BRCA1 gene: function and deficiency

Abstract

The BRCA1 protein, a hereditary breast and ovarian cancer-causing gene product, is known as a multifunctional protein that performs various functions in cells. It is well known, along with BRCA 2, to cause hereditary breast and ovarian cancer, but here we will specifically focus on BRCA1. We introduce the mechanism and the latest report on homologous recombination repair, replication, involvement in checkpoint regulation, transcription, chromatin remodeling, and cytoplasmic function (centrosome regulation, apoptosis, selective autophagy), and consider the possibility of carcinogenesis from inhibition of the intracellular functions in each. We also consider the possibility of drug development based on each function. Finally, we will explain, from data obtained through basic research, that an appropriate regimen is important for raising the response rate for poly (ADP)-ribose polymerase inhibitors, in the case of low susceptibility, iatrogenic toxicity, tolerance, etc.

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References

  1. 1.

    Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Wooster R, Neuhausen SL, Mangion J et al (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 265:2088–2090

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    O’Donovan PJ, Livingston DM (2010) BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis 31:961–967

    Article  PubMed  Google Scholar 

  4. 4.

    Venkitaraman AR (2014) Cancer suppression by the chromosome custodians, BRCA1 and BRCA2. Science 343:1470–1475

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Thompson D, Easton D, Breast Cancer Linkage Consortium (2002) Variation in BRCA1 cancer risks by mutation position. Cancer Epidemiol Biomark Prev 11:329–336

    CAS  Google Scholar 

  6. 6.

    Rebbeck TR, Mitra N, Wan F et al (2015) Association of type and location of BRCA1 and BRCA2 mutations with risk of breastand ovarian cancer. JAMA 313:1347–1361

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Manke IA, Lowery DM, Nguyen A et al (2003) BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302:636–639

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Rodriguez M, Yu X, Chen J et al (2003) Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains. J Biol Chem 278:52914–52918

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Yu X, Chini CC, He M et al (2003) The BRCT domain is a phospho-protein binding domain. Science 302:639–642

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Wu LC, Wang ZW, Tsan JT et al (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 14:430–440

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Hashizume R, Fukuda M, Maeda I et al (2001) The RING heterodimer BRCA1–BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J Biol Chem 276:14537–14540

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Ruffner H, Joazeiro CA, Hemmati D et al (2001) Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci USA 98:5134–5139

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Brzovic PS, Rajagopal P, Hoyt DW et al (2001) Structure of a BRCA1–BARD1 heterodimeric RING–RING complex. Nat Struct Biol 8:833–837

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Drost R, Bouwman P, Rottenberg S et al (2011) BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. Cancer Cell 20:797–809

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Scully R, Chen J, Plug A et al (1997) Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88:265–275

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Li M, Yu X (2013) Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell 23:693–704

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Wang B, Matsuoka S, Ballif BA et al (2007) Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316:1194–1198

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kim H, Chen J, Yu X (2007) Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316:1202–1205

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Kim H, Huang J, Chen J (2007) CCDC98 is a BRCA1–BRCT domain-binding protein involved in the DNA damage response. Nat Struct Mol Biol 14:710–715

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Yu X, Wu LC, Bowcock AM et al (1998) The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J Biol Chem 273:25388–25392

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Yu X, Fu S, Lai M et al (2006) BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev 20:1721–1726

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Cantor SB, Bell DW, Ganesan S et al (2001) BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105:149–160

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Litman R, Peng M, Jin Z et al (2005) BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8:255–265

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Sobhian B, Shao G, Lilli DR et al (2007) RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316:1198–1202

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Paull TT, Rogakou EP, Yamazaki V et al (2000) A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr Biol 10:886–895

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Stewart GS, Wang B, Bignell CR et al (2003) MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421:961–966

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Hu Y, Scully R, Sobhian B et al (2011) RAP80-directed tuning of BRCA1 homologous recombination function at ionizing radiation-induced nuclear foci. Genes Dev 25:685–700

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Li Y, Luo K, Yin Y et al (2017) USP13 regulates the RAP80–BRCA1 complex dependent DNA damage response. Nat Commun 8:15752

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Escribano-Díaz C, Orthwein A, Fradet-Turcotte A et al (2013) A cell cycle-dependent regulatory circuit composed of 53BP1–RIF1 and BRCA1–CtIP controls DNA repair pathway choice. Mol Cell 49:872–883

    Article  PubMed  Google Scholar 

  30. 30.

    Chandramouly G, Kwok A, Huang B et al (2013) BRCA1 and CtIP suppress long-tract gene conversion between sister chromatids. Nat Commun 4:2404

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Cruz-García A, López-Saavedra A, Huertas P (2014) BRCA1 accelerates CtIP-mediated DNA-end resection. Cell Rep 9:451–459

    Article  PubMed  Google Scholar 

  32. 32.

    Sartori AA, Lukas C, Coates J et al (2007) Human CtIP promotes DNA end resection. Nature 450:509–514

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Reczek CR, Szabolcs M, Stark JM et al (2013) The interaction between CtIP and BRCA1 is not essential for resection-mediated DNA repair or tumor suppression. J Cell Biol 201:693–707

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Andreassen PR, Ren K (2009) Fanconi anemia proteins, DNA interstrand crosslink repair pathways, and cancer therapy. Curr Cancer Drug Targets 9:101–117

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Michl J, Zimmer J, Tarsounas M (2016) Interplay between Fanconi anemia and homologous recombination pathways in genome integrity. EMBO J 35:909–923

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Gupta R, Sharma S, Sommers JA et al (2007) FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein. Blood 110:2390–2398

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Zhang F, Fan Q, Ren K (2010) FANCJ/BRIP1 recruitment and regulation of FANCD2 in DNA damage responses. Chromosoma 119:637–649

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Zhang F, Ma J, Wu J et al (2009) PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol 19:524–529

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Friedman LS, Ostermeyer EA, Szabo CI et al (1994) Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet 8:399–404

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Futreal PA, Liu Q, Shattuck-Eidens D et al (1994) BRCA1 mutations in primary breast and ovarian carcinomas. Science 266:120–122

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Gayther SA, Harrington P, Russell P et al (1996) Rapid detection of regionally clustered germ-line BRCA1 mutations by multiplex heteroduplex analysis. UKCCCR Familial Ovarian Cancer Study Group. Am J Hum Genet 58:451–456

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Yu X, Chen J (2004) DNA damage-induced cell cycle checkpoint control requires CtIP, a phosphorylation-dependent binding partner of BRCA1 C-terminal domains. Mol Cell Biol 24:9478–9486

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Gong Z, Kim JE, Leung CC et al (2010) BACH1/FANCJ acts with top BP1 and participates early in DNA replication checkpoint control. Mol Cell 37:438–446

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Kumaraswamy E, Shiekhattar R (2007) Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase. Mol Cell Biol 27:6733–6741

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Varma AK, Brown RS, Birrane G et al (2005) Structural basis for cell cycle checkpoint control by the BRCA1–CtIP complex. Biochemistry 44:10941–10946

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Monteiro AN, August A, Hanafusa H (1996) Evidence for a transcriptional activation function of BRCA1 C-terminal region. Proc Natl Acad Sci USA 93:13595–13599

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Scully R, Anderson SF, Chao DM et al (1997) BRCA1 is a component of the RNA polymerase II holoenzyme. Proc Natl Acad Sci USA 94:5605–5610

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Somasundaram K, Zhang H, Zeng YX et al (1997) Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature 389:187–190

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Ouchi T, Monteiro AN, August A et al (1998) BRCA1 regulates p53-dependent gene expression. Proc Natl Acad Sci USA 95:2302–2306

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Zhang H, Somasundaram K, Peng Y et al (1998) BRCA1 physically associates with p53 and stimulates its transcriptional activity. Oncogene 16:1713–1721

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Bochar DA, Wang L, Beniya H et al (2000) BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102:257–265

    CAS  Article  PubMed  Google Scholar 

  52. 52.

    Filipponi D, Muller J, Emelyanov A et al (2013) Wip1 controls global Heterochromatin silencing via ATM/BRCA1-dependent DNA methylation. Cancer Cell 24:528–541

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Zhu Q, Pao GM, Huynh AM et al (2011) BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature 477:179–184

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Chan JY (2011) A clinical overview of centrosome amplification in human cancers. Int J Biol Sci 7:1122–1144

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Starita LM, Machida Y, Sankaran S et al (2004) BRCA1-dependent ubiquitination of gamma-tubulin regulates centrosome number. Mol Cell Biol 24:8457–8466

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Ko MJ, Murata K, Hwang DS et al (2006) Inhibition of BRCA1 in breast cell lines causes the centrosome duplication cycle to be disconnected from the cell cycle. Oncogene 25:298–303

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Matsuzawa A, Kanno S, Nakayama M et al (2014) The BRCA1/BARD1-interacting protein OLA1 functions in centrosome regulation. Mol Cell 53:101–114

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Sankaran S, Starita LM, Groen AC et al (2005) Centrosomal microtubule nucleation activity is inhibited by BRCA1-dependent ubiquitination. Mol Cell Biol 25:8656–8668

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Kais Z, Chiba N, Ishioka C et al (2012) Functional differences among BRCA1 missense mutations in the control of centrosome duplication. Oncogene 31:799–804

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Harkin DP, Bean JM, Miklos D et al (1999) Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97:575–586

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Fabbro M, Rodriguez JA, Baer R et al (2002) BARD1 induces BRCA1 intranuclear foci formation by increasing RING-dependent BRCA1 nuclear import and inhibiting BRCA1 nuclear export. J Biol Chem 277:21315–21324

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Fabbro M, Schuechner S, Au WW et al (2004) BARD1 regulates BRCA1 apoptotic function by a mechanism involving nuclear retention. Exp Cell Res 298:661–673

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Shao N, Chai YL, Shyam E et al (1996) Induction of apoptosis by the tumor suppressor protein BRCA1. Oncogene 13:1–7

    CAS  PubMed  Google Scholar 

  64. 64.

    Zielinski CC, Budinsky AC, Wagner TM et al (2003) Defect of tumour necrosis factor-alpha (TNF-alpha) production and TNF-alpha-induced ICAM-1-expression in BRCA1 mutations carriers. Breast Cancer Res Treat 81:99–105

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Lin D, Chai Y, Izadpanah R et al (2016) NPR3 protects cardiomyocytes from apoptosis through inhibition of cytosolic BRCA1 and TNF-α. Cell Cycle 15:2414–2419

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Sumpter R Jr, Sirasanagandla S, Fernández ÁF et al (2016) Fanconi anemia proteins function in mitophagy and immunity. Cell 165:867–881

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Gong Y, Zack TI, Morris LG et al (2014) Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat Gen 46:588–594

    CAS  Article  Google Scholar 

  68. 68.

    Fujiwara M, Marusawa H, Wang HQ et al (2008) Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene 27:6002–6011

    CAS  Article  PubMed  Google Scholar 

  69. 69.

    Poulogiannis G, McIntyre RE, Dimitriadi M et al (2010) PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc Natl Acad Sci USA 107:15145–15150

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Chourasia AH, Boland ML, Macleod KF (2015) Mitophagy and cancer. Cancer Metab 3:4

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Byrski T, Gronwald J, Huzarski T et al (2010) Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 28:375–379

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Byrski T, Dent R, Blecharz P et al (2012) Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res 14:R110

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Fisher AE, Hochegger H, Takeda S et al (2007) Poly(ADP-ribose) polymerase 1 accelerates single-strand break repair in concert with poly(ADP-ribose) glycohydrolase. Mol Cell Biol 27:5597–5605

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–917

    CAS  Article  PubMed  Google Scholar 

  75. 75.

    Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Rottenberg S, Jaspers JE, Kersbergen A et al (2008) High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci USA 105:17079–17084

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Fong PC, Yap TA, Boss DS et al (2010) Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 28:2512–2519

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Audeh MW, Carmichael J, Penson RT et al (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376:245–251

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Tutt A, Robson M, Garber JE et al (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376:235–244

    CAS  Article  PubMed  Google Scholar 

  80. 80.

    Gelmon KA, Tischkowitz M, Mackay H et al (2011) 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 12:852–861

    CAS  Article  PubMed  Google Scholar 

  81. 81.

    Kaye SB, Lubinski J, Matulonis U et al (2012) 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 30:372–379

    CAS  Article  PubMed  Google Scholar 

  82. 82.

    Sakai W, Swisher EM, Karlan BY et al (2008) Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451:1116–1120

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Edwards SL, Brough R, Lord CJ et al (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111–1115

    CAS  Article  PubMed  Google Scholar 

  84. 84.

    Norquist B, Wurz KA, Pennil CC et al (2011) Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol 29:3008–3015

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Wiedemeyer WR, Beach JA, Karlan BY (2014) Reversing platinum resistance in high-grade serous ovarian carcinoma: targeting brca and the homologous recombination system. Front Oncol 4:34

    Article  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134

    CAS  Article  PubMed  Google Scholar 

  87. 87.

    Lheureux S, Bruce JP, Burnier JV et al (2017) Somatic BRCA1/2 recovery as a resistance mechanism after exceptional response to poly(ADP-ribose) polymerase inhibition. J Clin Oncol 35:1240–1249

    Article  PubMed  Google Scholar 

  88. 88.

    Schoonen PM, Talens F, Stok C et al (2017) Progression through mitosis promotes PARP inhibitor-induced cytotoxicity in homologous recombination-deficient cancer cells. Nat Commun 8:15981

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Duan W, Rangan A, Vankayalapati H et al (2001) Design and synthesis of fluoroquinophenoxazines that interact with human telomeric G-quadruplexes and their biological effects. Mol Cancer Ther 1:103–120

    CAS  PubMed  Google Scholar 

  90. 90.

    Cheung I, Schertzer M, Rose A et al (2002) Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA. Nat Genet 31:405–409

    CAS  Article  PubMed  Google Scholar 

  91. 91.

    Youds JL, Barber LJ, Ward JD et al (2008) DOG-1 is the Caenorhabditis elegans BRIP1/FANCJ homologue and functions in interstrand cross-link repair. Mol Cell Biol 28:1470–1479

    CAS  Article  PubMed  Google Scholar 

  92. 92.

    Wu Y, Shin-ya K, Brosh RM Jr (2008) FANCJ helicase defective in Fanconia anemia and breast cancer unwinds G-quadruplex DNA to defend genomic stability. Mol Cell Biol 28:4116–4128

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Zimmer J, Tacconi EM, Folio C et al (2016) Targeting BRCA1 and BRCA2 deficiencies with G-quadruplex-interacting compounds. Mol Cell 61:449–460

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Xu H, Di Antonio M, McKinney S et al (2017) CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun 8:14432

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank all members of the Department of Molecular Genetics of the Tokyo Medical and Dental University who provided helpful discussion.

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Correspondence to Yoshio Miki.

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Conflict of interest

Yoshio Miki received honoraria from AstraZenaca Co., Ltd. Miho Takaoka has no conflict of interest to disclose.

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Takaoka, M., Miki, Y. BRCA1 gene: function and deficiency. Int J Clin Oncol 23, 36–44 (2018). https://doi.org/10.1007/s10147-017-1182-2

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Keywords

  • BRCA1
  • Hereditary breast and ovarian cancer
  • Gene mutation
  • PARP inhibitor