The role of BRCA1 in homologous recombination repair in response to replication stress: significance in tumorigenesis and cancer therapy

Cell & Bioscience

Junran Zhang¹ 

[1] Department of Radiation Oncology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, BRB 323, Cleveland, OH, 44106, USA

关键词: Sister chromatid exchange;    DNA double strand breaks;    Poly(ADP-ribose) polymerase (PARP) inhibitor;    Replication arrest;    Homologous recombination;    BRCA1;   

Others  :  792943
DOI  :  10.1186/2045-3701-3-11

 received in 2012-08-20, accepted in 2012-12-20,  发布年份 2013

【 摘 要 】

Germ line mutations in breast cancer gene 1 (BRCA1) predispose women to breast and ovarian cancers. Although BRCA1 is involved in many important biological processes, the function of BRCA1 in homologous recombination (HR) mediated repair is considered one of the major mechanisms contributing to its tumor suppression activity, and the cause of hypersensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors when BRCA1 is defective. Mounting evidence suggests that the mechanism of repairing DNA double strand breaks (DSBs) by HR is different than the mechanism operating when DNA replication is blocked. Although BRCA1 has been recognized as a central component in HR, the precise role of BRCA1 in HR, particularly under replication stress, has remained largely unknown. Given the fact that DNA lesions caused by replication blockages are the primary substrates for HR in mitotic cells, functional analysis of BRCA1 in HR repair in the context of replication stress should benefit our understanding of the molecular mechanisms underlying tumorigenesis associated with BRCA1 deficiencies, as well as the development of therapeutic approaches for cancer patients carrying BRCA1 mutations or reduced BRCA1 expression. This review focuses on the current advances in this setting and also discusses the significance in tumorigenesis and cancer therapy.

【 授权许可】

   
2013 Zhang; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Hoeijmakers JH: Genome maintenance mechanisms for preventing cancer. Nature 2001, 411(6835):366-374.
• [2]Borde V: The multiple roles of the Mre11 complex for meiotic recombination. Chromosome Res 2007, 15(5):551-563.
• [3]Assenmacher N, Hopfner KP: MRE11/RAD50/NBS1: complex activities. Chromosoma 2004, 113(4):157-166.
• [4]Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J, Baer R, Lukas J, Jackson SP: Human CtIP promotes DNA end resection. Nature 2007, 450(7169):509-514.
• [5]Sung P, Krejci L, Van Komen S, Sehorn MG: Rad51 recombinase and recombination mediators. J Biol Chem 2003, 278(44):42729-42732.
• [6]Sung P, Klein H: Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 2006, 7(10):739-750.
• [7]Liu Y, West SC: Happy Hollidays: 40th anniversary of the Holliday junction. Nat Rev Mol Cell Biol 2004, 5(11):937-944.
• [8]Liu Y, Masson JY, Shah R, O'Regan P, West SC: RAD51C is required for Holliday junction processing in mammalian cells. Science 2004, 303(5655):243-246.
• [9]Alberts B: Molecular biology of the cell. 5th edition. New York: Garland Science; 2008.
• [10]Heller RC, Marians KJ: Replisome assembly and the direct restart of stalled replication forks. Nat Rev Mol Cell Biol 2006, 7(12):932-943.
• [11]Hanada K, Budzowska M, Modesti M, Maas A, Wyman C, Essers J, Kanaar R: The structure-specific endonuclease Mus81-Eme1 promotes conversion of interstrand DNA crosslinks into double-strands breaks. EMBO J 2006, 25(20):4921-4932.
• [12]Hanada K, Budzowska M, Davies SL, van Drunen E, Onizawa H, Beverloo HB, Maas A, Essers J, Hickson ID, Kanaar R: The structure-specific endonuclease Mus81 contributes to replication restart by generating double-strand DNA breaks. Nat Struct Mol Biol 2007, 14(11):1096-1104.
• [13]Wilson DM 3rd, Thompson LH: Molecular mechanisms of sister-chromatid exchange. Mutat Res 2007, 616(1–2):11-23.
• [14]Petermann E, Orta ML, Issaeva N, Schultz N, Helleday T: Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol Cell 2010, 37(4):492-502.
• [15]Wyman C, Kanaar R: DNA double-strand break repair: all's well that ends well. Annu Rev Genet 2006, 40:363-383.
• [16]Elvers I, Johansson F, Groth P, Erixon K, Helleday T: UV stalled replication forks restart by re-priming in human fibroblasts. Nucleic Acids Res 2011, 39(16):7049-7057.
• [17]Saintigny Y, Delacote F, Vares G, Petitot F, Lambert S, Averbeck D, Lopez BS: Characterization of homologous recombination induced by replication inhibition in mammalian cells. EMBO J 2001, 20(14):3861-3870.
• [18]Lundin C, Erixon K, Arnaudeau C, Schultz N, Jenssen D, Meuth M, Helleday T: Different roles for nonhomologous end joining and homologous recombination following replication arrest in mammalian cells. Mol Cell Biol 2002, 22(16):5869-5878.
• [19]Feng Z, Zhang J: A dual role of BRCA1 in two distinct homologous recombination mediated repair in response to replication arrest. Nucleic Acids Res 2012, 40(2):726-738.
• [20]Johnson RD, Jasin M: Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. EMBO J 2000, 19(13):3398-3407.
• [21]Arnaudeau C, Lundin C, Helleday T: DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J Mol Biol 2001, 307(5):1235-1245.
• [22]Saleh-Gohari N, Bryant HE, Schultz N, Parker KM, Cassel TN, Helleday T: Spontaneous homologous recombination is induced by collapsed replication forks that are caused by endogenous DNA single-strand breaks. Mol Cell Biol 2005, 25(16):7158-7169.
• [23]Shi W, Feng Z, Zhang J, Gonzalez-Suarez I, Vanderwaal RP, Wu X, Powell SN, Roti Roti JL, Gonzalo S, Zhang J: The Role of RPA2 Phosphorylation in Homologous Recombination in Response to Replication Arrest. Carcinogenesis 2010, 31(6):994-1002.
• [24]Wolff S, Bodycote J, Painter RB: Sister chromatid exchanges induced in Chinese hamster cells by UV irradiation of different stages of the cell cycle: the necessity for cells to pass through S. Mutat Res 1974, 25(1):73-81.
• [25]Sonoda E, Sasaki MS, Morrison C, Yamaguchi-Iwai Y, Takata M, Takeda S: Sister chromatid exchanges are mediated by homologous recombination in vertebrate cells. Mol Cell Biol 1999, 19(7):5166-5169.
• [26]Latt SA: Sister chromatid exchange formation. Annu Rev Genet 1981, 15:11-55.
• [27]Takata M, Sasaki MS, Tachiiri S, Fukushima T, Sonoda E, Schild D, Thompson LH, Takeda S: Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. Mol Cell Biol 2001, 21(8):2858-2866.
• [28]Dronkert ML, Beverloo HB, Johnson RD, Hoeijmakers JH, Jasin M, Kanaar R: Mouse RAD54 affects DNA double-strand break repair and sister chromatid exchange. Mol Cell Biol 2000, 20(9):3147-3156.
• [29]Smiraldo PG, Gruver AM, Osborn JC, Pittman DL: Extensive chromosomal instability in Rad51d-deficient mouse cells. Cancer Res 2005, 65(6):2089-2096.
• [30]Hinz JM, Tebbs RS, Wilson PF, Nham PB, Salazar EP, Nagasawa H, Urbin SS, Bedford JS, Thompson LH: Repression of mutagenesis by Rad51D-mediated homologous recombination. Nucleic Acids Res 2006, 34(5):1358-1368.
• [31]Natarajan AT, Palitti F: DNA repair and chromosomal alterations. Mutat Res 2008, 657(1):3-7.
• [32]Chaganti RS, Schonberg S, German J: A manyfold increase in sister chromatid exchanges in Bloom's syndrome lymphocytes. Proc Natl Acad Sci U S A 1974, 71(11):4508-4512.
• [33]Wu L, Davies SL, North PS, Goulaouic H, Riou JF, Turley H, Gatter KC, Hickson ID: The Bloom's syndrome gene product interacts with topoisomerase III. J Biol Chem 2000, 275(13):9636-9644.
• [34]Johnson FB, Lombard DB, Neff NF, Mastrangelo MA, Dewolf W, Ellis NA, Marciniak RA, Yin Y, Jaenisch R, Guarente L: Association of the Bloom syndrome protein with topoisomerase IIIalpha in somatic and meiotic cells. Cancer Res 2000, 60(5):1162-1167.
• [35]Wu L, Hickson ID: RecQ helicases and topoisomerases: components of a conserved complex for the regulation of genetic recombination. Cell Mol Life Sci 2001, 58(7):894-901.
• [36]Wu L, Davies SL, Levitt NC, Hickson ID: Potential role for the BLM helicase in recombinational repair via a conserved interaction with RAD51. J Biol Chem 2001, 276(22):19375-19381.
• [37]Karow JK, Constantinou A, Li JL, West SC, Hickson ID: The Bloom's syndrome gene product promotes branch migration of holliday junctions. Proc Natl Acad Sci U S A 2000, 97(12):6504-6508.
• [38]Wu L, Hickson ID: The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 2003, 426(6968):870-874.
• [39]Kikuchi K, Abdel-Aziz HI, Taniguchi Y, Yamazoe M, Takeda S, Hirota K: Bloom DNA helicase facilitates homologous recombination between diverged homologous sequences. J Biol Chem 2009, 284(39):26360-26367.
• [40]Davies SL, North PS, Dart A, Lakin ND, Hickson ID: Phosphorylation of the Bloom's syndrome helicase and its role in recovery from S-phase arrest. Mol Cell Biol 2004, 24(3):1279-1291.
• [41]Alabert C, Bianco JN, Pasero P: Differential regulation of homologous recombination at DNA breaks and replication forks by the Mrc1 branch of the S-phase checkpoint. EMBO J 2009, 28(8):1131-1141.
• [42]Richards RI: Fragile and unstable chromosomes in cancer: causes and consequences. Trends in genetics: TIG 2001, 17(6):339-345.
• [43]Glover TW, Stein CK: Induction of sister chromatid exchanges at common fragile sites. Am J Hum Genet 1987, 41(5):882-890.
• [44]Hirsch B: Sister chromatid exchanges are preferentially induced at expressed and nonexpressed common fragile sites. Hum Genet 1991, 87(3):302-306.
• [45]Casper AM, Nghiem P, Arlt MF, Glover TW: ATR regulates fragile site stability. Cell 2002, 111(6):779-789.
• [46]Casper AM, Durkin SG, Arlt MF, Glover TW: Chromosomal instability at common fragile sites in Seckel syndrome. Am J Hum Genet 2004, 75(4):654-660.
• [47]Narod SA, Foulkes WD: BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer 2004, 4(9):665-676.
• [48]Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, et al.: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 2003, 72(5):1117-1130.
• [49]Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, et al.: Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 2000, 92(7):564-569.
• [50]Russell PA, Pharoah PD, De Foy K, Ramus SJ, Symmonds I, Wilson A, Scott I, Ponder BA, Gayther SA: Frequent loss of BRCA1 mRNA and protein expression in sporadic ovarian cancers. International journal of cancer Journal international du cancer 2000, 87(3):317-321.
• [51]Thompson ME, Jensen RA, Obermiller PS, Page DL, Holt JT: Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet 1995, 9(4):444-450.
• [52]Wilson CA, Ramos L, Villasenor MR, Anders KH, Press MF, Clarke K, Karlan B, Chen JJ, Scully R, Livingston D, et al.: Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet 1999, 21(2):236-240.
• [53]Deng CX, Brodie SG: Roles of BRCA1 and its interacting proteins. BioEssays: news and reviews in molecular, cellular and developmental biology 2000, 22(8):728-737.
• [54]Gudmundsdottir K, Ashworth A: The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 2006, 25(43):5864-5874.
• [55]Moynahan ME, Jasin M: Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 2010, 11(3):196-207.
• [56]Helleday T: Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis 2010, 31(6):955-960.
• [57]Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, Ashley T, Livingston DM: Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 1997, 88(2):265-275.
• [58]Jin Y, Xu XL, Yang MC, Wei F, Ayi TC, Bowcock AM, Baer R: Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains. Proc Natl Acad Sci U S A 1997, 94(22):12075-12080.
• [59]Scully R, Chen J, Ochs RL, Keegan K, Hoekstra M, Feunteun J, Livingston DM: Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 1997, 90(3):425-435.
• [60]Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, et al.: Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell 1998, 2(3):317-328.
• [61]Shen SX, Weaver Z, Xu X, Li C, Weinstein M, Chen L, Guan XY, Ried T, Deng CX: A targeted disruption of the murine Brca1 gene causes gamma-irradiation hypersensitivity and genetic instability. Oncogene 1998, 17(24):3115-3124.
• [62]Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, Harris CC, Ried T, Deng CX: Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 1999, 3(3):389-395.
• [63]Moynahan ME, Chiu JW, Koller BH, Jasin M: Brca1 controls homology-directed DNA repair. Mol Cell 1999, 4(4):511-518.
• [64]Moynahan ME, Cui TY, Jasin M: Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 2001, 61(12):4842-4850.
• [65]Zhang J, Ma Z, Treszezamsky A, Powell SN: MDC1 interacts with Rad51 and facilitates homologous recombination. Nat Struct Mol Biol 2005, 12(10):902-909.
• [66]Longerich S, Orelli BJ, Martin RW, Bishop DK, Storb U: Brca1 in immunoglobulin gene conversion and somatic hypermutation. DNA Repair 2008, 7(2):253-266.
• [67]Pathania S, Nguyen J, Hill SJ, Scully R, Adelmant GO, Marto JA, Feunteun J, Livingston DM: BRCA1 is required for postreplication repair after UV-induced DNA damage. Mol Cell 2011, 44(2):235-251.
• [68]Kato H: Induction of sister chromatid exchanges by UV light and its inhibition by caffeine. Exp Cell Res 1973, 82(2):383-390.
• [69]Eppink B, Tafel AA, Hanada K, van Drunen E, Hickson ID, Essers J, Kanaar R: The response of mammalian cells to UV-light reveals Rad54-dependent and independent pathways of homologous recombination. DNA Repair 2011, 10(11):1095-1105.
• [70]Saleh-Gohari N, Helleday T: Strand invasion involving short tract gene conversion is specifically suppressed in BRCA2-deficient hamster cells. Oncogene 2004, 23(56):9136-9141.
• [71]Kasparek TR, Humphrey TC: DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Semin Cell Dev Biol 2011, 22(8):886-897.
• [72]Petermann E, Helleday T: Pathways of mammalian replication fork restart. Nat Rev Mol Cell Biol 2010, 11(10):683-687.
• [73]Roy R, Chun J, Powell SN: BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 2012, 12(1):68-78.
• [74]Liu Y, West SC: Distinct functions of BRCA1 and BRCA2 in double-strand break repair. Breast cancer research: BCR 2002, 4(1):9-13. BioMed Central Full Text
• [75]Schild D, Wiese C: Overexpression of RAD51 suppresses recombination defects: a possible mechanism to reverse genomic instability. Nucleic Acids Res 2010, 38(4):1061-1070.
• [76]Feng Z, Scott SP, Bussen W, Sharma GG, Guo G, Pandita TK, Powell SN: Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc Natl Acad Sci U S A 2011, 108(2):686-691.
• [77]Martin RW, Orelli BJ, Yamazoe M, Minn AJ, Takeda S, Bishop DK: RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors. Cancer Res 2007, 67(20):9658-9665.
• [78]Yun MH, Hiom K: CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 2009, 459(7245):460-463.
• [79]Yu X, Chen J: DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Mol Cell Biol 2004, 24(21):9478-9486.
• [80]Greenberg RA, Sobhian B, Pathania S, Cantor SB, Nakatani Y, Livingston DM: Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes. Genes Dev 2006, 20(1):34-46.
• [81]Michel B, Boubakri H, Baharoglu Z, LeMasson M, Lestini R: Recombination proteins and rescue of arrested replication forks. DNA Repair 2007, 6(7):967-980.
• [82]Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA: Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev 2005, 19(9):1040-1052.
• [83]Cortez D: Unwind and slow down: checkpoint activation by helicase and polymerase uncoupling. Genes Dev 2005, 19(9):1007-1012.
• [84]Bunting SF, Callen E, Wong N, Chen HT, 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 2010, 141(2):243-254.
• [85]Cao L, Xu X, Bunting SF, Liu J, Wang RH, Cao LL, Wu JJ, Peng TN, Chen J, Nussenzweig A, et al.: A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol Cell 2009, 35(4):534-541.
• [86]Bouwman P, Aly A, Escandell JM, 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 2010, 17(6):688-695.
• [87]Hu Y, Scully R, Sobhian B, Xie A, Shestakova E, Livingston DM: RAP80-directed tuning of BRCA1 homologous recombination function at ionizing radiation-induced nuclear foci. Genes Dev 2011, 25(7):685-700.
• [88]Chapman JR, Sossick AJ, Boulton SJ, Jackson SP: BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J Cell Sci 2012, 125(Pt 15):3529-3534.
• [89]Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D, Yabuki Y, Ogata H, Ohta T: The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J Biol Chem 2001, 276(18):14537-14540.
• [90]Brzovic PS, Keeffe JR, Nishikawa H, Miyamoto K, Fox D 3rd, Fukuda M, Ohta T, Klevit R: Binding and recognition in the assembly of an active BRCA1/BARD1 ubiquitin-ligase complex. Proc Natl Acad Sci U S A 2003, 100(10):5646-5651.
• [91]Ruffner H, Joazeiro CA, Hemmati D, Hunter T, Verma IM: Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci U S A 2001, 98(9):5134-5139.
• [92]Couch FJ, Weber BL: Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene, Breast Cancer Information Core. Hum Mutat 1996, 8(1):8-18.
• [93]Shattuck-Eidens D, McClure M, Simard J, Labrie F, Narod S, Couch F, Hoskins K, Weber B, Castilla L, Erdos M, et al.: A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA: the journal of the American Medical Association 1995, 273(7):535-541.
• [94]Ransburgh DJ, Chiba N, Ishioka C, Toland AE, Parvin JD: Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination. Cancer Res 2010, 70(3):988-995.
• [95]Reid LJ, Shakya R, Modi AP, Lokshin M, Cheng JT, Jasin M, Baer R, Ludwig T: E3 ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks. Proc Natl Acad Sci U S A 2008, 105(52):20876-20881.
• [96]Pierce AJ, Hu P, Han M, Ellis N, Jasin M: Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev 2001, 15(24):3237-3242.
• [97]Zhuang J, Zhang J, Willers H, Wang H, Chung JH, van Gent DC, Hallahan DE, Powell SN, Xia F: Checkpoint kinase 2-mediated phosphorylation of BRCA1 regulates the fidelity of nonhomologous end-joining. Cancer Res 2006, 66(3):1401-1408.
• [98]Wang HC, Chou WC, Shieh SY, Shen CY: Ataxia telangiectasia mutated and checkpoint kinase 2 regulate BRCA1 to promote the fidelity of DNA end-joining. Cancer Res 2006, 66(3):1391-1400.
• [99]Zhang J, Willers H, Feng Z, Ghosh JC, Kim S, Weaver DT, Chung JH, Powell SN, Xia F: Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Mol Cell Biol 2004, 24(2):708-718.
• [100]Thompson EG, Fares H, Dixon K: BRCA1 requirement for the fidelity of plasmid DNA double-strand break repair in cultured breast epithelial cells. Environ Mol Mutagen 2012, 53(1):32-43.
• [101]Turner BC, Ottey M, Zimonjic DB, Potoczek M, Hauck WW, Pequignot E, Keck-Waggoner CL, Sevignani C, Aldaz CM, McCue PA, et al.: The fragile histidine triad/common chromosome fragile site 3B locus and repair-deficient cancers. Cancer Res 2002, 62(14):4054-4060.
• [102]Bunting SF, Callen E, Kozak ML, Kim JM, Wong N, Lopez-Contreras AJ, Ludwig T, Baer R, Faryabi RB, Malhowski A, et al.: BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol Cell 2012, 46(2):125-135.
• [103]Kastan MB, Bartek J: Cell-cycle checkpoints and cancer. Nature 2004, 432(7015):316-323.
• [104]Cressman VL, Backlund DC, Avrutskaya AV, Leadon SA, Godfrey V, Koller BH: Growth retardation, DNA repair defects, and lack of spermatogenesis in BRCA1-deficient mice. Mol Cell Biol 1999, 19(10):7061-7075.
• [105]Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA, Harris CC, Deng CX: Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat Genet 2001, 28(3):266-271.
• [106]Ramus SJ, Bobrow LG, Pharoah PD, Finnigan DS, Fishman A, Altaras M, Harrington PA, Gayther SA, Ponder BA, Friedman LS: Increased frequency of TP53 mutations in BRCA1 and BRCA2 ovarian tumours. Genes Chromosomes Cancer 1999, 25(2):91-96.
• [107]Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A, Kerkhoven RM, van Vliet MH, Wessels LF, Peterse JL, et al.: Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci U S A 2007, 104(29):12111-12116.
• [108]Hakem R, de la Pompa JL, Elia A, Potter J, Mak TW: Partial rescue of Brca1 (5–6) early embryonic lethality by p53 or p21 null mutation. Nat Genet 1997, 16(3):298-302.
• [109]Holstege H, Joosse SA, van Oostrom CT, Nederlof PM, de Vries A, Jonkers J: High incidence of protein-truncating TP53 mutations in BRCA1-related breast cancer. Cancer Res 2009, 69(8):3625-3633.
• [110]Cao L, Kim S, Xiao C, Wang RH, Coumoul X, Wang X, Li WM, Xu XL, De Soto JA, Takai H, et al.: ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency. EMBO J 2006, 25(10):2167-2177.
• [111]Tommiska J, Bartkova J, Heinonen M, Hautala L, Kilpivaara O, Eerola H, Aittomaki K, Hofstetter B, Lukas J, von Smitten K, et al.: The DNA damage signalling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. Oncogene 2008, 27(17):2501-2506.
• [112]Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, et al.: Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 2002, 31(1):55-59.
• [113]Lee JS, Collins KM, Brown AL, Lee CH, Chung JH: hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 2000, 404(6774):201-204.
• [114]Kim SS, Cao L, Li C, Xu X, Huber LJ, Chodosh LA, Deng CX: Uterus hyperplasia and increased carcinogen-induced tumorigenesis in mice carrying a targeted mutation of the Chk2 phosphorylation site in Brca1. Mol Cell Biol 2004, 24(21):9498-9507.
• [115]Abraham RT: Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev 2001, 15(17):2177-2196.
• [116]Chen J: Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage. Cancer Res 2000, 60(18):5037-5039.
• [117]Gatei M, Zhou BB, Hobson K, Scott S, Young D, Khanna KK: Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites, In vivo assessment using phospho-specific antibodies. J Biol Chem 2001, 276(20):17276-17280.
• [118]Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT: Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev 2000, 14(23):2989-3002.
• [119]Kote-Jarai Z, Williams RD, Cattini N, Copeland M, Giddings I, Wooster R, TePoele RH, Workman P, Gusterson B, Peacock J, et al.: Gene expression profiling after radiation-induced DNA damage is strongly predictive of BRCA1 mutation carrier status. Clinical cancer research: an official journal of the American Association for Cancer Research 2004, 10(3):958-963.
• [120]Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, et al.: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005, 434(7035):917-921.
• [121]Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005, 434(7035):913-917.
• [122]McCabe N, Lord CJ, Tutt AN, Martin NM, Smith GC, Ashworth A: BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of Poly (ADP-Ribose) polymerase: an issue of potency. Cancer Biol Ther 2005, 4(9):934-936.
• [123]Shaheen M, Allen C, Nickoloff JA, Hromas R: Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood 2011, 117(23):6074-6082.
• [124]Weil MK, Chen AP: PARP inhibitor treatment in ovarian and breast cancer. Curr Probl Cancer 2011, 35(1):7-50.
• [125]Strom CE, Johansson F, Uhlen M, Szigyarto CA, Erixon K, Helleday T: Poly (ADP-ribose) polymerase (PARP) is not involved in base excision repair but PARP inhibition traps a single-strand intermediate. Nucleic Acids Res 2011, 39(8):3166-3175.
• [126]Helleday T, Bryant HE, Schultz N: Poly(ADP-ribose) polymerase (PARP-1) in homologous recombination and as a target for cancer therapy. Cell Cycle 2005, 4(9):1176-1178.
• [127]Schultz N, Lopez E, Saleh-Gohari N, Helleday T: Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res 2003, 31(17):4959-4964.
• [128]de Murcia JM, Niedergang C, Trucco C, Ricoul M, Dutrillaux B, Mark M, Oliver FJ, Masson M, Dierich A, LeMeur M, et al.: Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc Natl Acad Sci U S A 1997, 94(14):7303-7307.
• [129]Simbulan-Rosenthal CM, Haddad BR, Rosenthal DS, Weaver Z, Coleman A, Luo R, Young HM, Wang ZQ, Ried T, Smulson ME: Chromosomal aberrations in PARP(−/−) mice: genome stabilization in immortalized cells by reintroduction of poly(ADP-ribose) polymerase cDNA. Proc Natl Acad Sci U S A 1999, 96(23):13191-13196.
• [130]Bryant HE, Petermann E, Schultz N, Jemth AS, Loseva O, Issaeva N, Johansson F, Fernandez S, McGlynn P, Helleday T: PARP is activated at stalled forks to mediate Mre11-dependent replication restart and recombination. EMBO J 2009, 28(17):2601-2615.
• [131]Guha M: PARP inhibitors stumble in breast cancer. Nat Biotechnol 2011, 29(5):373-374.
• [132]Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, Villegas E, Jacquemont C, Farrugia DJ, Couch FJ, et al.: Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 2008, 451(7182):1116-1120.
• [133]Dhillon KK, Swisher EM, Taniguchi T: Secondary mutations of BRCA1/2 and drug resistance. Cancer Sci 2011, 102(4):663-669.
• [134]Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, et al.: High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A 2008, 105(44):17079-17084.
• [135]Issaeva N, Thomas HD, Djureinovic T, Jaspers JE, Stoimenov I, Kyle S, Pedley N, Gottipati P, Zur R, Sleeth K, et al.: 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance. Cancer Res 2010, 70(15):6268-6276.
• [136]De Soto JA, Deng CX: PARP-1 inhibitors: are they the long-sought genetically specific drugs for BRCA1/2-associated breast cancers? Int J Med Sci 2006, 3(4):117-123.
• [137]Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, et al.: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Eng J Med 2009, 361(2):123-134.