Cooper, C.D.; Aitkenhead, H.; Gileadi, O. Structure of the helicase domain of DNA polymerase theta reveals a possible role in the microhomology-mediated end-joining pathway. Structure,  2015, 23(12), 2319-2330.
[115] 
Ahmad, A.; Robinson, A.R.; Duensing, A.; Van Drunen, E.; Beverloo, H.B.; Weisberg, D.B.; Hasty, P.; Hoeijmakers, J.H.; Niedernhofer, L.J. ERCC1-XPF endonuclease facilitates DNA double-strand break repair. Mol. Cell. Biol.,  2008, 28(16), 5082-5092.
[116] 
McNeil, E.M.; Melton, D.W. DNA repair endonuclease ERCC1-XPF as a novel therapeutic target to overcome chemoresistance in cancer therapy. Nucleic Acids Res.,  2012, 40(20), 9990-10004.
[117] 
Sharma, S.; Javadekar, S.M.; Pandey, M.; Srivastava, M.; Kumari, R.; Raghavan, S.C. Homology and enzymatic requirements of microhomology-dependent alternative end joining. Cell Death Dis.,  2015, 6, e1697.
[118] 
Liang, L.; Deng, L.; Chen, Y.; Li, G.C.; Shao, C.; Tischfield, J.A. Modulation of DNA end joining by nuclear proteins. J. Biol. Chem.,  2005, 280(36), 31442-31449.
[119] 
Wu, X.; Wilson, T.E.; Lieber, M.R. A role for FEN-1 in non-homologous DNA end joining: The order of strand annealing and nucleolytic processing events. Proc. Natl. Acad. Sci. USA,  1999, 96(4), 1303-1308.
[120] 
Liang, L.; Deng, L.; Nguyen, S.C.; Zhao, X.; Maulion, C.D.; Shao, C.; Tischfield, J.A. Human DNA ligases I and III, but not ligase IV, are required for microhomology-mediated end joining of DNA double-strand breaks. Nucleic Acids Res.,  2008, 36(10), 3297-3310.
[121] 
Paul, K.; Wang, M.; Mladenov, E.; Bencsik-Theilen, A.; Bednar, T.; Wu, W.; Arakawa, H.; Iliakis, G. DNA ligases I and III cooperate in alternative non-homologous end-joining in vertebrates. PLoS One,  2013, 8(3), e59505.
[122] 
Bhargava, R.; Onyango, D.O.; Stark, J.M. Regulation of single-strand annealing and its role in genome maintenance. Trends Genet.,  2016, 32(9), 566-575.
[123] 
Moynahan, M.E.; Jasin, M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat. Rev. Mol. Cell Biol.,  2010, 11(3), 196-207.
[124] 
Jasin, M.; Rothstein, R. Repair of strand breaks by homologous recombination. Cold Spring Harb. Perspect. Biol.,  2013, 5(11), a012740.
[125] 
San Filippo, J.; Sung, P.; Klein, H. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem.,  2008, 77, 229-257.
[126] 
Heyer, W.D.; Ehmsen, K.T.; Liu, J. Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet.,  2010, 44, 113-139.
[127] 
Lamarche, B.J.; Orazio, N.I.; Weitzman, M.D. The MRN complex in double-strand break repair and telomere maintenance. FEBS Lett.,  2010, 584(17), 3682-3695.
[128] 
Symington, L.S. Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair. Microbiol. Mol. Biol. Rev.,  2002, 66(4), 630-670.
[129] 
Mimitou, E.P.; Symington, L.S. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature,  2008, 455(7214), 770-774.
[130] 
Haring, S.J.; Mason, A.C.; Binz, S.K.; Wold, M.S. Cellular functions of human RPA1. Multiple roles of domains in replication, repair, and checkpoints. J. Biol. Chem.,  2008, 283(27), 19095-19111.
[131] 
Jensen, R.B.; Ozes, A.; Kim, T.; Estep, A.; Kowalczykowski, S.C. BRCA2 is epistatic to the RAD51 paralogs in response to DNA damage. DNA Repair (Amst.),  2013, 12(4), 306-311.
[132] 
Yonetani, Y.; Hochegger, H.; Sonoda, E.; Shinya, S.; Yoshikawa, H.; Takeda, S.; Yamazoe, M. Differential and collaborative actions of Rad51 paralog proteins in cellular response to DNA damage. Nucleic Acids Res.,  2005, 33(14), 4544-4552.
[133] 
Sigurdsson, S.; Van Komen, S.; Bussen, W.; Schild, D.; Albala, J.S.; Sung, P. Mediator function of the human Rad51B-Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange. Genes Dev.,  2001, 15(24), 3308-3318.
[134] 
Chun, J.; Buechelmaier, E.S.; Powell, S.N. Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway. Mol. Cell. Biol.,  2013, 33(2), 387-395.
[135] 
Stoppa-Lyonnet, D. The biological effects and clinical implications of BRCA mutations: Where do we go from here? Eur. J. Hum. Genet.,  2016, 24(Suppl. 1), S3-S9.
[136] 
Greenberg, R.A.; Sobhian, B.; Pathania, S.; Cantor, S.B.; Nakatani, Y.; Livingston, D.M. Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes. Genes Dev.,  2006, 20(1), 34-46.
[137] 
Liu, J.; Doty, T.; Gibson, B.; Heyer, W.D. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat. Struct. Mol. Biol.,  2010, 17(10), 1260-1262.
[138] 
Zhang, H.; Tombline, G.; Weber, B.L. BRCA1, BRCA2, and DNA damage response: Collision or collusion? Cell,  1998, 92(4), 433-436.
[139] 
Fradet-Turcotte, A.; Sitz, J.; Grapton, D.; Orthwein, A. BRCA2 functions: From DNA repair to replication fork stabilization. Endocr. Relat. Cancer,  2016, 23(10), T1-T17.
[140] 
Sy, S.M.; Huen, M.S.; Chen, J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc. Natl. Acad. Sci. USA,  2009, 106(17), 7155-7160.
[141] 
Sy, S.M.; Huen, M.S.; Zhu, Y.; Chen, J. PALB2 regulates recombinational repair through chromatin association and oligomerization. J. Biol. Chem.,  2009, 284(27), 18302-18310.
[142] 
Zhang, F.; Ma, J.; Wu, J.; Ye, L.; Cai, H.; Xia, B.; Yu, X. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol.,  2009, 19(6), 524-529.
[143] 
Pauty, J.; Rodrigue, A.; Couturier, A.; Buisson, R.; Masson, J.Y. Exploring the roles of PALB2 at the crossroads of DNA repair and cancer. Biochem. J.,  2014, 460(3), 331-342.
[144] 
Onaka, A.T.; Toyofuku, N.; Inoue, T.; Okita, A.K.; Sagawa, M.; Su, J.; Shitanda, T.; Matsuyama, R.; Zafar, F.; Takahashi, T.S.; Masukata, H.; Nakagawa, T. Rad51 and Rad54 promote noncrossover recombination between centromere repeats on the same chromatid to prevent isochromosome formation. Nucleic Acids Res.,  2016, 44(22), 10744-10757.
[145] 
Forget, A.L.; Kowalczykowski, S.C. Single-molecule imaging brings Rad51 nucleoprotein filaments into focus. Trends Cell Biol.,  2010, 20(5), 269-276.
[146] 
Szostak, J.W.; Orr-Weaver, T.L.; Rothstein, R.J.; Stahl, F.W. The double-strand-break repair model for recombination. Cell,  1983, 33(1), 25-35.
[147] 
Van Den Bosch, M.; Lohman, P.H.; Pastink, A. DNA double-strand break repair by homologous recombination. Biol. Chem.,  2002, 383(6), 873-892.
[148] 
Maloisel, L.; Fabre, F.; Gangloff, S. DNA polymerase delta is preferentially recruited during homologous recombination to promote heteroduplex DNA extension. Mol. Cell. Biol.,  2008, 28(4), 1373-1382.
[149] 
Nassif, N.; Penney, J.; Pal, S.; Engels, W.R.; Gloor, G.B. Efficient copying of nonhomologous sequences from ectopic sites via P-element-induced gap repair. Mol. Cell. Biol.,  1994, 14(3), 1613-1625.
[150] 
Pâques, F.; Haber, J.E. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev.,  1999, 63(2), 349-404.
[151] 
Benson, F.E.; Baumann, P.; West, S.C. Synergistic actions of Rad51 and Rad52 in recombination and DNA repair. Nature,  1998, 391(6665), 401-404.
[152] 
Ma, C.J.; Kwon, Y.; Sung, P.; Greene, E.C. Human RAD52 interactions with replication protein A and the RAD51 presynaptic complex. J. Biol. Chem.,  2017, 292(28), 11702-11713.
[153] 
New, J.H.; Sugiyama, T.; Zaitseva, E.; Kowalczykowski, S.C. Rad52 protein stimulates DNA strand exchange by Rad51 and replication protein A. Nature,  1998, 391(6665), 407-410.
[154] 
Gibb, B.; Ye, L.F.; Kwon, Y.; Niu, H.; Sung, P.; Greene, E.C. Protein dynamics during presynaptic-complex assembly on individual single-stranded DNA molecules. Nat. Struct. Mol. Biol.,  2014, 21(10), 893-900.
[155] 
Krogh, B.O.; Symington, L.S. Recombination proteins in yeast. Annu. Rev. Genet.,  2004, 38, 233-271.
[156] 
Rijkers, T.; Van Den Ouweland, J.; Morolli, B.; Rolink, A.G.; Baarends, W.M.; Van Sloun, P.P.; Lohman, P.H.; Pastink, A. Targeted inactivation of mouse RAD52 reduces homologous recombination but not resistance to ionizing radiation. Mol. Cell. Biol.,  1998, 18(11), 6423-6429.
[157] 
Yamaguchi-Iwai, Y.; Sonoda, E.; Buerstedde, J.M.; Bezzubova, O.; Morrison, C.; Takata, M.; Shinohara, A.; Takeda, S. Homologous recombination, but not DNA repair, is reduced in vertebrate cells deficient in RAD52. Mol. Cell. Biol.,  1998, 18(11), 6430-6435.
[158] 
Kumar, A.; Purohit, S.; Sharma, N.K.; Aberrant, D.N. Aberrant DNA double-strand break repair threads in breast carcinoma: Orchestrating genomic insult survival. J. Cancer Prev.,  2016, 21(4), 227-234.
[159] 
Lim, D.S.; Hasty, P. A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53. Mol. Cell. Biol.,  1996, 16(12), 7133-7143.
[160] 
Sonoda, E.; Sasaki, M.S.; Buerstedde, J.M.; Bezzubova, O.; Shinohara, A.; Ogawa, H.; Takata, M.; Yamaguchi-Iwai, Y.; Takeda, S. Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death. EMBO J.,  1998, 17(2), 598-608.
[161] 
Feng, Z.; Scott, S.P.; Bussen, W.; Sharma, G.G.; Guo, G.; Pandita, T.K.; Powell, S.N. Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc. Natl. Acad. Sci. USA,  2011, 108(2), 686-691.
[162] 
O’Neil, N.J.; Bailey, M.L.; Hieter, P. Synthetic lethality and cancer. Nat. Rev. Genet.,  2017, 18(10), 613-623.
[163] 
Farmer, H.; McCabe, N.; Lord, C.J.; Tutt, A.N.; Johnson, D.A.; Richardson, T.B.; Santarosa, M.; Dillon, K.J.; Hickson, I.; Knights, C.; Martin, N.M.; Jackson, S.P.; Smith, G.C.; Ashworth, A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature,  2005, 434(7035), 917-921.
[164] 
Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature,  2005, 434(7035), 913-917.
[165] 
Reynolds, P.; Cooper, S.; Lomax, M.; O’Neill, P. Disruption of PARP1 function inhibits base excision repair of a sub-set of DNA lesions. Nucleic Acids Res.,  2015, 43(8), 4028-4038.
[166] 
Dantzer, F.; De La Rubia, G.; Ménissier-De Murcia, J.; Hostomsky, Z.; De Murcia, G.; Schreiber, V. Base excision repair is impaired in mammalian cells lacking Poly(ADP-ribose) polymerase-1. Biochemistry,  2000, 39(25), 7559-7569.
[167] 
Simbulan-Rosenthal, C.M.; Haddad, B.R.; Rosenthal, D.S.; Weaver, Z.; Coleman, A.; Luo, R.; Young, H.M.; Wang, Z.Q.; Ried, T.; Smulson, M.E. Chromosomal aberrations in PARP(-/-) mice: genome stabilization in immortalized cells by reintroduction of poly(ADP-ribose) polymerase cDNA. Proc. Natl. Acad. Sci. USA,  1999, 96(23), 13191-13196.
[168] 
De Murcia, J.M.; Niedergang, C.; Trucco, C.; Ricoul, M.; Dutrillaux, B.; Mark, M.; Oliver, F.J.; Masson, M.; Dierich, A.; LeMeur, M.; Walztinger, C.; Chambon, P.; De Murcia, G. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc. Natl. Acad. Sci. USA,  1997, 94(14), 7303-7307.
[169] 
Audeh, M.W.; Carmichael, J.; Penson, R.T.; Friedlander, M.; Powell, B.; Bell-McGuinn, K.M.; Scott, C.; Weitzel, J.N.; Oaknin, A.; Loman, N.; Lu, K.; Schmutzler, R.K.; Matulonis, U.; Wickens, M.; Tutt, A. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: A proof-of-concept trial. Lancet,  2010, 376(9737), 245-251.
[170] 
Yap, T.A.; Sandhu, S.K.; Carden, C.P.; de Bono, J.S. Poly(ADP-ribose) polymerase (PARP) inhibitors: Exploiting a synthetic lethal strategy in the clinic. CA Cancer J. Clin.,  2011, 61(1), 31-49.
[171] 
Brown, J.S.; Kaye, S.B.; Yap, T.A. PARP inhibitors: The race is on. Br. J. Cancer,  2016, 114(7), 713-715.
[172] 
Hopkins, T.A.; Shi, Y.; Rodriguez, L.E.; Solomon, L.R.; Donawho, C.K.; DiGiammarino, E.L.; Panchal, S.C.; Wilsbacher, J.L.; Gao, W.; Olson, A.M.; Stolarik, D.F.; Osterling, D.J.; Johnson, E.F.; Maag, D. Mechanistic dissection of PARP1 trapping and the impact on in vivo tolerability and efficacy of PARP inhibitors. Mol. Cancer Res.,  2015, 13(11), 1465-1477.
[173] 
Helleday, T. The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings. Mol. Oncol.,  2011, 5(4), 387-393.
[174] 
Malyuchenko, N.V.; Kotova, E.Y.; Kulaeva, O.I.; Kirpichnikov, M.P.; Studitskiy, V.M. PARP1 Inhibitors: Antitumor drug design. Acta Nat.,  2015, 7(3), 27-37.
[175] 
Mao, Z.; Jiang, Y.; Liu, X.; Seluanov, A.; Gorbunova, V. DNA repair by homologous recombination, but not by nonhomologous end joining, is elevated in breast cancer cells. Neoplasia,  2009, 11(7), 683-691.
[176] 
Risch, H.A.; McLaughlin, J.R.; Cole, D.E.; Rosen, B.; Bradley, L.; Kwan, E.; Jack, E.; Vesprini, D.J.; Kuperstein, G.; Abrahamson, J.L.; Fan, I.; Wong, B.; Narod, S.A. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am. J. Hum. Genet.,  2001, 68(3), 700-710.
[177] 
Frey, M.K.; Pothuri, B. Homologous Recombination Deficiency (HRD) testing in ovarian cancer clinical practice: A review of the literature. Gynecol. Oncol. Res. Pract.,  2017, 4, 4.
[178] 
Tung, N.; Battelli, C.; Allen, B.; Kaldate, R.; Bhatnagar, S.; Bowles, K.; Timms, K.; Garber, J.E.; Herold, C.; Ellisen, L.; Krejdovsky, J.; DeLeonardis, K.; Sedgwick, K.; Soltis, K.; Roa, B.; Wenstrup, R.J.; Hartman, A.R. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer,  2015, 121(1), 25-33.
[179] 
Zhen, D.B.; Rabe, K.G.; Gallinger, S.; Syngal, S.; Schwartz, A.G.; Goggins, M.G.; Hruban, R.H.; Cote, M.L.; McWilliams, R.R.; Roberts, N.J.; Cannon-Albright, L.A.; Li, D.; Moyes, K.; Wenstrup, R.J.; Hartman, A.R.; Seminara, D.; Klein, A.P.; Petersen, G.M. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: A PACGENE study. Genet. Med.,  2015, 17(7), 569-577.
[180] 
Rosen, E.M.; Fan, S.; Goldberg, I.D. BRCA1 and prostate cancer. Cancer Invest.,  2001, 19(4), 396-412.
[181] 
Mai, P.L.; Chatterjee, N.; Hartge, P.; Tucker, M.; Brody, L.; Struewing, J.P.; Wacholder, S. Potential excess mortality in BRCA1/2 mutation carriers beyond breast, ovarian, prostate, and pancreatic cancers, and melanoma. PLoS One,  2009, 4(3), e4812.
[182] 
Deutsch, E.; Jarrousse, S.; Buet, D.; Dugray, A.; Bonnet, M.L.; Vozenin-Brotons, M.C.; Guilhot, F.; Turhan, A.G.; Feunteun, J.; Bourhis, J. Down-regulation of BRCA1 in BCR-ABL-expressing hematopoietic cells. Blood,  2003, 101(11), 4583-4588.
[183] 
Podszywalow-Bartnicka, P.; Wolczyk, M.; Kusio-Kobialka, M.; Wolanin, K.; Skowronek, K.; Nieborowska-Skorska, M.; Dasgupta, Y.; Skorski, T.; Piwocka, K. Downregulation of BRCA1 protein in BCR-ABL1 leukemia cells depends on stress-triggered TIAR-mediated suppression of translation. Cell Cycle,  2014, 13(23), 3727-3741.
[184] 
Chan, N.; Bristow, R.G. “Contextual” synthetic lethality and/or loss of heterozygosity: Tumor hypoxia and modification of DNA repair. Clin. Cancer Res.,  2010, 16(18), 4553-4560.
[185] 
Turner, N.; Tutt, A.; Ashworth, A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat. Rev. Cancer,  2004, 4(10), 814-819.
[186] 
Eppink, B.; Krawczyk, P.M.; Stap, J.; Kanaar, R. Hyperthermia-induced DNA repair deficiency suggests novel therapeutic anti-cancer strategies. Int. J. Hyperthermia,  2012, 28(6), 509-517.
[187] 
Krawczyk, P.M.; Eppink, B.; Essers, J.; Stap, J.; Rodermond, H.; Odijk, H.; Zelensky, A.; Van Bree, C.; Stalpers, L.J.; Buist, M.R.; Soullié, T.; Rens, J.; Verhagen, H.J.; O’Connor, M.J.; Franken, N.A.; Ten Hagen, T.L.; Kanaar, R.; Aten, J.A. Mild hyperthermia inhibits homologous recombination, induces BRCA2 degradation, and sensitizes cancer cells to poly (ADP-ribose) polymerase-1 inhibition. Proc. Natl. Acad. Sci. USA,  2011, 108(24), 9851-9856.
[188] 
Oei, A.L.; Ahire, V.R.; Van Leeuwen, C.M.; Ten Cate, R.; Stalpers, L.J.; Crezee, J.; Kok, H.P.; Franken, N.A. Enhancing radiosensitisation of BRCA2-proficient and BRCA2-deficient cell lines with hyperthermia and PARP1-i. Int. J. Hyperthermia,  2017, 34(1), 1-10.
[189] 
Oei, A.L.; Van Leeuwen, C.M.; Ahire, V.R.; Rodermond, H.M.; Ten Cate, R.; Westermann, A.M.; Stalpers, L.J.; Crezee, J.; Kok, H.P.; Krawczyk, P.M.; Kanaar, R.; Franken, N.A. Enhancing synthetic lethality of PARP-inhibitor and cisplatin in BRCA-proficient tumour cells with hyperthermia. Oncotarget,  2017, 8(17), 28116-28124.
[190] 
Antoniou, A.C.; Foulkes, W.D.; Tischkowitz, M. Breast-cancer risk in families with mutations in PALB2. N. Engl. J. Med.,  2014, 371(17), 1651-1652.
[191] 
Rahman, N.; Seal, S.; Thompson, D.; Kelly, P.; Renwick, A.; Elliott, A.; Reid, S.; Spanova, K.; Barfoot, R.; Chagtai, T.; Jayatilake, H.; McGuffog, L.; Hanks, S.; Evans, D.G.; Eccles, D.; Easton, D.F.; Stratton, M.R.; Stratton, M.R. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet.,  2007, 39(2), 165-167.
[192] 
Ratajska, M.; Antoszewska, E.; Piskorz, A.; Brozek, I.; Borg, Å.; Kusmierek, H.; Biernat, W. Limon, J. Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast Cancer Res. Treat.,  2012, 131(1), 89-97.
[193] 
Irminger-Finger, I.; Ratajska, M.; Pilyugin, M. New concepts on BARD1: Regulator of BRCA pathways and beyond. Int. J. Biochem. Cell Biol.,  2016, 72, 1-17.
[194] 
Sopik, V.; Akbari, M.R.; Narod, S.A. Genetic testing for RAD51C mutations: In the clinic and community. Clin. Genet.,  2015, 88(4), 303-312.
[195] 
Meindl, A.; Hellebrand, H.; Wiek, C.; Erven, V.; Wappenschmidt, B.; Niederacher, D.; Freund, M.; Lichtner, P.; Hartmann, L.; Schaal, H.; Ramser, J.; Honisch, E.; Kubisch, C.; Wichmann, H.E.; Kast, K.; Deissler, H.; Engel, C.; Müller-Myhsok, B.; Neveling, K.; Kiechle, M.; Mathew, C.G.; Schindler, D.; Schmutzler, R.K.; Hanenberg, H. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat. Genet.,  2010, 42(5), 410-414.
[196] 
Loveday, C.; Turnbull, C.; Ramsay, E.; Hughes, D.; Ruark, E.; Frankum, J.R.; Bowden, G.; Kalmyrzaev, B.; Warren-Perry, M.; Snape, K.; Adlard, J.W.; Barwell, J.; Berg, J.; Brady, A.F.; Brewer, C.; Brice, G.; Chapman, C.; Cook, J.; Davidson, R.; Donaldson, A.; Douglas, F.; Greenhalgh, L.; Henderson, A.; Izatt, L.; Kumar, A.; Lalloo, F.; Miedzybrodzka, Z.; Morrison, P.J.; Paterson, J.; Porteous, M.; Rogers, M.T.; Shanley, S.; Walker, L.; Eccles, D.; Evans, D.G.; Renwick, A.; Seal, S.; Lord, C.J.; Ashworth, A.; Reis-Filho, J.S.; Antoniou, A.C.; Rahman, N.; Rahman, N. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat. Genet.,  2011, 43(9), 879-882.
[197] 
McCabe, N.; Turner, N.C.; Lord, C.J.; Kluzek, K.; Bialkowska, A.; Swift, S.; Giavara, S.; O’Connor, M.J.; Tutt, A.N.; Zdzienicka, M.Z.; Smith, G.C.; Ashworth, A. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res.,  2006, 66(16), 8109-8115.
[198] 
Hiramoto, T.; Nakanishi, T.; Sumiyoshi, T.; Fukuda, T.; Matsuura, S.; Tauchi, H.; Komatsu, K.; Shibasaki, Y.; Inui, H.; Watatani, M.; Yasutomi, M.; Sumii, K.; Kajiyama, G.; Kamada, N.; Miyagawa, K.; Kamiya, K. Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer. Oncogene,  1999, 18(22), 3422-3426.
[199] 
McAndrew, E.N.; Lepage, C.C.; McManus, K.J. The synthetic lethal killing of RAD54B-deficient colorectal cancer cells by PARP1 inhibition is enhanced with SOD1 inhibition. Oncotarget,  2016, 7(52), 87417-87430.
[200] 
Wesoly, J.; Agarwal, S.; Sigurdsson, S.; Bussen, W.; Van Komen, S.; Qin, J.; Van Steeg, H.; Van Benthem, J.; Wassenaar, E.; Baarends, W.M.; Ghazvini, M.; Tafel, A.A.; Heath, H.; Galjart, N.; Essers, J.; Grootegoed, J.A.; Arnheim, N.; Bezzubova, O.; Buerstedde, J.M.; Sung, P.; Kanaar, R. Differential contributions of mammalian Rad54 paralogs to recombination, DNA damage repair, and meiosis. Mol. Cell. Biol.,  2006, 26(3), 976-989.
[201] 
McManus, K.J.; Barrett, I.J.; Nouhi, Y.; Hieter, P. Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing. Proc. Natl. Acad. Sci. USA,  2009, 106(9), 3276-3281.
[202] 
Oh, S.; Wang, Y.; Zimbric, J.; Hendrickson, E.A. Human LIGIV is synthetically lethal with the loss of Rad54B-dependent recombination and is required for certain chromosome fusion events induced by telomere dysfunction. Nucleic Acids Res.,  2013, 41(3), 1734-1749.
[203] 
Czyż, M.; Toma, M.; Gajos-Michniewicz, A.; Majchrzak, K.; Hoser, G.; Szemraj, J.; Nieborowska-Skorska, M.; Cheng, P.; Gritsyuk, D.; Levesque, M.; Dummer, R.; Sliwinski, T.; Skorski, T. PARP1 inhibitor olaparib (Lynparza) exerts synthetic lethal effect against ligase 4-deficient melanomas. Oncotarget,  2016, 7(46), 75551-75560.
[204] 
Newman, E.A.; Lu, F.; Bashllari, D.; Wang, L.; Opipari, A.W.; Castle, V.P. Alternative NHEJ pathway components are therapeutic targets in high-risk neuroblastoma. Mol. Cancer Res.,  2015, 13(3), 470-482.
[205] 
Fan, J.; Li, L.; Small, D.; Rassool, F. Cells expressing FLT3/ITD mutations exhibit elevated repair errors generated through alternative NHEJ pathways: Implications for genomic instability and therapy. Blood,  2010, 116(24), 5298-5305.
[206] 
Gafencu, G.A.; Tomuleasa, C.I.; Ghiaur, G. PARP inhibitors in acute myeloid leukaemia therapy: How a synthetic lethality approach can be a valid therapeutic alternative. Med. Hypotheses,  2017, 104, 30-34.
[207] 
Narne, P.; Pandey, V.; Simhadri, P.K.; Phanithi, P.B. Poly(ADP-ribose)polymerase-1 hyperactivation in neurodegenerative diseases: The death knell tolls for neurons. Semin. Cell Dev. Biol.,  2017, 63, 154-166.
[208] 
Fisher, A.E.; Hochegger, H.; Takeda, S.; Caldecott, K.W. Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase. Mol. Cell. Biol.,  2007, 27(15), 5597-5605.
[209] 
Slade, D.; Dunstan, M.S.; Barkauskaite, E.; Weston, R.; Lafite, P.; Dixon, N.; Ahel, M.; Leys, D.; Ahel, I. The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase. Nature,  2011, 477(7366), 616-620.
[210] 
Koh, D.W.; Lawler, A.M.; Poitras, M.F.; Sasaki, M.; Wattler, S.; Nehls, M.C.; Stöger, T.; Poirier, G.G.; Dawson, V.L.; Dawson, T.M. Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality. Proc. Natl. Acad. Sci. USA,  2004, 101(51), 17699-17704.
[211] 
Cortes, U.; Tong, W.M.; Coyle, D.L.; Meyer-Ficca, M.L.; Meyer, R.G.; Petrilli, V.; Herceg, Z.; Jacobson, E.L.; Jacobson, M.K.; Wang, Z.Q. Depletion of the 110-kilodalton isoform of poly(ADP-ribose) glycohydrolase increases sensitivity to genotoxic and endotoxic stress in mice. Mol. Cell. Biol.,  2004, 24(16), 7163-7178.
[212] 
Hanai, S.; Kanai, M.; Ohashi, S.; Okamoto, K.; Yamada, M.; Takahashi, H.; Miwa, M. Loss of poly(ADP-ribose) glycohydrolase causes progressive neurodegeneration in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA,  2004, 101(1), 82-86.
[213] 
Fathers, C.; Drayton, R.M.; Solovieva, S.; Bryant, H.E. Inhibition of poly(ADP-ribose) glycohydrolase (PARG) specifically kills BRCA2-deficient tumor cells. Cell Cycle,  2012, 11(5), 990-997.
[214] 
Gravells, P.; Grant, E.; Smith, K.M.; James, D.I.; Bryant, H.E. Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase. DNA Repair (Amst.),  2017, 52, 81-91.
[215] 
Noll, A.; Illuzzi, G.; Amé, J.C.; Dantzer, F.; Schreiber, V. PARG deficiency is neither synthetic lethal with BRCA1 nor PTEN deficiency. Cancer Cell Int.,  2016, 16, 53.
[216] 
Gibson, B.A.; Kraus, W.L. New insights into the molecular and cellular functions of poly(ADP-ribose) and PARPs. Nat. Rev. Mol. Cell Biol.,  2012, 13(7), 411-424.
[217] 
Ji, Y.; Tulin, A.V. The roles of PARP1 in gene control and cell differentiation. Curr. Opin. Genet. Dev.,  2010, 20(5), 512-518.
[218] 
Wahlberg, E.; Karlberg, T.; Kouznetsova, E.; Markova, N.; Macchiarulo, A.; Thorsell, A.G.; Pol, E.; Frostell, Å.; Ekblad, T.; Öncü, D.; Kull, B.; Robertson, G.M.; Pellicciari, R.; Schüler, H.; Weigelt, J. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat. Biotechnol.,  2012, 30(3), 283-288.
[219] 
Lok, B.H.; Carley, A.C.; Tchang, B.; Powell, S.N. RAD52 inactivation is synthetically lethal with deficiencies in BRCA1 and PALB2 in addition to BRCA2 through RAD51-mediated homologous recombination. Oncogene,  2013, 32(30), 3552-3558.
[220] 
Lok, B.H.; Powell, S.N. Molecular pathways: Understanding the role of Rad52 in homologous recombination for therapeutic advancement. Clin. Cancer Res.,  2012, 18(23), 6400-6406.
[221] 
Tarsounas, M.; Davies, D.; West, S.C. BRCA2-dependent and independent formation of RAD51 nuclear foci. Oncogene,  2003, 22(8), 1115-1123.
[222] 
Chandramouly, G.; McDevitt, S.; Sullivan, K.; Kent, T.; Luz, A.; Glickman, J.F.; Andrake, M.; Skorski, T.; Pomerantz, R.T. Small-molecule disruption of RAD52 rings as a mechanism for precision medicine in BRCA-deficient cancers. Chem. Biol.,  2015, 22(11), 1491-1504.
[223] 
Huang, F.; Goyal, N.; Sullivan, K.; Hanamshet, K.; Patel, M.; Mazina, O.M.; Wang, C.X.; An, W.F.; Spoonamore, J.; Metkar, S.; Emmitte, K.A.; Cocklin, S.; Skorski, T.; Mazin, A.V. Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors. Nucleic Acids Res.,  2016, 44(9), 4189-4199.
[224] 
Sullivan, K.; Cramer-Morales, K.; McElroy, D.L.; Ostrov, D.A.; Haas, K.; Childers, W.; Hromas, R.; Skorski, T. Identification of a small molecule inhibitor of RAD52 by structure-based selection. PLoS One,  2016, 11(1), e0147230.
[225] 
Cramer-Morales, K.; Nieborowska-Skorska, M.; Scheibner, K.; Padget, M.; Irvine, D.A.; Sliwinski, T.; Haas, K.; Lee, J.; Geng, H.; Roy, D.; Slupianek, A.; Rassool, F.V.; Wasik, M.A.; Childers, W.; Copland, M.; Müschen, M.; Civin, C.I.; Skorski, T. Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. Blood,  2013, 122(7), 1293-1304.
[226] 
Lord, C.J.; Tutt, A.N.; Ashworth, A. Synthetic lethality and cancer therapy: Lessons learned from the development of PARP inhibitors. Annu. Rev. Med.,  2015, 66, 455-470.
[227] 
Lee, J.M.; Ledermann, J.A.; Kohn, E.C. PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann. Oncol.,  2014, 25(1), 32-40.
[228] 
Papeo, G.; Forte, B.; Orsini, P.; Perrera, C.; Posteri, H.; Scolaro, A.; Montagnoli, A. Poly(ADP-ribose) polymerase inhibition in cancer therapy: Are we close to maturity? Expert Opin. Ther. Pat.,  2009, 19(10), 1377-1400.
[229] 
Purnell, M.R.; Whish, W.J. Novel inhibitors of poly(ADP-ribose) synthetase. Biochem. J.,  1980, 185(3), 775-777.
[230] 
Sebolt-Leopold, J.S.; Scavone, S.V. Enhancement of alkylating agent activity in vitro by PD 128763, a potent poly(ADP-ribose) synthetase inhibitor. Int. J. Radiat. Oncol. Biol. Phys.,  1992, 22(3), 619-621.
[231] 
Ruf, A.; De Murcia, G.; Schulz, G.E. Inhibitor and NAD+ binding to poly(ADP-ribose) polymerase as derived from crystal structures and homology modeling. Biochemistry,  1998, 37(11), 3893-3900.
[232] 
Marsischky, G.T.; Wilson, B.A.; Collier, R.J. Role of glutamic acid 988 of human poly-ADP-ribose polymerase in polymer formation. Evidence for active site similarities to the ADP-ribosylating toxins. J. Biol. Chem.,  1995, 270(7), 3247-3254.
[233] 
Shen, Y.; Rehman, F.L.; Feng, Y.; Boshuizen, J.; Bajrami, I.; Elliott, R.; Wang, B.; Lord, C.J.; Post, L.E.; Ashworth, A. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin. Cancer Res.,  2013, 19(18), 5003-5015.
[234] 
 Food and Drug Administration. Drug approvals and databases:
Rucaparib (Rubraca).
                    www.fda.gov/drugs/informationondrugs/approveddrugs/ucm533891.htm
                (accessed July 27, 2017).
[235] 
 Food and Drug Administration. Drug approvals and databases:
Niraparib (Zejula).
                    www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm548487.htm
                (accessed July 27, 2017).
[236] 
Gunderson, C.C.; Moore, K.N. BRACAnalysis CDx as a companion diagnostic tool for Lynparza. Expert Rev. Mol. Diagn.,  2015, 15(9), 1111-1116.
[237] 
Jenner, Z.B.; Sood, A.K.; Coleman, R.L. Evaluation of rucaparib and companion diagnostics in the PARP inhibitor landscape for recurrent ovarian cancer therapy. Future Oncol.,  2016, 12(12), 1439-1456.
[238] 
 MyRiad. Technical Specifications: BRACAnalysis CDx®.
                    myriadweb.
s3.amazonaws.com/myriadpro.com/Test%20Request%
20Forms/CTRL%200538%20rev2%20BRACAnalysis%
20CDx%20Technical%20Information_FINAL%20PM
RC%20APPROVED.pdf
                (accessed August 08, 2017).
[239] 
 myriad-web.s3.amazonaws.com/myChoice/downloads/ myChoiceHRDTechSpecs.pdf
                (Accessed June, 2017).
[240] 
Frampton, G.M.; Fichtenholtz, A.; Otto, G.A.; Wang, K.; Downing, S.R.; He, J.; Schnall-Levin, M.; White, J.; Sanford, E.M.; An, P.; Sun, J.; Juhn, F.; Brennan, K.; Iwanik, K.; Maillet, A.; Buell, J.; White, E.; Zhao, M.; Balasubramanian, S.; Terzic, S.; Richards, T.; Banning, V.; Garcia, L.; Mahoney, K.; Zwirko, Z.; Donahue, A.; Beltran, H.; Mosquera, J.M.; Rubin, M.A.; Dogan, S.; Hedvat, C.V.; Berger, M.F.; Pusztai, L.; Lechner, M.; Boshoff, C.; Jarosz, M.; Vietz, C.; Parker, A.; Miller, V.A.; Ross, J.S.; Curran, J.; Cronin, M.T.; Stephens, P.J.; Lipson, D.; Yelensky, R. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat. Biotechnol.,  2013, 31(11), 1023-1031.
[241] 
 Foundation Medicine Inc. Technical Specifications: FoundationOne
®.
                    assets.contentful.com/vhribv12lmne/6YRrchSINOeSu48YwuesoY/caeec492925a7d569ce4e070866f709b/F1_-_Tech_Specs.pdf
                (accessed August 08, 2017).
[242] 
Venere, M. A GEMA of a personalized medicine strategy. Sci. Transl. Med.,  2017, 9(391), eaan4294.
[243] 
Yuan, Z.; Chen, J.; Li, W.; Li, D.; Chen, C.; Gao, C.; Jiang, Y. PARP inhibitors as antitumor agents: a patent update (2013-2015). Expert Opin. Ther. Pat.,  2017, 27(3), 363-382.
[244] 
Menear, K.A.; Adcock, C.; Boulter, R.; Cockcroft, X.L.; Copsey, L.; Cranston, A.; Dillon, K.J.; Drzewiecki, J.; Garman, S.; Gomez, S.; Javaid, H.; Kerrigan, F.; Knights, C.; Lau, A.; Loh, V.M., Jr; Matthews, I.T.; Moore, S.; O’Connor, M.J.; Smith, G.C.; Martin, N.M. 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J. Med. Chem.,  2008, 51(20), 6581-6591.
[245] 
Fong, P.C.; Boss, D.S.; Yap, T.A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.; Mortimer, P.; Swaisland, H.; Lau, A.; O’Connor, M.J.; Ashworth, A.; Carmichael, J.; Kaye, S.B.; Schellens, J.H.; De Bono, J.S. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med.,  2009, 361(2), 123-134.
[246] 
Mateo, J.; Moreno, V.; Gupta, A.; Kaye, S.B.; Dean, E.; Middleton, M.R.; Friedlander, M.; Gourley, C.; Plummer, R.; Rustin, G.; Sessa, C.; Leunen, K.; Ledermann, J.; Swaisland, H.; Fielding, A.; Bannister, W.; Nicum, S.; Molife, L.R. An adaptive study to determine the optimal dose of the tablet formulation of the PARP inhibitor olaparib. Target. Oncol.,  2016, 11(3), 401-415.
[247] 
Chase, D.M.; Patel, S.; Shields, K. Profile of olaparib in the treatment of advanced ovarian cancer. Int. J. Womens Health,  2016, 8, 125-129.
[248] 
Konecny, G.E.; Kristeleit, R.S. PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: Current practice and future directions. Br. J. Cancer,  2016, 115(10), 1157-1173.
[249] 
Domchek, S.M.; Aghajanian, C.; Shapira-Frommer, R.; Schmutzler, R.K.; Audeh, M.W.; Friedlander, M.; Balmaña, J.; Mitchell, G.; Fried, G.; Stemmer, S.M.; Hubert, A.; Rosengarten, O.; Loman, N.; Robertson, J.D.; Mann, H.; Kaufman, B. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy. Gynecol. Oncol.,  2016, 140(2), 199-203.
[250] 
Fong, P.C.; Yap, T.A.; Boss, D.S.; Carden, C.P.; Mergui-Roelvink, M.; Gourley, C.; De Greve, J.; Lubinski, J.; Shanley, S.; Messiou, C.; A’Hern, R.; Tutt, A.; Ashworth, A.; Stone, J.; Carmichael, J.; Schellens, J.H.; de Bono, J.S.; Kaye, S.B. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J. Clin. Oncol.,  2010, 28(15), 2512-2519.
[251] 
Kaye, S.B.; Lubinski, J.; Matulonis, U.; Ang, J.E.; Gourley, C.; Karlan, B.Y.; Amnon, A.; Bell-McGuinn, K.M.; Chen, L.M.; Friedlander, M.; Safra, T.; Vergote, I.; Wickens, M.; Lowe, E.S.; Carmichael, J.; Kaufman, B. Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J. Clin. Oncol.,  2012, 30(4), 372-379.
[252] 
Gelmon, K.A.; Tischkowitz, M.; Mackay, H.; Swenerton, K.; Robidoux, A.; Tonkin, K.; Hirte, H.; Huntsman, D.; Clemons, M.; Gilks, B.; Yerushalmi, R.; Macpherson, E.; Carmichael, J.; Oza, A. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase 2, multicentre, open-label, non-randomised study. Lancet Oncol.,  2011, 12(9), 852-861.
[253] 
Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.; Meier, W.; Shapira-Frommer, R.; Safra, T.; Matei, D.; Macpherson, E.; Watkins, C.; Carmichael, J.; Matulonis, U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N. Engl. J. Med.,  2012, 366(15), 1382-1392.
[254] 
Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.L.; Meier, W.; Shapira-Frommer, R.; Safra, T.; Matei, D.; Fielding, A.; Spencer, S.; Dougherty, B.; Orr, M.; Hodgson, D.; Barrett, J.C.; Matulonis, U. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol.,  2014, 15(8), 852-861.
[255] 
Kaufman, B.; Shapira-Frommer, R.; Schmutzler, R.K.; Audeh, M.W.; Friedlander, M.; Balmaña, J.; Mitchell, G.; Fried, G.; Stemmer, S.M.; Hubert, A.; Rosengarten, O.; Steiner, M.; Loman, N.; Bowen, K.; Fielding, A.; Domchek, S.M. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol.,  2015, 33(3), 244-250.
[256] 
 AstraZeneca. Highlights of prescribing information: Lynparza
™.
                    azpicentral.com/Lynparza/pi_lynparza.pdf#page=1
                (Accessed August 08, 2017).
[257] 
 ClinicalTrials. A database of publicly and privately supported
clinical studies.clinicaltrials.gov/
(Accessed August 08,
2017).
[258] 
Thomas, H.D.; Calabrese, C.R.; Batey, M.A.; Canan, S.; Hostomsky, Z.; Kyle, S.; Maegley, K.A.; Newell, D.R.; Skalitzky, D.; Wang, L.Z.; Webber, S.E.; Curtin, N.J. Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Mol. Cancer Ther.,  2007, 6(3), 945-956.
[259] 
 ClovisOncology. Highlights of prescribing information:
Rubraca™.
                    clovisoncology.com/files/rubraca-prescribing-info.pdf
                (Accessed August 08, 2017).
[260] 
Parrish, K.E.; Cen, L.; Murray, J.; Calligaris, D.; Kizilbash, S.; Mittapalli, R.K.; Carlson, B.L.; Schroeder, M.A.; Sludden, J.; Boddy, A.V.; Agar, N.Y.; Curtin, N.J.; Elmquist, W.F.; Sarkaria, J.N. Efficacy of PARP inhibitor rucaparib in orthotopic glioblastoma xenografts is limited by ineffective drug penetration into the central nervous system. Mol. Cancer Ther.,  2015, 14(12), 2735-2743.
[261] 
Drew, Y.; Mulligan, E.A.; Vong, W.T.; Thomas, H.D.; Kahn, S.; Kyle, S.; Mukhopadhyay, A.; Los, G.; Hostomsky, Z.; Plummer, E.R.; Edmondson, R.J.; Curtin, N.J. Therapeutic potential of poly(ADP-ribose) polymerase inhibitor AG014699 in human cancers with mutated or methylated BRCA1 or BRCA2. J. Natl. Cancer Inst.,  2011, 103(4), 334-346.
[262] 
Ihnen, M.; Zu Eulenburg, C.; Kolarova, T.; Qi, J.W.; Manivong, K.; Chalukya, M.; Dering, J.; Anderson, L.; Ginther, C.; Meuter, A.; Winterhoff, B.; Jones, S.; Velculescu, V.E.; Venkatesan, N.; Rong, H.M.; Dandekar, S.; Udar, N.; Jänicke, F.; Los, G.; Slamon, D.J.; Konecny, G.E. Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer. Mol. Cancer Ther.,  2013, 12(6), 1002-1015.
[263] 
Kristeleit, R.S.; Burris, H.A.; Lo Russo, P.; Patel, M.R.; Asghar, U.S.; El-Khouly, F.; Calvert, A.H.; Infante, J.R.; Hilton, J.F.; Tolaney, S.M. Phase 1/2 study of oral rucaparib: Final phase 1 results. J. Clin. Oncol.,  2014, 32(15)
[264] 
Shapiro, G.; Kristeleit, R.; Middleton, M.; Burris, H.; Molife, L.R.; Evans, J.; Wilson, R.; LoRusso, P.; Spicer, J.; Dieras, V. Abstract A218: Pharmacokinetics of orally administered rucaparib in patients with advanced solid tumors. Mol. Cancer Ther.,  2013, 12(11)(Suppl.), A218.
[265] 
Drew, Y.; Ledermann, J.; Hall, G.; Rea, D.; Glasspool, R.; Highley, M.; Jayson, G.; Sludden, J.; Murray, J.; Jamieson, D.; Halford, S.; Acton, G.; Backholer, Z.; Mangano, R.; Boddy, A.; Curtin, N.; Plummer, R. Phase 2 multicentre trial investigating intermittent and continuous dosing schedules of the poly(ADP-ribose) polymerase inhibitor rucaparib in germline BRCA mutation carriers with advanced ovarian and breast cancer. Br. J. Cancer,  2016, 114(12), e21.
[266] 
Swisher, E.; Brenton, J.; Kaufmann, S.; Oza, A.; Coleman, R.; O’Malley, D.; Konecny, G.; Ma, L.; Harrell, M.; Visscher, D. 215 Updated clinical and preliminary correlative results of ARIEL2, a phase 2 study to identify ovarian cancer patients likely to respond to rucaparib. Eur. J. Cancer,  2014, 50, 73.
[267] 
McNeish, I.A.; Oza, A.M.; Coleman, R.L.; Scott, C.L.; Konecny, G.E.; Tinker, A.; O’Malley, D.M.; Brenton, J.; Kristeleit, R.S.; Bell-McGuinn, K. Results of ARIEL2: A Phase 2 trial to prospectively identify ovarian cancer patients likely to respond to rucaparib using tumor genetic analysis. J. Clin. Oncol.,  2015, 33(15), 5508-5508.
[268] 
Shapira-Frommer, R.; Oza, A.M.; Domchek, S.M.; Balmaña, J.; Patel, M.R.; Chen, L.M.; Drew, Y.; Burris, H.A.; Korach, J.; Flynn, M. A phase II open-label, multicenter study of single-agent rucaparib in the treatment of patients with relapsed ovarian cancer and a deleterious BRCA mutation. J. Clin. Oncol.,  2015, 33(15), 5513-5513.
[269] 
 ArielStudy. General information on Ariel studies.
arielstudy.com
                (Accessed August 08, 2017).
[270] 
Jones, P.; Altamura, S.; Boueres, J.; Ferrigno, F.; Fonsi, M.; Giomini, C.; Lamartina, S.; Monteagudo, E.; Ontoria, J.M.; Orsale, M.V.; Palumbi, M.C.; Pesci, S.; Roscilli, G.; Scarpelli, R.; Schultz-Fademrecht, C.; Toniatti, C.; Rowley, M. Discovery of 2-4-[(3S)-piperidin-3-yl]phenyl-2H-indazole-7-carboxamide (MK-4827): A novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors. J. Med. Chem.,  2009, 52(22), 7170-7185.
[271] 
 Zejula. Highlights of prescribing information: Zejula™. zejula.com/docs/Zejula_(niraparib)_Full_Prescribing_ Information.pdf
                (Accessed August 08, 2017).
[272] 
 Tesaro. TESARO Announces Acceptance for Review of
Niraparib Marketing Authorization Application by EMA. ir.tesarobio.com/releasedetail.cfm?releaseid=995985
                (Accessed August 08, 2017).
[273] 
Jones, P.; Wilcoxen, K.; Rowley, M.; Toniatti, C. Niraparib: A Poly(ADP-ribose) Polymerase (PARP) inhibitor for the treatment of tumors with defective homologous recombination. J. Med. Chem.,  2015, 58(8), 3302-3314.
[274] 
Wang, L.; Mason, K.A.; Ang, K.K.; Buchholz, T.; Valdecanas, D.; Mathur, A.; Buser-Doepner, C.; Toniatti, C.; Milas, L. MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest. New Drugs,  2012, 30(6), 2113-2120.
[275] 
Mueller, S.; Bhargava, S.; Molinaro, A.M.; Yang, X.; Kolkowitz, I.; Olow, A.; Wehmeijer, N.; Orbach, S.; Chen, J.; Matthay, K.K.; Haas-Kogan, D.A. Poly (ADP-Ribose) polymerase inhibitor MK-4827 together with radiation as a novel therapy for metastatic neuroblastoma. Anticancer Res.,  2013, 33(3), 755-762.
[276] 
Bridges, K.A.; Toniatti, C.; Buser, C.A.; Liu, H.; Buchholz, T.A.; Meyn, R.E. Niraparib (MK-4827), a novel poly(ADP-Ribose) polymerase inhibitor, radiosensitizes human lung and breast cancer cells. Oncotarget,  2014, 5(13), 5076-5086.
[277] 
Al Hilli, M.M.; Becker, M.A.; Weroha, S.J.; Flatten, K.S.; Hurley, R.M.; Harrell, M.I.; Oberg, A.L.; Maurer, M.J.; Hawthorne, K.M.; Hou, X.; Harrington, S.C.; McKinstry, S.; Meng, X.W.; Wilcoxen, K.M.; Kalli, K.R.; Swisher, E.M.; Kaufmann, S.H.; Haluska, P. In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma. Gynecol. Oncol.,  2016, 143(2), 379-388.
[278] 
Sandhu, S.K.; Schelman, W.R.; Wilding, G.; Moreno, V.; Baird, R.D.; Miranda, S.; Hylands, L.; Riisnaes, R.; Forster, M.; Omlin, A.; Kreischer, N.; Thway, K.; Gevensleben, H.; Sun, L.; Loughney, J.; Chatterjee, M.; Toniatti, C.; Carpenter, C.L.; Iannone, R.; Kaye, S.B.; De Bono, J.S.; Wenham, R.M. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: A phase 1 dose-escalation trial. Lancet Oncol.,  2013, 14(9), 882-892.
[279] 
Kanjanapan, Y.; Lheureux, S.; Oza, A.M. Niraparib for the treatment of ovarian cancer. Expert Opin. Pharmacother.,  2017, 18(6), 631-640.
[280] 
Mirza, M.R.; Monk, B.J.; Herrstedt, J.; Oza, A.M.; Mahner, S.; Redondo, A.; Fabbro, M.; Ledermann, J.A.; Lorusso, D.; Vergote, I.; Ben-Baruch, N.E.; Marth, C.; Mądry, R.; Christensen, R.D.; Berek, J.S.; Dørum, A.; Tinker, A.V.; du Bois, A.; González-Martín, A.; Follana, P.; Benigno, B.; Rosenberg, P.; Gilbert, L.; Rimel, B.J.; Buscema, J.; Balser, J.P.; Agarwal, S.; Matulonis, U.A. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med.,  2016, 375(22), 2154-2164.
[281] 
Donawho, C.K.; Luo, Y.; Luo, Y.; Penning, T.D.; Bauch, J.L.; Bouska, J.J.; Bontcheva-Diaz, V.D.; Cox, B.F.; De Weese, T.L.; Dillehay, L.E.; Ferguson, D.C.; Ghoreishi-Haack, N.S.; Grimm, D.R.; Guan, R.; Han, E.K.; Holley-Shanks, R.R.; Hristov, B.; Idler, K.B.; Jarvis, K.; Johnson, E.F.; Kleinberg, L.R.; Klinghofer, V.; Lasko, L.M.; Liu, X.; Marsh, K.C.; Mc Gonigal, T.P.; Meulbroek, J.A.; Olson, A.M.; Palma, J.P.; Rodriguez, L.E.; Shi, Y.; Stavropoulos, J.A.; Tsurutani, A.C.; Zhu, G.D.; Rosenberg, S.H.; Giranda, V.L.; Frost, D.J. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin. Cancer Res.,  2007, 13(9), 2728-2737.
[282] 
Penning, T.D.; Zhu, G.D.; Gandhi, V.B.; Gong, J.; Liu, X.; Shi, Y.; Klinghofer, V.; Johnson, E.F.; Donawho, C.K.; Frost, D.J.; Bontcheva-Diaz, V.; Bouska, J.J.; Osterling, D.J.; Olson, A.M.; Marsh, K.C.; Luo, Y.; Giranda, V.L. Discovery of the Poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J. Med. Chem.,  2009, 52(2), 514-523.
[283] 
Albert, J.M.; Cao, C.; Kim, K.W.; Willey, C.D.; Geng, L.; Xiao, D.; Wang, H.; Sandler, A.; Johnson, D.H.; Colevas, A.D.; Low, J.; Rothenberg, M.L.; Lu, B. Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. Clin. Cancer Res.,  2007, 13(10), 3033-3042.
[284] 
Kummar, S.; Kinders, R.; Gutierrez, M.E.; Rubinstein, L.; Parchment, R.E.; Phillips, L.R.; Ji, J.; Monks, A.; Low, J.A.; Chen, A.; Murgo, A.J.; Collins, J.; Steinberg, S.M.; Eliopoulos, H.; Giranda, V.L.; Gordon, G.; Helman, L.; Wiltrout, R.; Tomaszewski, J.E.; Doroshow, J.H. Phase 0 clinical trial of the poly (ADP-ribose) polymerase inhibitor ABT-888 in patients with advanced malignancies. J. Clin. Oncol.,  2009, 27(16), 2705-2711.
[285] 
Coleman, R.L.; Sill, M.W.; Bell-McGuinn, K.; Aghajanian, C.; Gray, H.J.; Tewari, K.S.; Rubin, S.C.; Rutherford, T.J.; Chan, J.K.; Chen, A.; Swisher, E.M. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation. An NRG oncology/gynecologic oncology group study. Gynecol. Oncol.,  2015, 137(3), 386-391.
[286] 
Kummar, S.; Chen, A.; Ji, J.; Zhang, Y.; Reid, J.M.; Ames, M.; Jia, L.; Weil, M.; Speranza, G.; Murgo, A.J.; Kinders, R.; Wang, L.; Parchment, R.E.; Carter, J.; Stotler, H.; Rubinstein, L.; Hollingshead, M.; Melillo, G.; Pommier, Y.; Bonner, W.; Tomaszewski, J.E.; Doroshow, J.H. Phase I study of PARP inhibitor ABT-888 in combination with topotecan in adults with refractory solid tumors and lymphomas. Cancer Res.,  2011, 71(17), 5626-5634.
[287] 
Kummar, S.; Ji, J.; Morgan, R.; Lenz, H.J.; Puhalla, S.L.; Belani, C.P.; Gandara, D.R.; Allen, D.; Kiesel, B.; Beumer, J.H.; Newman, E.M.; Rubinstein, L.; Chen, A.; Zhang, Y.; Wang, L.; Kinders, R.J.; Parchment, R.E.; Tomaszewski, J.E.; Doroshow, J.H. A phase I study of veliparib in combination with metronomic cyclophosphamide in adults with refractory solid tumors and lymphomas. Clin. Cancer Res.,  2012, 18(6), 1726-1734.
[288] 
Reiss, K.A.; Herman, J.M.; Zahurak, M.; Brade, A.; Dawson, L.A.; Scardina, A.; Joffe, C.; Petito, E.; Hacker-Prietz, A.; Kinders, R.J.; Wang, L.; Chen, A.; Temkin, S.; Horiba, N.; Siu, L.L.; Azad, N.S. A Phase I study of veliparib (ABT-888) in combination with low-dose fractionated whole abdominal radiation therapy in patients with advanced solid malignancies and peritoneal carcinomatosis. Clin. Cancer Res.,  2015, 21(1), 68-76.
[289] 
Murai, J.; Huang, S.Y.; Renaud, A.; Zhang, Y.; Ji, J.; Takeda, S.; Morris, J.; Teicher, B.; Doroshow, J.H.; Pommier, Y. Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib. Mol. Cancer Ther.,  2014, 13(2), 433-443.
[290] 
Wang, B.; Chu, D.; Feng, Y.; Shen, Y.; Aoyagi-Scharber, M.; Post, L.E. Discovery and characterization of (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido [4,3,2-de]phthalazin-3-one (BMN 673, Talazoparib), a novel, highly potent, and orally efficacious poly(ADP-ribose) polymerase-1/2 Inhibitor, as an anticancer agent. J. Med. Chem.,  2016, 59(1), 335-357.
[291] 
Andrei, A.Z.; Hall, A.; Smith, A.L.; Bascuñana, C.; Malina, A.; Connor, A.; Altinel-Omeroglu, G.; Huang, S.; Pelletier, J.; Huntsman, D.; Gallinger, S.; Omeroglu, A.; Metrakos, P.; Zogopoulos, G. Increased in vitro and in vivo sensitivity of BRCA2-associated pancreatic cancer to the poly(ADP-ribose) polymerase-1/2 inhibitor BMN 673. Cancer Lett.,  2015, 364(1), 8-16.
[292] 
Huang, J.; Wang, L.; Cong, Z.; Amoozgar, Z.; Kiner, E.; Xing, D.; Orsulic, S.; Matulonis, U.; Goldberg, M.S. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(-/-) murine model of ovarian cancer. Biochem. Biophys. Res. Commun.,  2015, 463(4), 551-556.
[293] 
Engert, F.; Kovac, M.; Baumhoer, D.; Nathrath, M.; Fulda, S. Osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor talazoparib alone or in combination with chemotherapeutics. Oncotarget,  2017, 8(30), 48794-48806.
[294] 
De Bono, J.; Ramanathan, R.K.; Mina, L.; Chugh, R.; Glaspy, J.; Rafii, S.; Kaye, S.; Sachdev, J.; Heymach, J.; Smith, D.C.; Henshaw, J.W.; Herriott, A.; Patterson, M.; Curtin, N.J.; Byers, L.A.; Wainberg, Z.A. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov.,  2017, 7(6), 620-629.
[295] 
Wainberg, Z.A.; Rafii, S.; Ramanathan, R.K.; Mina, L.A.; Byers, L.A.; Chugh, R.; Goldman, J.W.; Sachdev, J.C.; Matei, D.E.; Wheler, J.J. Safety and antitumor activity of the PARP inhibitor BMN673 in a phase 1 trial recruiting metastatic Small-Cell Lung Cancer (SCLC) and germline BRCA-mutation carrier cancer patients. J. Clin. Oncol.,  2014, 32(15), 7522-7522.
[296] 
Piha-Paul, S.A.; Goldstein, J.B.; Hess, K.R.; Fu, S.; Hong, D.S.; Janku, F.; Karp, D.D.; Naing, A.; Subbiah, V.; Tsimberidou, A.M. Phase II study of the PARP inhibitor talazoparib (BMN-673) in advanced cancer patients with somatic alterations in BRCA1/2, mutations/deletions in PTEN or PTEN loss, a homologous recombination defect, mutations/deletions in other BRCA pathway genes and germline mutation S in BRCA1/2 (not breast or ovarian cancer). J. Clin. Oncol.,  2015, 33(15)
[http://dx.doi.org/10.1200/jco.2015.33.15_suppl.tps2617] 
[297] 
Miknyoczki, S.; Chang, H.; Grobelny, J.; Pritchard, S.; Worrell, C.; McGann, N.; Ator, M.; Husten, J.; Deibold, J.; Hudkins, R.; Zulli, A.; Parchment, R.; Ruggeri, B. The selective poly(ADP-ribose) polymerase-1(2) inhibitor, CEP-8983, increases the sensitivity of chemoresistant tumor cells to temozolomide and irinotecan but does not potentiate myelotoxicity. Mol. Cancer Ther.,  2007, 6(8), 2290-2302.
[298] 
Jian, W.; Xu, H.G.; Chen, J.; Xu, Z.X.; Levitt, J.M.; Stanley, J.A.; Yang, E.S.; Lerner, S.P.; Sonpavde, G. Activity of CEP-9722, a poly (ADP-ribose) polymerase inhibitor, in urothelial carcinoma correlates inversely with homologous recombination repair response to DNA damage. Anticancer Drugs,  2014, 25(8), 878-886.
[299] 
Plummer, R. Poly(ADP-ribose)polymerase (PARP) inhibitors: From bench to bedside. Clin. Oncol. (R. Coll. Radiol.),  2014, 26(5), 250-256.
[300] 
Dréan, A.; Lord, C.J.; Ashworth, A. PARP inhibitor combination therapy. Crit. Rev. Oncol. Hematol.,  2016, 108, 73-85.
[301] 
Satoh, M.S.; Poirier, G.G.; Lindahl, T. NAD(+)-dependent repair of damaged DNA by human cell extracts. J. Biol. Chem.,  1993, 268(8), 5480-5487.
[302] 
Rothkamm, K.; Löbrich, M. 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,  2003, 100(9), 5057-5062.
[303] 
Chatterjee, S.; Berger, N.A. X-ray-induced damage repair in exponentially growing and growth arrested confluent poly(adenosine diphosphate-ribose) polymerase-deficient V79 chinese hamster cell line. Int. J. Oncol.,  2000, 17(5), 955-962.
[304] 
Eggermont, A.M.; Kirkwood, J.M. Re-evaluating the role of dacarbazine in metastatic melanoma: What have we learned in 30 years? Eur. J. Cancer,  2004, 40(12), 1825-1836.
[305] 
Newlands, E.S.; Stevens, M.F.; Wedge, S.R.; Wheelhouse, R.T.; Brock, C. Temozolomide: A review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat. Rev.,  1997, 23(1), 35-61.
[306] 
Kaina, B. Mechanisms and consequences of methylating agent-induced SCEs and chromosomal aberrations: a long road traveled and still a far way to go. Cytogenet. Genome Res.,  2004, 104(1-4), 77-86.
[307] 
Kaina, B.; Christmann, M.; Naumann, S.; Roos, W.P. MGMT: Key node in the battle against genotoxicity, carcinogenicity and apoptosis induced by alkylating agents. DNA Repair (Amst.),  2007, 6(8), 1079-1099.
[308] 
Roos, W.P.; Nikolova, T.; Quiros, S.; Naumann, S.C.; Kiedron, O.; Zdzienicka, M.Z.; Kaina, B. Brca2/Xrcc2 dependent HR, but not NHEJ, is required for protection against O(6)-methylguanine triggered apoptosis, DSBs and chromosomal aberrations by a process leading to SCEs. DNA Repair (Amst.),  2009, 8(1), 72-86.
[309] 
Gill, S.J.; Travers, J.; Pshenichnaya, I.; Kogera, F.A.; Barthorpe, S.; Mironenko, T.; Richardson, L.; Benes, C.H.; Stratton, M.R.; McDermott, U.; Jackson, S.P.; Garnett, M.J. Combinations of PARP inhibitors with temozolomide drive PARP1 trapping and apoptosis in Ewing’s sarcoma. PLoS One,  2015, 10(10), e0140988.
[310] 
Khan, O.A.; Gore, M.; Lorigan, P.; Stone, J.; Greystoke, A.; Burke, W.; Carmichael, J.; Watson, A.J.; McGown, G.; Thorncroft, M.; Margison, G.P.; Califano, R.; Larkin, J.; Wellman, S.; Middleton, M.R. A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. Br. J. Cancer,  2011, 104(5), 750-755.
[311] 
Sikov, W.M. Assessing the role of platinum agents in aggressive breast cancers. Curr. Oncol. Rep.,  2015, 17(2), 3.
[312] 
Chen, G.; Zeller, W.J. Reversal of acquired cisplatin resistance by nicotinamide in vitro and in vivo. Cancer Chemother. Pharmacol.,  1993, 33(2), 157-162.
[313] 
Lee, J.M.; Hays, J.L.; Annunziata, C.M.; Noonan, A.M.; Minasian, L.; Zujewski, J.A.; Yu, M.; Gordon, N.; Ji, J.; Sissung, T.M.; Figg, W.D.; Azad, N.; Wood, B.J.; Doroshow, J.; Kohn, E.C. Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. J. Natl. Cancer Inst.,  2014, 106(6), dju089.
[314] 
Jordan, M.A.; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer,  2004, 4(4), 253-265.
[315] 
Kang, B.; Guo, R.F.; Tan, X.H.; Zhao, M.; Tang, Z.B.; Lu, Y.Y. Expression status of ataxia-telangiectasia-mutated gene correlated with prognosis in advanced gastric cancer. Mutat. Res.,  2008, 638(1-2), 17-25.
[316] 
Bang, Y.J. Im, S.A.; Lee, K.W.; Cho, J.Y.; Song, E.K.; Lee, K.H.; Kim, Y.H.; Park, J.O.; Chun, H.G.; Zang, D.Y.; Fielding, A.; Rowbottom, J.; Hodgson, D.; O’Connor, M.J.; Yin, X.; Kim, W.H. Im, S.A.; Lee, K.W.; Cho, J.Y.; Song, E.K.; Lee, K.H.; Kim, Y.H.; Park, J.O.; Chun, H.G.; Zang, D.Y. Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J. Clin. Oncol.,  2015, 33(33), 3858-3865.
[317] 
Hastak, K.; Alli, E.; Ford, J.M. Synergistic chemosensitivity of triple-negative breast cancer cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin. Cancer Res.,  2010, 70(20), 7970-7980.
[318] 
Murai, J. Targeting DNA repair and replication stress in the treatment of ovarian cancer. Int. J. Clin. Oncol.,  2017, 22(4), 619-628.
[319] 
Binaschi, M.; Zunino, F.; Capranico, G. Mechanism of action of DNA topoisomerase inhibitors. Stem Cells,  1995, 13(4), 369-379.
[320] 
Das, B.B.; Huang, S.Y.; Murai, J.; Rehman, I.; Amé, J.C.; Sengupta, S.; Das, S.K.; Majumdar, P.; Zhang, H.; Biard, D.; Majumder, H.K.; Schreiber, V.; Pommier, Y. PARP1-TDP1 coupling for the repair of topoisomerase I-induced DNA damage. Nucleic Acids Res.,  2014, 42(7), 4435-4449.
[321] 
Nitiss, J.L. Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer,  2009, 9(5), 338-350.
[322] 
Sui, H.; Shi, C.; Yan, Z.; Li, H. Combination of erlotinib and a PARP inhibitor inhibits growth of A2780 tumor xenografts due to increased autophagy. Drug Des. Devel. Ther.,  2015, 9, 3183-3190.
[323] 
Lim, J.J.; Yang, K.; Taylor-Harding, B.; Wiedemeyer, W.R.; Buckanovich, R.J. VEGFR3 inhibition chemosensitizes ovarian cancer stemlike cells through down-regulation of BRCA1 and BRCA2. Neoplasia,  2014, 16(4), 343-353.
[324] 
West, A.C.; Johnstone, R.W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest.,  2014, 124(1), 30-39.
[325] 
Krumm, A.; Barckhausen, C.; Kücük, P.; Tomaszowski, K.H.; Loquai, C.; Fahrer, J.; Krämer, O.H.; Kaina, B.; Roos, W.P. Enhanced histone deacetylase activity in malignant melanoma provokes RAD51 and FANCD2-triggered drug resistance. Cancer Res.,  2016, 76(10), 3067-3077.
[326] 
Min, A.; Im, S.A.; Kim, D.K.; Song, S.H.; Kim, H.J.; Lee, K.H.; Kim, T.Y.; Han, S.W.; Oh, D.Y.; Kim, T.Y.; O’Connor, M.J.; Bang, Y.J. Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances anti-tumor effects of the Poly (ADP-Ribose) Polymerase (PARP) inhibitor olaparib in triple-negative breast cancer cells. Breast Cancer Res.,  2015, 17, 33.
[327] 
Sullivan, K.; Cramer-Morales, K.; Mc Elroy, D.L.; Ostrov, D.A.; Haas, K.; Childers, W.; Hromas, R.; Skorski, T. Identification of a small molecule inhibitor of RAD52 by structure-based selection. PLoS One,  2016, 11(1), e0147230.
[328] 
Hengel, S.R.; Malacaria, E.; Folly da Silva Constantino, L.; Bain, F.E.; Diaz, A.; Koch, B.G.; Yu, L.; Wu, M.; Pichierri, P.; Spies, M.A.; Spies, M. Small-molecule inhibitors identify the RAD52-ssDNA interaction as critical for recovery from replication stress and for survival of BRCA2 deficient cells. eLife,  2016, 5, e14740.
[329] 
Alsop, K.; Fereday, S.; Meldrum, C.; deFazio, A.; Emmanuel, C.; George, J.; Dobrovic, A.; Birrer, M.J.; Webb, P.M.; Stewart, C.; Friedlander, M.; Fox, S.; Bowtell, D.; Mitchell, G. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: A report from the Australian Ovarian Cancer Study Group. J. Clin. Oncol.,  2012, 30(21), 2654-2663.
[330] 
Drost, R.; Bouwman, P.; Rottenberg, S.; Boon, U.; Schut, E.; Klarenbeek, S.; Klijn, C.; Van Der Heijden, I.; Van Der Gulden, H.; Wientjens, E.; Pieterse, M.; Catteau, A.; Green, P.; Solomon, E.; Morris, J.R.; Jonkers, J. BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell,  2011, 20(6), 797-809.
[331] 
Konstantinopoulos, P.A.; Ceccaldi, R.; Shapiro, G.I.; D’Andrea, A.D. Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov.,  2015, 5(11), 1137-1154.
[332] 
Sakai, W.; Swisher, E.M.; Karlan, B.Y.; Agarwal, M.K.; Higgins, J.; Friedman, C.; Villegas, E.; Jacquemont, C.; Farrugia, D.J.; Couch, F.J.; Urban, N.; Taniguchi, T. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature,  2008, 451(7182), 1116-1120.
[333] 
Swisher, E.M.; Sakai, W.; Karlan, B.Y.; Wurz, K.; Urban, N.; Taniguchi, T. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res.,  2008, 68(8), 2581-2586.
[334] 
Edwards, S.L.; Brough, R.; Lord, C.J.; Natrajan, R.; Vatcheva, R.; Levine, D.A.; Boyd, J.; Reis-Filho, J.S.; Ashworth, A. Resistance to therapy caused by intragenic deletion in BRCA2. Nature,  2008, 451(7182), 1111-1115.
[335] 
Norquist, B.; Wurz, K.A.; Pennil, C.C.; Garcia, R.; Gross, J.; Sakai, W.; Karlan, B.Y.; Taniguchi, T.; Swisher, E.M. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J. Clin. Oncol.,  2011, 29(22), 3008-3015.
[336] 
Bouwman, P.; Aly, A.; Escandell, J.M.; Pieterse, M.; Bartkova, J.; Van Der Gulden, H.; Hiddingh, S.; Thanasoula, M.; Kulkarni, A.; Yang, Q.; Haffty, B.G.; Tommiska, J.; Blomqvist, C.; Drapkin, R.; Adams, D.J.; Nevanlinna, H.; Bartek, J.; Tarsounas, M.; Ganesan, S.; Jonkers, J. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol.,  2010, 17(6), 688-695.
[337] 
Oplustilova, L.; Wolanin, K.; Mistrik, M.; Korinkova, G.; Simkova, D.; Bouchal, J.; Lenobel, R.; Bartkova, J.; Lau, A.; O’Connor, M.J.; Lukas, J.; Bartek, J. Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment. Cell Cycle,  2012, 11(20), 3837-3850.
[338] 
Rottenberg, S.; Jaspers, J.E.; Kersbergen, A.; Van Der Burg, E.; Nygren, A.O.; Zander, S.A.; Derksen, P.W.; De Bruin, M.; Zevenhoven, J.; Lau, A.; Boulter, R.; Cranston, A.; O’Connor, M.J.; Martin, N.M.; Borst, P.; Jonkers, J. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl. Acad. Sci. USA,  2008, 105(44), 17079-17084.
[339] 
Wurzer, G.; Herceg, Z.; Wesierska-Gadek, J. Increased resistance to anticancer therapy of mouse cells lacking the poly(ADP-ribose) polymerase attributable to up-regulation of the multidrug resistance gene product P-glycoprotein. Cancer Res.,  2000, 60(15), 4238-4244.
Rights & Permissions Print Cite
Article Metrics
59
7
1
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867325666180201114306	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
当代药物化学

DNA双链断裂修复 - 相关的合成致死率

摘要

当代药物化学

DNA双链断裂修复 - 相关的合成致死率

摘要 Play Pause

Related Journals

Related Books

Related Articles

摘要
