Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy

Cell Chemical Biology

Volumn 24, Issue 9, 2017, Pages 1101-1119

  Hengel, Sarah R ^a   Spies, M Ashley ^a,b   Spies, Maria ^a  

^a UNIVERSITY OF IOWA   (United States)

^b UNIVERSITY OF IOWA   (United States)

Author keywords

BLM DNA helicase; BRCA1; BRCA2; DNA repair; homologous recombination; MRE11; PARP inhibitors; PARP1 (poly(ADP ribose)polymerase1); RAD51; RAD52; RECQ1 DNA helicase; TOP1; WRN DNA helicase

Indexed keywords

ANTINEOPLASTIC AGENT; BRCA1 PROTEIN; BRCA2 PROTEIN; DNA HELICASE; MRE11 PROTEIN; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 1; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; RAD51 PROTEIN; RAD52 PROTEIN; SMALL MOLECULE TRANSPORT AGENT; DNA BINDING PROTEIN; DOUBLE STRAND BREAK REPAIR PROTEIN MRE11; MRE11A PROTEIN, HUMAN;

CANCER RESISTANCE; CANCER THERAPY; DNA DAMAGE; DNA REPAIR; DNA SYNTHESIS; ENZYME ACTIVE SITE; ENZYME ACTIVITY; HUMAN; LETHALITY; PRIORITY JOURNAL; REVIEW; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECT; METABOLISM; MOLECULAR LIBRARY; NEOPLASM; PATHOLOGY; PHARMACOLOGY;

DNA HELICASES; DNA REPAIR; DNA-BINDING PROTEINS; HUMANS; MRE11 HOMOLOGUE PROTEIN; NEOPLASMS; POLY(ADP-RIBOSE) POLYMERASE INHIBITORS; RAD51 RECOMBINASE; RAD52 DNA REPAIR AND RECOMBINATION PROTEIN; SMALL MOLECULE LIBRARIES;

EID: 85029660285     PISSN: 24519456     EISSN: 24519448     Source Type: Journal    
DOI: 10.1016/j.chembiol.2017.08.027     Document Type: Review

References (147)

1. Aggarwal, M., Banerjee, T., Sommers, J.A., Brosh, R.M. Jr., Targeting an Achilles' heel of cancer with a WRN helicase inhibitor. Cell Cycle 12 (2013), 3329–3335.
2. Aggarwal, M., Banerjee, T., Sommers, J.A., Iannascoli, C., Pichierri, P., Shoemaker, R.H., Brosh, R.M. Jr., Werner syndrome helicase has a critical role in DNA damage responses in the absence of a functional Fanconi anemia pathway. Cancer Res. 73 (2013), 5497–5507.
3. Aggarwal, M., Sommers, J.A., Shoemaker, R.H., Brosh, R.M. Jr., Inhibition of helicase activity by a small molecule impairs Werner syndrome helicase (WRN) function in the cellular response to DNA damage or replication stress. Proc. Natl. Acad. Sci. USA 108 (2011), 1525–1530.
4. Alagpulinsa, D.A., Ayyadevara, S., Shmookler Reis, R.J., A small-molecule inhibitor of RAD51 reduces homologous recombination and sensitizes multiple myeloma cells to doxorubicin. Front. Oncol., 4, 2014, 289.
5. Altmeyer, M., Messner, S., Hassa, P.O., Fey, M., Hottiger, M.O., Molecular mechanism of poly(ADP-ribosyl)ation by PARP1 and identification of lysine residues as ADP-ribose acceptor sites. Nucleic Acids Res. 37 (2009), 3723–3738.
6. Ame, J.C., Spenlehauer, C., de Murcia, G., The PARP superfamily. BioEssays 26 (2004), 882–893.
7. Anantha, R.W., Simhadri, S., Foo, T.K., Miao, S., Liu, J., Shen, Z., Ganesan, S., Xia, B., Functional and mutational landscapes of BRCA1 for homology-directed repair and therapy resistance. Elife, 6, 2017, 10.7554/eLife.21350.
8. Arkin, M.R., Tang, Y., Wells, J.A., Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem. Biol. 21 (2014), 1102–1114.
9. Ashworth, A., A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J. Clin. Oncol. 26 (2008), 3785–3790.
10. Berti, M., Ray Chaudhuri, A., Thangavel, S., Gomathinayagam, S., Kenig, S., Vujanovic, M., Odreman, F., Glatter, T., Graziano, S., Mendoza-Maldonado, R., et al. Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat. Struct. Mol. Biol. 20 (2013), 347–354.
11. Bhatia, V., Barroso, S.I., Garcia-Rubio, M.L., Tumini, E., Herrera-Moyano, E., Aguilera, A., BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511 (2014), 362–365.
12. Bhowmick, R., Minocherhomji, S., Hickson, I.D., RAD52 facilitates mitotic DNA synthesis following replication stress. Mol. Cell 64 (2016), 1117–1126.
13. Bouwman, P., Aly, A., Escandell, J.M., Pieterse, M., Bartkova, J., van der Gulden, H., Hiddingh, S., Thanasoula, M., Kulkarni, A., Yang, Q., et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17 (2010), 688–695.
14. Bouwman, P., van der Gulden, H., van der Heijden, I., Drost, R., Klijn, C.N., Prasetyanti, P., Pieterse, M., Wientjens, E., Seibler, J., Hogervorst, F.B., et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 3 (2013), 1142–1155.
15. 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 434 (2005), 913–917.
16. Budke, B., Kalin, J.H., Pawlowski, M., Zelivianskaia, A.S., Wu, M., Kozikowski, A.P., Connell, P.P., An optimized RAD51 inhibitor that disrupts homologous recombination without requiring Michael acceptor reactivity. J. Med. Chem. 56 (2013), 254–263.
17. Budke, B., Logan, H.L., Kalin, J.H., Zelivianskaia, A.S., Cameron McGuire, W., Miller, L.L., Stark, J.M., Kozikowski, A.P., Bishop, D.K., Connell, P.P., RI-1: a chemical inhibitor of RAD51 that disrupts homologous recombination in human cells. Nucleic Acids Res. 40 (2012), 7347–7357.
18. Budke, B., Lv, W., Kozikowski, A.P., Connell, P.P., Recent developments using small molecules to target RAD51: how to best modulate RAD51 for anticancer therapy?. ChemMedChem 11 (2016), 2468–2473.
19. Bugreev, D.V., Rossi, M.J., Mazin, A.V., Cooperation of RAD51 and RAD54 in regression of a model replication fork. Nucleic Acids Res. 39 (2011), 2153–2164.
20. Bunting, S.F., Callen, E., Wong, N., Chen, H.T., Polato, F., Gunn, A., Bothmer, A., Feldhahn, N., Fernandez-Capetillo, O., Cao, L., et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141 (2010), 243–254.
21. Caldecott, K.W., Single-strand break repair and genetic disease. Nat. Rev. Genet. 9 (2008), 619–631.
22. Carreira, A., Kowalczykowski, S.C., Two classes of BRC repeats in BRCA2 promote RAD51 nucleoprotein filament function by distinct mechanisms. Proc. Natl. Acad. Sci. USA 108 (2011), 10448–10453.
23. Cavanagh, H., Rogers, K.M., The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers. Hered. Cancer Clin. Pract., 13, 2015, 16.
24. Ceballos, S.J., Heyer, W.D., Functions of the Snf2/Swi2 family Rad54 motor protein in homologous recombination. Biochim. Biophys. Acta 1809 (2011), 509–523.
25. Cejka, P., DNA end resection: nucleases team up with the right partners to initiate homologous recombination. J. Biol. Chem. 290 (2015), 22931–22938.
26. 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. 22 (2015), 1491–1504.
27. Choi, Y.E., Meghani, K., Brault, M.E., Leclerc, L., He, Y.Z.J., Day, T.A., Elias, K.M., Drapkin, R., Weinstock, D.M., Dao, F., et al. Platinum and PARP inhibitor resistance due to overexpression of microRNA-622 in BRCA1-mutant ovarian cancer. Cell Rep. 14 (2016), 429–439.
28. Chuang, H.C., Kapuriya, N., Kulp, S.K., Chen, C.S., Shapiro, C.L., Differential anti-proliferative activities of poly(ADP-ribose) polymerase (PARP) inhibitors in triple-negative breast cancer cells. Breast Cancer Res. Treat. 134 (2012), 649–659.
29. Couedel, C., Mills, K.D., Barchi, M., Shen, L., Olshen, A., Johnson, R.D., Nussenzweig, A., Essers, J., Kanaar, R., Li, G.C., et al. Collaboration of homologous recombination and nonhomologous end-joining factors for the survival and integrity of mice and cells. Genes Dev. 18 (2004), 1293–1304.
30. Cramer-Morales, K., Nieborowska-Skorska, M., Scheibner, K., Padget, M., Irvine, D.A., Sliwinski, T., Haas, K., Lee, J., Geng, H., Roy, D., et al. Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. Blood 122 (2013), 1293–1304.
31. Daley, J.M., Gaines, W.A., Kwon, Y., Sung, P., Regulation of DNA pairing in homologous recombination. Cold Spring Harbor Perspect. Biol., 6, 2014, a017954.
32. De Lorenzo, S.B., Patel, A.G., Hurley, R.M., Kaufmann, S.H., The elephant and the blind men: making sense of PARP inhibitors in homologous recombination deficient tumor cells. Front. Oncol., 3, 2013, 228.
33. Deakyne, J.S., Huang, F., Negri, J., Tolliday, N., Cocklin, S., Mazin, A.V., Analysis of the activities of RAD54, a SWI2/SNF2 protein, using a specific small-molecule inhibitor. J. Biol. Chem. 288 (2013), 31567–31580.
34. Decker, P., Muller, S., Modulating poly (ADP-ribose) polymerase activity: potential for the prevention and therapy of pathogenic situations involving DNA damage and oxidative stress. Curr. Pharm. Biotechnol. 3 (2002), 275–283.
35. Dobzhansky, T., Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura. Genetics 31 (1946), 269–290.
36. Doe, C.L., Osman, F., Dixon, J., Whitby, M.C., DNA repair by a Rad22-Mus81-dependent pathway that is independent of Rhp51. Nucleic Acids Res. 32 (2004), 5570–5581.
37. Donawho, C.K., Luo, Y., Luo, Y., Penning, T.D., Bauch, J.L., Bouska, J.J., Bontcheva-Diaz, V.D., Cox, B.F., DeWeese, T.L., Dillehay, L.E., et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin. Cancer Res. 13 (2007), 2728–2737.
38. Dupre, A., Boyer-Chatenet, L., Sattler, R.M., Modi, A.P., Lee, J.-H., Nicolette, M.L., Kopelovich, L., Jasin, M., Baer, R., Paull, T.T., et al. A forward chemical genetic screen reveals an inhibitor of the Mre11-Rad50-Nbs1 complex. Nat. Chem. Biol. 4 (2008), 119–125.
39. 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 451 (2008), 1111–1115.
40. 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., et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434 (2005), 917–921.
41. 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 108 (2011), 686–691.
42. Fox, B.M., Xiao, X., Antony, S., Kohlhagen, G., Pommier, Y., Staker, B.L., Stewart, L., Cushman, M., Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids. J. Med. Chem. 46 (2003), 3275–3282.
43. Friedman, L.S., Szabo, C.I., Ostermeyer, E.A., Dowd, P., Butler, L., Park, T., Lee, M.K., Goode, E.L., Rowell, S.E., King, M.C., Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. Am. J. Hum. Genet. 57 (1995), 1284–1297.
44. Grimme, J.M., Honda, M., Wright, R., Okuno, Y., Rothenberg, E., Mazin, A.V., Ha, T., Spies, M., Human Rad52 binds and wraps single-stranded DNA and mediates annealing via two hRad52-ssDNA complexes. Nucleic Acids Res. 38 (2010), 2917–2930.
45. Hanamshet, K., Mazina, O.M., Mazin, A.V., Reappearance from obscurity: mammalian Rad52 in homologous recombination. Genes, 7, 2016, 10.3390/genes7090063.
46. Harris, M.N., Medrek, T.J., Golomb, F.M., Gumport, S.L., Postel, A.H., Wright, J.C., Chemotherapy with streptonigrin in advanced cancer. Cancer 18 (1965), 49–57.
47. Hartwell, L.H., Szankasi, P., Roberts, C.J., Murray, A.W., Friend, S.H., Integrating genetic approaches into the discovery of anticancer drugs. Science 278 (1997), 1064–1068.
48. Hatchi, E., Skourti-Stathaki, K., Ventz, S., Pinello, L., Yen, A., Kamieniarz-Gdula, K., Dimitrov, S., Pathania, S., McKinney, K.M., Eaton, M.L., et al. BRCA1 recruitment to transcriptional pause sites is required for r-loop-driven DNA damage repair. Mol. Cell 57 (2015), 636–647.
49. 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., et al. Small-molecule inhibitors identify the RAD52-ssDNA interaction as critical for recovery from replication stress and for survival of BRCA2 deficient cells. Elife, 5, 2016, e14740.
50. Heyer, W.D., Regulation of recombination and genomic maintenance. Cold Spring Harbor Perspect. Biol., 7, 2015, a016501.
51. Hill, S.J., Rolland, T., Adelmant, G., Xia, X.F., Owen, M.S., Dricot, A., Zack, T.I., Sahni, N., Jacob, Y., Hao, T., et al. Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev. 28 (2014), 1957–1975.
52. Honda, M., Okuno, Y., Yoo, J., Ha, T., Spies, M., Tyrosine phosphorylation enhances RAD52-mediated annealing by modulating its DNA binding. EMBO J. 30 (2011), 3368–3382.
53. Huang, F., Goyal, N., Sullivan, K., Hanamshet, K., Patel, M., Mazina, O.M., Wang, C.X., An, W.F., Spoonamore, J., Metkar, S., et al. Targeting BRCA1- and BRCA2-deficient cells with RAD52 small molecule inhibitors. Nucleic Acids Res. 44 (2016), 4189–4199.
54. Huang, F., Mazin, A.V., A small molecule inhibitor of human RAD51 potentiates breast cancer cell killing by therapeutic agents in mouse xenografts. PLoS One, 9, 2014, e100993.
55. Huang, F., Mazina, O.M., Zentner, I.J., Cocklin, S., Mazin, A.V., Inhibition of homologous recombination in human cells by targeting RAD51 recombinase. J. Med. Chem. 55 (2012), 3011–3020.
56. Huang, F., Motlekar, N.A., Burgwin, C.M., Napper, A.D., Diamond, S.L., Mazin, A.V., Identification of specific inhibitors of human RAD51 recombinase using high-throughput screening. ACS Chem. Biol. 6 (2011), 628–635.
57. Huang, Y., Li, L., DNA crosslinking damage and cancer - a tale of friend and foe. Transl. Cancer Res. 2 (2013), 144–154.
58. Incorvaia, L., Passiglia, F., Rizzo, S., Galvano, A., Listi, A., Barraco, N., Maragliano, R., Calo, V., Natoli, C., Ciaccio, M., et al. “Back to a false normality”: new intriguing mechanisms of resistance to PARP inhibitors. Oncotarget 8 (2017), 23891–23904.
59. Ishida, T., Takizawa, Y., Kainuma, T., Inoue, J., Mikawa, T., Shibata, T., Suzuki, H., Tashiro, S., Kurumizaka, H., DIDS, a chemical compound that inhibits RAD51-mediated homologous pairing and strand exchange. Nucleic Acids Res. 37 (2009), 3367–3376.
60. Jacquemont, C., Simon, J.A., D'Andrea, A.D., Taniguchi, T., Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin. Mol. Cancer, 11, 2012, 26.
61. Jasin, M., Rothstein, R., Repair of strand breaks by homologous recombination. Cold Spring Harbor Perspect. Biol., 5, 2013, a012740.
62. Jayathilaka, K., Sheridan, S.D., Bold, T.D., Bochenska, K., Logan, H.L., Weichselbaum, R.R., Bishop, D.K., Connell, P.P., A chemical compound that stimulates the human homologous recombination protein RAD51. Proc. Natl. Acad. Sci. USA 105 (2008), 15848–15853.
63. Jeggo, P.A., Lobrich, M., How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability. Biochem. J. 471 (2015), 1–11.
64. Jensen, R.B., Carreira, A., Kowalczykowski, S.C., Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 467 (2010), 678–683.
65. Jiang, Q., Greenberg, R.A., Deciphering the BRCA1 tumor suppressor network. J. Biol. Chem. 290 (2015), 17724–17732.
66. Johannes, J.W., Bates, S., Beigie, C., Belmonte, M.A., Breen, J., Cao, S., Centrella, P.A., Clark, M.A., Cuozzo, J.W., Dumelin, C.E., et al. Structure based design of non-natural peptidic macrocyclic Mcl-1 inhibitors. ACS Med. Chem. Lett. 8 (2017), 239–244.
67. Jones, P., Altamura, S., Boueres, J., Ferrigno, F., Fonsi, M., Giomini, C., Lamartina, S., Monteagudo, E., Ontoria, J.M., Orsale, M.V., et al. 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. 52 (2009), 7170–7185.
68. Kass, E.M., Jasin, M., Collaboration and competition between DNA double-strand break repair pathways. FEBS Lett. 584 (2010), 3703–3708.
69. Kelley, M.R., Fishel, M.L., DNA repair proteins as molecular targets for cancer therapeutics. Anticancer Agents Med. Chem. 8 (2008), 417–425.
70. Kim, T.M., Son, M.Y., Dodds, S., Hu, L., Hasty, P., Deletion of BRCA2 exon 27 causes defects in response to both stalled and collapsed replication forks. Mutat. Res. 766–767 (2014), 66–72.
71. Klein, H.L., The consequences of Rad51 overexpression for normal and tumor cells. DNA Repair 7 (2008), 686–693.
72. Knezevic, C.E., Wright, G., Remsing Rix, L.L., Kim, W., Kuenzi, B.M., Luo, Y., Watters, J.M., Koomen, J.M., Haura, E.B., Monteiro, A.N., et al. Proteome-wide profiling of clinical PARP inhibitors reveals compound-specific secondary targets. Cell Chem. Biol. 23 (2016), 1490–1503.
73. Kobayashi, H., Ohno, S., Sasaki, Y., Matsuura, M., Hereditary breast and ovarian cancer susceptibility genes (review). Oncol. Rep. 30 (2013), 1019–1029.
74. Kolinjivadi, A.M., Sannino, V., de Antoni, A., Techer, H., Baldi, G., Costanzo, V., Moonlighting at replication forks - a new life for homologous recombination proteins BRCA1, BRCA2 and RAD51. FEBS Lett. 591 (2017), 1083–1100.
75. Konishi, H., Mohseni, M., Tamaki, A., Garay, J.P., Croessmann, S., Karnan, S., Ota, A., Wong, H.Y., Konishi, Y., Karakas, B., et al. Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells. Proc. Natl. Acad. Sci. USA 108 (2011), 17773–17778.
76. Koster, D.A., Palle, K., Bot, E.S., Bjornsti, M.A., Dekker, N.H., Antitumour drugs impede DNA uncoiling by topoisomerase I. Nature 448 (2007), 213–217.
77. Kottemann, M.C., Smogorzewska, A., Fanconi anaemia and the repair of Watson and Crick DNA crosslinks. Nature 493 (2013), 356–363.
78. Kowalczykowski, S.C., An overview of the molecular mechanisms of recombinational DNA repair. Cold Spring Harbor Perspect. Biol., 7, 2015, 10.1101/cshperspect.a016410.
79. Krishnakumar, R., Kraus, W.L., The PARP side of the nucleus: molecular actions, physiological outcomes, and clinical targets. Mol. Cell 39 (2010), 8–24.
80. Langelier, M.-F., Pascal, J.M., PARP-1 mechanism for coupling DNA damage detection to poly(ADP-ribose) synthesis. Curr. Opin. Struct. Biol. 23 (2013), 134–143.
81. Larsen, N.B., Hickson, I.D., RecQ helicases: conserved guardians of genomic integrity. Adv. Exp. Med. Biol. 767 (2013), 161–184.
82. Ledermann, J.A., Harter, P., Gourley, C., Friedlander, M., Vergote, I., Rustin, G., Scott, C., Meier, W., Shapira-Frommer, R., Safra, T., et al. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol. 17 (2016), 1579–1589.
83. Li, J., Zou, C., Bai, Y., Wazer, D.E., Band, V., Gao, Q., DSS1 is required for the stability of BRCA2. Oncogene 25 (2006), 1186–1194.
84. 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. 17 (2010), 1260–1262.
85. Liu, Y., Burness, M.L., Martin-Trevino, R., Guy, J., Bai, S., Harouaka, R., Brooks, M.D., Shang, L., Fox, A., Luther, T.K., et al. RAD51 mediates resistance of cancer stem cells to parp inhibition in triple-negative breast cancer. Clin. Cancer Res. 23 (2016), 514–522.
86. 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 32 (2012), 3552–3558.
87. Lord, C.J., Ashworth, A., PARP inhibitors: synthetic lethality in the clinic. Science 355 (2017), 1152–1158.
88. Lupo, B., Trusolino, L., Inhibition of poly(ADP-ribosyl)ation in cancer: old and new paradigms revisited. Biochim. Biophys. Acta 1846 (2014), 201–215.
89. Lv, W., Budke, B., Kozikowski, A.P., Connell, P.P., Development of small molecules that specifically inhibit the D-loop activity of RAD51. Int. J. Radiat. Oncol. 96 (2016), S16–S17.
90. Lv, W., Budke, B., Pawlowski, M., Connell, P.P., Kozikowski, A.P., Development of small molecules that specifically inhibit the D-loop activity of RAD51. J. Med. Chem. 59 (2016), 4511–4525.
91. Mazina, O.M., Keskin, H., Hanamshet, K., Storici, F., Mazin, A.V., Rad52 inverse strand exchange drives RNA-templated DNA double-strand break repair. Mol. Cell 67 (2017), 19–29.e13.
92. Menear, K.A., Adcock, C., Boulter, R., Cockcroft, X.L., Copsey, L., Cranston, A., Dillon, K.J., Drzewiecki, J., Garman, S., Gomez, S., et al. 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. 51 (2008), 6581–6591.
93. Moschetti, T., Sharpe, T., Fischer, G., Marsh, M.E., Ng, H.K., Morgan, M., Scott, D.E., Blundell, T.L., R Venkitaraman, A., Skidmore, J., et al. Engineering archeal surrogate systems for the development of protein-protein interaction inhibitors against human RAD51. J. Mol. Biol. 428 (2016), 4589–4607.
94. Moynahan, M.E., Jasin, M., Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat. Rev. Mol. Cell Biol. 11 (2010), 196–207.
95. Murata, S., Zhang, C., Finch, N., Zhang, K., Campo, L., Breuer, E.K., Predictors and modulators of synthetic lethality: an update on PARP inhibitors and personalized medicine. Biomed. Res. Int., 2016, 2016, 2346585.
96. Murfuni, I., Basile, G., Subramanyam, S., Malacaria, E., Bignami, M., Spies, M., Franchitto, A., Pichierri, P., Survival of the replication checkpoint deficient cells requires MUS81-RAD52 function. PLoS Genet., 9, 2013, e1003910.
97. Normand, A., Riviere, E., Renodon-Corniere, A., Identification and characterization of human Rad51 inhibitors by screening of an existing drug library. Biochem. Pharmacol. 91 (2014), 293–300.
98. Park, J.Y., Zhang, F., Andreassen, P.R., PALB2: the hub of a network of tumor suppressors involved in DNA damage responses. Biochim. Biophys. Acta 1846 (2014), 263–275.
99. Patel, A.G., Sarkaria, J.N., Kaufmann, S.H., Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells. Proc. Natl. Acad. Sci. USA 108 (2011), 3406–3411.
100. Pellegrini, L., Yu, D.S., Lo, T., Anand, S., Lee, M., Blundell, T.L., Venkitaraman, A.R., Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 420 (2002), 287–293.
101. Pommier, Y., Barcelo, J.M., Rao, V.A., Sordet, O., Jobson, A.G., Thibaut, L., Miao, Z.H., Seiler, J.A., Zhang, H., Marchand, C., et al. Repair of topoisomerase I-mediated DNA damage. Prog. Nucleic Acid Res. Mol. Biol. 81 (2006), 179–229.
102. Pommier, Y., Redon, C., Rao, V.A., Seiler, J.A., Sordet, O., Takemura, H., Antony, S., Meng, L., Liao, Z., Kohlhagen, G., et al. Repair of and checkpoint response to topoisomerase I-mediated DNA damage. Mutat. Res. 532 (2003), 173–203.
103. Powell, S.N., Kachnic, L.A., Therapeutic exploitation of tumor cell defects in homologous recombination. Anticancer Agents Med. Chem. 8 (2008), 448–460.
104. Prakash, R., Zhang, Y., Feng, W., Jasin, M., Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harbor Perspect. Biol., 7, 2015, a016600.
105. Price, M., Monteiro, A.N.A., Fine tuning chemotherapy to match BRCA1 status. Biochem. Pharmacol. 80 (2010), 647–653.
106. Purnell, M.R., Whish, W.J., Novel inhibitors of poly(ADP-ribose) synthetase. Biochem. J. 185 (1980), 775–777.
107. Rankin, P.W., Jacobson, E.L., Benjamin, R.C., Moss, J., Jacobson, M.K., Quantitative studies of inhibitors of ADP-ribosylation in vitro and in vivo. J. Biol. Chem. 264 (1989), 4312–4317.
108. Ray Chaudhuri, A., Hashimoto, Y., Herrador, R., Neelsen, K.J., Fachinetti, D., Bermejo, R., Cocito, A., Costanzo, V., Lopes, M., Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat. Struct. Mol. Biol. 19 (2012), 417–423.
109. 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. 18 (1998), 6423–6429.
110. Rosenthal, A.S., Dexheimer, T.S., Gileadi, O., Nguyen, G.H., Chu, W.K., Hickson, I.D., Jadhav, A., Simeonov, A., Maloney, D.J., Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom Helicase. Bioorg. Med. Chem. Lett. 23 (2013), 5660–5666.
111. Rosenthal, A.S., Dexheimer, T.S., Nguyen, G., Gileadi, O., Vindigni, A., Simeonov, A., Jadhav, A., Hickson, I., Maloney, D.J., Discovery of ML216, a small molecule inhibitor of bloom (BLM) helicase. Probe Reports from the NIH Molecular Libraries Program, 2010, National Center for Biotechnology Information (US).
112. Saeki, H., Siaud, N., Christ, N., Wiegant, W.W., van Buul, P.P., Han, M., Zdzienicka, M.Z., Stark, J.M., Jasin, M., Suppression of the DNA repair defects of BRCA2-deficient cells with heterologous protein fusions. Proc. Natl. Acad. Sci. USA 103 (2006), 8768–8773.
113. 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., et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451 (2008), 1116–U1119.
114. Schlacher, K., Christ, N., Siaud, N., Egashira, A., Wu, H., Jasin, M., Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145 (2011), 529–542.
115. Schlacher, K., Wu, H., Jasin, M., A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22 (2012), 106–116.
116. Scott, D.E., Coyne, A.G., Venkitaraman, A., Blundell, T.L., Abell, C., Hyvonen, M., Small-molecule inhibitors that target protein-protein interactions in the RAD51 family of recombinases. ChemMedChem 10 (2015), 296–303.
117. Shaheen, M., Allen, C., Nickoloff, J.A., Hromas, R., Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood 117 (2011), 6074–6082.
118. Shibata, A., Moiani, D., Arvai, A.S., Perry, J., Harding, S.M., Genois, M.-M., Maity, R., van Rossum-Fikkert, S., Kertokalio, A., Romoli, F., et al. DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Mol. Cell 53 (2014), 7–18.
119. Shivji, M.K., Davies, O.R., Savill, J.M., Bates, D.L., Pellegrini, L., Venkitaraman, A.R., A region of human BRCA2 containing multiple BRC repeats promotes RAD51-mediated strand exchange. Nucleic Acids Res. 34 (2006), 4000–4011.
120. Sotiriou, S.K., Kamileri, I., Lugli, N., Evangelou, K., Da-Re, C., Huber, F., Padayachy, L., Tardy, S., Nicati, N.L., Barriot, S., et al. Mammalian RAD52 functions in break-induced replication repair of collapsed DNA replication forks. Mol. Cell 64 (2016), 1127–1134.
121. Spies, M., Fishel, R., Mismatch repair during homologous and homeologous recombination. Cold Spring Harbor Perspect. Biol., 7, 2015, 10.1101/cshperspect.a022657.
122. Struewing, J.P., Abeliovich, D., Peretz, T., Avishai, N., Kaback, M.M., Collins, F.S., Brody, L.C., The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals (vol 11, pg 198, 1995). Nat. Genet., 12, 1996, 110.
123. Subramanyam, S., Jones, W.T., Spies, M., Spies, M.A., Contributions of the RAD51 N-terminal domain to BRCA2-RAD51 interaction. Nucleic Acids Res. 41 (2013), 9020–9032.
124. Sugimura, K., Takebayashi, S., Taguchi, H., Takeda, S., Okumura, K., PARP-1 ensures regulation of replication fork progression by homologous recombination on damaged DNA. J. Cell Biol. 183 (2008), 1203–1212.
125. 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, 11, 2016, e0147230.
126. 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. 68 (2008), 2581–2586.
127. Symington, L.S., End resection at double-strand breaks: mechanism and regulation. Cold Spring Harbor Perspect. Biol., 6, 2014, 10.1101/cshperspect.a016436.
128. Symington, L.S., Mechanism and regulation of DNA end resection in eukaryotes. Crit. Rev. Biochem. Mol. Biol. 51 (2016), 195–212.
129. Taleb, N.N., Antifragile: Things that Gain from Disorder. First Edition, 2012, Random House.
130. Thakar, A., Parvin, J., Zlatanova, J., BRCA1/BARD1 E3 ubiquitin ligase can modify histones H2A and H2B in the nucleosome particle. J. Biomol. Struct. Dyn. 27 (2010), 399–406.
131. 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., et al. Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Mol. Cancer Ther. 6 (2007), 945–956.
132. Thorsell, A.G., Ekblad, T., Karlberg, T., Low, M., Pinto, A.F., Tresaugues, L., Moche, M., Cohen, M.S., Schuler, H., Structural basis for potency and promiscuity in poly(ADP-ribose) polymerase (PARP) and tankyrase inhibitors. J. Med. Chem. 60 (2017), 1262–1271.
133. Thorslund, T., McIlwraith, M.J., Compton, S.A., Lekomtsev, S., Petronczki, M., Griffith, J.D., West, S.C., The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat. Struct. Mol. Biol. 17 (2010), 1263–1265.
134. Wagner, L.M., Profile of veliparib and its potential in the treatment of solid tumors. OncoTargets Ther. 8 (2015), 1931–1939.
135. Wahlberg, E., Karlberg, T., Kouznetsova, E., Markova, N., Macchiarulo, A., Thorsell, A.-G., Pol, E., Frostell, A., Ekblad, T., Oncu, D., et al. Family-wide chemical profiling and structural analysis of PARP and tankyrase inhibitors. Nat. Biotech. 30 (2012), 283–288.
136. Wang, A.T., Kim, T., Wagner, J.E., Conti, B.A., Lach, F.P., Huang, A.L., Molina, H., Sanborn, E.M., Zierhut, H., Cornes, B.K., et al. A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Mol. Cell 59 (2015), 478–490.
137. Wang, Y., Krais, J.J., Bernhardy, A.J., Nicolas, E., Cai, K.Q., Harrell, M.I., Kim, H.H., George, E., Swisher, E.M., Simpkins, F., et al. RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance. J. Clin. Invest. 126 (2016), 3145–3157.
138. Wiegmans, A.P., Miranda, M., Wen, S.W., Al-Ejeh, F., Moller, A., RAD51 inhibition in triple negative breast cancer cells is challenged by compensatory survival signaling and requires rational combination therapy. Oncotarget 7 (2016), 60087–60100.
139. Wu, L.C., Wang, Z.W., Tsan, J.T., Spillman, M.A., Phung, A., Xu, X.L., Yang, M.C., Hwang, L.Y., Bowcock, A.M., Baer, R., Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat. Genet. 14 (1996), 430–440.
140. Wu, Y., Brosh, R.M., Helicase-inactivating mutations as a basis for dominant negative phenotypes. Cell Cycle 9 (2010), 4080–4090.
141. 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. 18 (1998), 6430–6435.
142. Yanez, R.J., Porter, A.C., Differential effects of Rad52p overexpression on gene targeting and extrachromosomal homologous recombination in a human cell line. Nucleic Acids Res. 30 (2002), 740–748.
143. Yang, H., Jeffrey, P.D., Miller, J., Kinnucan, E., Sun, Y., Thoma, N.H., Zheng, N., Chen, P.L., Lee, W.H., Pavletich, N.P., BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297 (2002), 1837–1848.
144. 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. 61 (2011), 31–49.
145. Yata, K., Bleuyard, J.Y., Nakato, R., Ralf, C., Katou, Y., Schwab, R.A., Niedzwiedz, W., Shirahige, K., Esashi, F., BRCA2 coordinates the activities of cell-cycle kinases to promote genome stability. Cell Rep. 7 (2014), 1547–1559.
146. Yu, X., Fu, S., Lai, M., Baer, R., Chen, J., BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 20 (2006), 1721–1726.
147. Zinovyev, A., Kuperstein, I., Barillot, E., Heyer, W.D., Synthetic lethality between gene defects affecting a single non-essential molecular pathway with reversible steps. PLoS Comput. Biol., 9, 2013, e1003016.