Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication

Abstract

The tumour suppressor breast cancer type 1 susceptibility protein (BRCA1) promotes DNA double-strand break (DSB) repair by homologous recombination and protects DNA replication forks from attrition. BRCA1 partners with BRCA1-associated RING domain protein 1 (BARD1) and other tumour suppressor proteins to mediate the initial nucleolytic resection of DNA lesions and the recruitment and regulation of the recombinase RAD51. The discovery of the opposing functions of BRCA1 and the p53-binding protein 1 (53BP1)-associated complex in DNA resection sheds light on how BRCA1 influences the choice of homologous recombination over non-homologous end joining and potentially other mutagenic pathways of DSB repair. Understanding the functional crosstalk between BRCA1–BARD1 and its cofactors and antagonists will illuminate the molecular basis of cancers that arise from a deficiency or misregulation of chromosome damage repair and replication fork maintenance. Such knowledge will also be valuable for understanding acquired tumour resistance to poly(ADP-ribose) polymerase (PARP) inhibitors and other therapeutics and for the development of new treatments. In this Review, we discuss recent advances in elucidating the mechanisms by which BRCA1–BARD1 functions in DNA repair, replication fork maintenance and tumour suppression, and its therapeutic relevance.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: The functional domains of BRCA1 and BARD1.
Fig. 2: The roles of BRCA1–BARD1 in DSB repair by homologous recombination.
Fig. 3: Antagonistic roles of BRCA1–BARD1 and the 53BP1 complex.
Fig. 4: Roles of the BRCA1 complex in protecting regressed replication forks and resolving R-loops.

References

  1. Saini, N. & Gordenin, D. A. Somatic mutation load and spectra: a record of DNA damage and repair in healthy human cells. Env. Mol. Mutagen. 59, 672–686 (2018).

    Article  CAS  Google Scholar 

  2. Tubbs, A. & Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Cell 168, 644–656 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Loeb, L. A. & Harris, C. C. Advances in chemical carcinogenesis: a historical review and prospective. Cancer Res. 68, 6863–6872 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Prakash, R., Zhang, Y., Feng, W. & Jasin, M. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb. Perspect. Biol. 7, a016600 (2015).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Konstantinopoulos, P. A., Ceccaldi, R., Shapiro, G. I. & D’Andrea, A. D. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 5, 1137–1154 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. McKinnon, P. J. Genome integrity and disease prevention in the nervous system. Genes. Dev. 31, 1180–1194 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Alt, F. W. & Schwer, B. DNA double-strand breaks as drivers of neural genomic change, function, and disease. DNA Repair 71, 158–163 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Gorthi, A. & Bishop, A. J. R. Ewing sarcoma fusion oncogene: at the crossroads of transcription and DNA damage response. Mol. Cell Oncol. 5, e1465014 (2018).

    Article  PubMed Central  PubMed  Google Scholar 

  9. Daley, J. M., Niu, H., Miller, A. S. & Sung, P. Biochemical mechanism of DSB end resection and its regulation. DNA Repair 32, 66–74 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Verma, P. & Greenberg, R. A. Noncanonical views of homology-directed DNA repair. Genes Dev. 30, 1138–1154 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. San Filippo, J., Sung, P. & Klein, H. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem. 77, 229–257 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. Sollier, J. & Cimprich, K. A. Breaking bad: R-loops and genome integrity. Trends Cell Biol. 25, 514–522 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Techer, H., Koundrioukoff, S., Nicolas, A. & Debatisse, M. The impact of replication stress on replication dynamics and DNA damage in vertebrate cells. Nat. Rev. Genet. 18, 535–550 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Feng, W. & Jasin, M. Homologous recombination and replication fork protection: BRCA2 and more! Cold Spring Harb. Symp. Quant. Biol. 82, 329–338 (2017).

    Article  PubMed  Google Scholar 

  15. Rickman, K. & Smogorzewska, A. Advances in understanding DNA processing and protection at stalled replication forks. J. Cell Biol. 218, 1096–1107 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Ira, G. et al. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431, 1011–1017 (2004).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Huertas, P., Cortes-Ledesma, F., Sartori, A. A., Aguilera, A. & Jackson, S. P. CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455, 689–692 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Gorodetska, I., Kozeretska, I. & Dubrovska, A. BRCA genes: the role in genome stability, cancer stemness and therapy resistance. J. Cancer 10, 2109–2127 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Cavanagh, H. & Rogers, K. M. The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers. Hered. Cancer Clin. Pract. 13, 16 (2015).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  20. Noh, J. M. et al. Associations between BRCA mutations in high-risk breast cancer patients and familial cancers other than breast or ovary. J. Breast Cancer 15, 283–287 (2012).

    Article  PubMed Central  PubMed  Google Scholar 

  21. Mersch, J. et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 121, 269–275 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Ghimenti, C. et al. Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Genes Chromosomes Cancer 33, 235–242 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Karppinen, S. M., Heikkinen, K., Rapakko, K. & Winqvist, R. Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer. J. Med. Genet. 41, e114 (2004).

    Article  PubMed Central  PubMed  Google Scholar 

  24. De Brakeleer, S. et al. Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum. Mutat. 31, E1175–E1185 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Rudd, M. F. et al. Variants in the GH-IGF axis confer susceptibility to lung cancer. Genome Res. 16, 693–701 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Esteban-Jurado, C. et al. Whole-exome sequencing identifies rare pathogenic variants in new predisposition genes for familial colorectal cancer. Genet. Med. 17, 131–142 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Suszynska, M. et al. BARD1 is a low/moderate breast cancer risk gene: evidence based on an association study of the central European p.Q564X recurrent mutation. Cancers 11, 740 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  28. Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Ashworth, A. & Lord, C. J. Synthetic lethal therapies for cancer: what’s next after PARP inhibitors? Nat. Rev. Clin. Oncol. 15, 564–576 (2018).

    Article  CAS  PubMed  Google Scholar 

  30. D’Andrea, A. D. Mechanisms of PARP inhibitor sensitivity and resistance. DNA Repair 71, 172–176 (2018).

    Article  CAS  PubMed  Google Scholar 

  31. Annunziato, S., Barazas, M., Rottenberg, S. & Jonkers, J. Genetic dissection of cancer development, therapy response, and resistance in mouse models of breast cancer. Cold Spring Harb. Symp. Quant. Biol. 81, 141–150 (2016).

    Article  PubMed  Google Scholar 

  32. Ludwig, T., Chapman, D. L., Papaioannou, V. E. & Efstratiadis, A. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 11, 1226–1241 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Hakem, R. et al. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 85, 1009–1023 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Liu, C. Y., Flesken-Nikitin, A., Li, S., Zeng, Y. & Lee, W. H. Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev. 10, 1835–1843 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Gowen, L. C., Johnson, B. L., Latour, A. M., Sulik, K. K. & Koller, B. H. Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat. Genet. 12, 191–194 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. McCarthy, E. E., Celebi, J. T., Baer, R. & Ludwig, T. Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. Mol. Cell Biol. 23, 5056–5063 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Xu, X. et al. Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nat. Genet. 22, 37–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  38. McCarthy, A. et al. A mouse model of basal-like breast carcinoma with metaplastic elements. J. Pathol. 211, 389–398 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Liu, X. 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. USA 104, 12111–12116 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shakya, R. et al. The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. Proc. Natl Acad. Sci. USA 105, 7040–7045 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. Koonin, E. V., Altschul, S. F. & Bork, P. BRCA1 protein products. Functional motifs. Nat. Genet. 13, 266–268 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Castilla, L. H. et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat. Genet. 8, 387–391 (1994).

    Article  CAS  PubMed  Google Scholar 

  44. Friedman, L. S. et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat. Genet. 8, 399–404 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Hall, J. M. et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250, 1684–1689 (1990). This study maps the first genomic region linked to inherited breast cancer.

    Article  CAS  PubMed  Google Scholar 

  46. Steichen-Gersdorf, E. et al. Familial site-specific ovarian cancer is linked to BRCA1 on 17q12-21. Am. J. Hum. Genet. 55, 870–875 (1994).

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Narod, S. A. et al. Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 338, 82–83 (1991).

    Article  CAS  PubMed  Google Scholar 

  48. King, M.-C., Marks, J. & Mandell, J. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302, 643–646 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Futreal, P. A. et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 266, 120–122 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Esteller, M. et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl Cancer Inst. 92, 564–569 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Foulkes, W. D., Smith, I. E. & Reis-Filho, J. S. Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Wu, L. C. et al. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat. Genet. 14, 430–440 (1996). This study isolates the BRCA1 partner BARD1.

    Article  CAS  PubMed  Google Scholar 

  53. Bosse, K. R. et al. Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity. Cancer Res. 72, 2068–2078 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Fu, W. et al. BARD1 gene polymorphisms confer nephroblastoma susceptibility. EBioMedicine 16, 101–105 (2017).

    Article  PubMed Central  PubMed  Google Scholar 

  55. Cimmino, F., Formicola, D. & Capasso, M. Dualistic role of BARD1 in cancer. Genes 8, 375 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  56. Brzovic, P. S., Rajagopal, P., Hoyt, D. W., King, M. C. & Klevit, R. E. Structure of a BRCA1-BARD1 heterodimeric RING-RING complex. Nat. Struct. Biol. 8, 833–837 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  58. Densham, R. M. & Morris, J. R. The BRCA1 ubiquitin ligase function sets a new trend for remodelling in DNA repair. Nucleus 8, 116–125 (2017).

    Article  CAS  PubMed  Google Scholar 

  59. Brzovic, P. S., Meza, J., King, M. C. & Klevit, R. E. The cancer-predisposing mutation C61G disrupts homodimer formation in the NH2-terminal BRCA1 RING finger domain. J. Biol. Chem. 273, 7795–7799 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Yu, X., Wu, L. C., Bowcock, A. M., Aronheim, A. & Baer, R. 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 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Yu, X., Chini, C. C., He, M., Mer, G. & Chen, J. The BRCT domain is a phospho-protein binding domain. Science 302, 639–642 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Manke, I. A., Lowery, D. M., Nguyen, A. & Yaffe, M. B. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302, 636–639 (2003).

    Article  CAS  PubMed  Google Scholar 

  63. Yu, X., Fu, S., Lai, M., Baer, R. & Chen, J. BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes Dev. 20, 1721–1726 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Chen, L., Nievera, C. J., Lee, A. Y. & Wu, X. Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J. Biol. Chem. 283, 7713–7720 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Billing, D. et al. The BRCT domains of the BRCA1 and BARD1 tumor suppressors differentially regulate homology-directed repair and stalled fork protection. Mol. Cell 72, 127–139 e8 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Wu, W. et al. Interaction of BARD1 and HP1 Is required for BRCA1 retention at sites of DNA damage. Cancer Res. 75, 1311–1321 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. Shakya, R. et al. BRCA1 tumor suppression depends on BRCT phosphoprotein binding, but not its E3 ligase activity. Science 334, 525–528 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. 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 106, 7155–7160 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Reid, S. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat. Genet. 39, 162–164 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet. 39, 165–167 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Nakamura, K. et al. H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids. Nat. Cell Biol. 21, 311–318 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Zhao, W. et al. BRCA1-BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 550, 360–365 (2017). BRCA1–BARD1 is shown to synergize with RAD51 in the formation of D-loops, which are a crucial DNA intermediate in DSB repair by homologous recombination.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Paull, T. T., Cortez, D., Bowers, B., Elledge, S. J. & Gellert, M. Direct DNA binding by Brca1. Proc. Natl Acad. Sci. USA 98, 6086–6091 (2001). This study demonstrates a DNA-binding activity in BRCA1, thereby providing evidence for a direct involvement.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ruffner, H., Joazeiro, C. A., Hemmati, D., Hunter, T. & Verma, I. M. 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 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Lorick, K. L. et al. RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc. Natl Acad. Sci. USA 96, 11364–11369 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Baer, R. & Ludwig, T. The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity. Curr. Opin. Genet. Dev. 12, 86–91 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Mallery, D. L., Vandenberg, C. J. & Hiom, K. Activation of the E3 ligase function of the BRCA1/BARD1 complex by polyubiquitin chains. EMBO J. 21, 6755–6762 (2002).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Xia, Y., Pao, G. M., Chen, H. W., Verma, I. M. & Hunter, T. Enhancement of BRCA1 E3 ubiquitin ligase activity through direct interaction with the BARD1 protein. J. Biol. Chem. 278, 5255–5263 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Christensen, D. E., Brzovic, P. S. & Klevit, R. E. E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages. Nat. Struct. Mol. Biol. 14, 941–948 (2007).

    Article  CAS  PubMed  Google Scholar 

  84. Wu-Baer, F., Lagrazon, K., Yuan, W. & Baer, R. The BRCA1/BARD1 heterodimer assembles polyubiquitin chains through an unconventional linkage involving lysine residue K6 of ubiquitin. J. Biol. Chem. 278, 34743–34746 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Reid, L. J. et al. 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. USA 105, 20876–20881 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Densham, R. M. et al. Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat. Struct. Mol. Biol. 23, 647–655 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  87. Stewart, M. D. et al. BARD1 is necessary for ubiquitylation of nucleosomal histone H2A and for transcriptional regulation of estrogen metabolism genes. Proc. Natl Acad. Sci. USA 115, 1316–1321 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhu, Q. et al. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nat. 477, 179–184 (2011).

    Article  CAS  Google Scholar 

  89. Zhu, Q. et al. Heterochromatin-encoded satellite RNAs induce breast cancer. Mol. Cell 70, 842–853 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  90. Stewart, M. D. et al. Tuning BRCA1 and BARD1 activity to investigate RING ubiquitin ligase mechanisms. Protein Sci. 26, 475–483 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Scully, R. et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88, 265–275 (1997). This study reveals interactions between BRCA1 and the recombinase RAD51 and documents a DNA repair phenotype of BRCA1-deficient cells.

    Article  CAS  PubMed  Google Scholar 

  93. Bhattacharyya, A., Ear, U. S., Koller, B. H., Weichselbaum, R. R. & Bishop, D. K. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J. Biol. Chem. 275, 23899–23903 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Huber, L. J. et al. Impaired DNA damage response in cells expressing an exon 11-deleted murine BRCA1 variant that localizes to nuclear foci. Mol. Cell. Biol. 21, 4005–4015 (2001).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  95. Zhao, W., Wiese, C., Kwon, Y., Hromas, R. & Sung, P. The BRCA tumor suppressor network in chromosome damage repair by homologous recombination. Annu. Rev. Biochem. 88, 221–245 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Chen, C. C., Feng, W., Lim, P. X., Kass, E. M. & Jasin, M. Homology-directed repair and the role of BRCA1, BRCA2, and related proteins in genome integrity and cancer. Annu. Rev. Cancer Biol. 2, 313–336 (2018).

    Article  PubMed  Google Scholar 

  97. Zhong, Q. et al. Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science 285, 747–750 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Symington, L. S. Mechanism and regulation of DNA end resection in eukaryotes. Crit. Rev. Biochem. Mol. Biol. 51, 195–212 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  100. Bunting, S. F. et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141, 243–254 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Xu, G. et al. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 521, 541–544 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  102. Cruz-Garcia, A., Lopez-Saavedra, A. & Huertas, P. BRCA1 accelerates CtIP-mediated DNA-end resection. Cell Rep. 9, 451–459 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Reczek, C. R., Szabolcs, M., Stark, J. M., Ludwig, T. & Baer, R. The interaction between CtIP and BRCA1 is not essential for resection-mediated DNA repair or tumor suppression. J. Cell Biol. 201, 693–707 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  104. Polato, F. et al. CtIP-mediated resection is essential for viability and can operate independently of BRCA1. J. Exp. Med. 211, 1027–1036 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  105. Kakarougkas, A. et al. Co-operation of BRCA1 and POH1 relieves the barriers posed by 53BP1 and RAP80 to resection. Nucleic Acids Res. 41, 10298–10311 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  106. Alagoz, M. et al. SETDB1, HP1 and SUV39 promote repositioning of 53BP1 to extend resection during homologous recombination in G2 cells. Nucleic Acids Res. 43, 7931–7944 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Xu, X. L. et al. Genetic interactions between tumor suppressors BRCA1 and p53 in apoptosis, cell cycle and tumorigenesis. Nat. Genet. 28, 266–271 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Cao, L. et al. ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency. EMBO J. 25, 2167–2177 (2006).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Iwabuchi, K., Bartel, P. L., Li, B., Marraccino, R. & Fields, S. Two cellular proteins that bind to wild-type but not mutant p53. Proc. Natl Acad. Sci. USA 91, 6098–6102 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Iwabuchi, K. et al. Stimulation of p53-mediated transcriptional activation by the p53-binding proteins, 53BP1 and 53BP2. J. Biol. Chem. 273, 26061–26068 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Schultz, L. B., Chehab, N. H., Malikzay, A. & Halazonetis, T. D. p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks. J. Cell Biol. 151, 1381–1390 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  112. DiTullio, R. A. Jr. et al. 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nat. Cell Biol. 4, 998–1002 (2002).

    Article  CAS  PubMed  Google Scholar 

  113. Wang, B., Matsuoka, S., Carpenter, P. B. & Elledge, S. J. 53BP1, a mediator of the DNA damage checkpoint. Science 298, 1435–1438 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Cao, L. et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol. Cell 35, 534–541 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  115. Bouwman, P. et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat. Struct. Mol. Biol. 17, 688–695 (2010). Bouwman et al. (2010) and Bunting et al. (2010) demonstrate the antagonism between BRCA1 and 53BP1 in the DNA damage response.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Li, M. et al. 53BP1 ablation rescues genomic instability in mice expressing ‘RING-less’ BRCA1. EMBO Rep. 17, 1532–1541 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  117. Bunting, S. F. et al. BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol. Cell 46, 125–135 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  118. Wang, Y. et al. RING domain-deficient BRCA1 promotes PARP inhibitor and platinum resistance. J. Clin. Invest. 126, 3145–3157 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  119. Drost, R. et al. BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1. J. Clin. Invest. 126, 2903–2918 (2016).

    Article  PubMed Central  PubMed  Google Scholar 

  120. Nacson, J. et al. BRCA1 mutation-specific responses to 53BP1 loss-induced homologous recombination and PARP inhibitor resistance. Cell Rep. 24, 3513–3527 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  121. Zong, D. et al. BRCA1 haploinsufficiency is masked by RNF168-mediated chromatin ubiquitylation. Mol. Cell 73, 1267–1281 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Chapman, J. R. et al. RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection. Mol. Cell 49, 858–871 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  123. Chapman, J. R., Sossick, A. J., Boulton, S. J. & Jackson, S. P. BRCA1-associated exclusion of 53BP1 from DNA damage sites underlies temporal control of DNA repair. J. Cell Sci. 125, 3529–3534 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  124. Chen, X. et al. The Fun30 nucleosome remodeller promotes resection of DNA double-strand break ends. Nature 489, 576–580 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  125. Costelloe, T. et al. The yeast Fun30 and human SMARCAD1 chromatin remodellers promote DNA end resection. Nature 489, 581–584 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  126. Kalb, R., Mallery, D. L., Larkin, C., Huang, J. T. & Hiom, K. BRCA1 is a histone-H2A-specific ubiquitin ligase. Cell Rep. 8, 999–1005 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  127. Simons, A. M. et al. BRCA1 DNA-binding activity is stimulated by BARD1. Cancer Res. 66, 2012–2018 (2006).

    Article  CAS  PubMed  Google Scholar 

  128. Martin, R. W. et al. RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors. Cancer Res. 67, 9658–9665 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Daza-Martin, M. et al. Isomerization of BRCA1-BARD1 promotes replication fork protection. Nature 571, 521–527 (2019).

    Article  CAS  PubMed  Google Scholar 

  130. Zhao, W. et al. Promotion of BRCA2-dependent homologous recombination by DSS1 via RPA targeting and DNA mimicry. Mol. Cell 59, 176–187 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  131. Jensen, R. B., Carreira, A. & Kowalczykowski, S. C. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 467, 678–683 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. San Filippo, J. et al. Recombination mediator and Rad51 targeting activities of a human BRCA2 polypeptide. J. Biol. Chem. 281, 11649–11657 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Sung, P. Function of yeast Rad52 protein as a mediator between replication protein A and the Rad51 recombinase. J. Biol. Chem. 272, 28194–28197 (1997).

    Article  CAS  PubMed  Google Scholar 

  134. Zelensky, A., Kanaar, R. & Wyman, C. Mediators of homologous DNA pairing. Cold Spring Harb. Perspect. Biol. 6, a016451 (2014).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  135. Scully, R. et al. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell 90, 425–435 (1997).

    Article  CAS  PubMed  Google Scholar 

  136. Wang, Y. et al. BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14, 927–939 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  137. Pathania, S. et al. BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat. Commun. 5, 5496 (2014).

    Article  PubMed  Google Scholar 

  138. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Schlacher, K. et al. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145, 529–542 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Schlacher, K., Wu, H. & Jasin, M. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22, 106–116 (2012). This study reveals the role of BRCA1 in DNA replication fork protection and documents its relationship with RAD51 and other DNA damage repair factors in fork protection.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  141. Wang, A. T. et al. A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Mol. Cell 59, 478–490 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  142. Lemacon, D. et al. MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells. Nat. Commun. 8, 860 (2017).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  143. Thangavel, S. et al. DNA2 drives processing and restart of reversed replication forks in human cells. J. Cell Biol. 208, 545–562 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  144. Iannascoli, C., Palermo, V., Murfuni, I., Franchitto, A. & Pichierri, P. The WRN exonuclease domain protects nascent strands from pathological MRE11/EXO1-dependent degradation. Nucleic Acids Res. 43, 9788–9803 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Hashimoto, Y., Ray Chaudhuri, A., Lopes, M. & Costanzo, V. Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis. Nat. Struct. Mol. Biol. 17, 1305–1311 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  146. Higgs, M. R. et al. BOD1L is required to suppress deleterious resection of stressed replication forks. Mol. Cell 59, 462–477 (2015).

    Article  CAS  PubMed  Google Scholar 

  147. Taglialatela, A. et al. Restoration of replication fork stability in BRCA1- and BRCA2-deficient cells by inactivation of SNF2-family fork remodelers. Mol. Cell 68, 414–430 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  148. Chaudhuri, A. R. et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 535, 382–387 (2016).

    Article  CAS  PubMed Central  Google Scholar 

  149. Przetocka, S. et al. CtIP-mediated fork protection synergizes with BRCA1 to suppress genomic instability upon DNA replication stress. Mol. Cell 72, 568–582 (2018).

    Article  CAS  PubMed  Google Scholar 

  150. Hashimoto, Y., Puddu, F. & Costanzo, V. RAD51- and MRE11-dependent reassembly of uncoupled CMG helicase complex at collapsed replication forks. Nat. Struct. Mol. Biol. 19, 17–24 (2012).

    Article  CAS  Google Scholar 

  151. Kolinjivadi, A. M. et al. Smarcal1-mediated fork reversal triggers Mre11-dependent degradation of nascent DNA in the absence of Brca2 and stable Rad51 nucleofilaments. Mol. Cell 67, 867–881 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  152. Aguilera, A. & Garcia-Muse, T. R loops: from transcription byproducts to threats to genome stability. Mol. Cell 46, 115–124 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. Santos-Pereira, J. M. & Aguilera, A. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16, 583–597 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. Hamperl, S. & Cimprich, K. A. Conflict resolution in the genome: how transcription and replication make it work. Cell 167, 1455–1467 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  155. Hill, S. J. et al. Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev. 28, 1957–1975 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  156. Hatchi, E. et al. BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol. Cell 57, 636–647 (2015). This study shows that BRCA1 acts with the putative RNA–DNA helicase senataxin to prevent the accumulation of R-loops at transcription pause sites.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Cohen, S. et al. Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations. Nat. Commun. 9, 533 (2018).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  158. Li, L. et al. DEAD box 1 facilitates removal of RNA and homologous recombination at DNA double-strand breaks. Mol. Cell Biol. 36, 2794–2810 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  159. Britton, S. et al. DNA damage triggers SAF-A and RNA biogenesis factors exclusion from chromatin coupled to R-loops removal. Nucleic Acids Res. 42, 9047–9062 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  160. Ohle, C. et al. Transient RNA-DNA hybrids are required for efficient double-strand break repair. Cell 167, 1001–1013 (2016).

    Article  CAS  PubMed  Google Scholar 

  161. Marnef, A., Cohen, S. & Legube, G. Transcription-coupled DNA double-strand break repair: active genes need special care. J. Mol. Biol. 429, 1277–1288 (2017).

    Article  CAS  PubMed  Google Scholar 

  162. Groh, M., Albulescu, L. O., Cristini, A. & Gromak, N. Senataxin: genome guardian at the interface of transcription and neurodegeneration. J. Mol. Biol. 429, 3181–3195 (2017).

    Article  CAS  PubMed  Google Scholar 

  163. Tarsounas, M. & Tijsterman, M. Genomes and G-quadruplexes: for better or for worse. J. Mol. Biol. 425, 4782–4789 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  166. Tacconi, E. M. et al. BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. EMBO Mol. Med. 9, 1398–1414 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  167. Ray Chaudhuri, A. & Nussenzweig, A. Thwarting endogenous stress: BRCA protects against aldehyde toxicity. EMBO Mol. Med. 9, 1331–1333 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  168. Garcia, M. J. & Benitez, J. The Fanconi anaemia/BRCA pathway and cancer susceptibility. Searching for new therapeutic targets. Clin. Transl Oncol. 10, 78–84 (2008).

    Article  CAS  PubMed  Google Scholar 

  169. Kim, H. & D’Andrea, A. D. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev. 26, 1393–1408 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  170. Clauson, C., Scharer, O. D. & Niedernhofer, L. Advances in understanding the complex mechanisms of DNA interstrand cross-link repair. Cold Spring Harb. Perspect. Biol. 5, a012732 (2013).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  172. Sawyer, S. L. et al. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov. 5, 135–142 (2015).

    Article  CAS  PubMed  Google Scholar 

  173. Domchek, S. M. et al. Biallelic deleterious BRCA1 mutations in a woman with early-onset ovarian cancer. Cancer Discov. 3, 399–405 (2013).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  175. Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature 434, 913–917 (2005).

    Article  CAS  PubMed  Google Scholar 

  176. Morales, J. et al. Review of poly(ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases. Crit. Rev. Eukaryot. Gene Expr. 24, 15–28 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  177. Pommier, Y., O’Connor, M. J. & de Bono, J. Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action. Sci. Transl Med. 8, 362ps17 (2016).

    Article  CAS  PubMed  Google Scholar 

  178. Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).

    Article  CAS  PubMed  Google Scholar 

  179. Ledermann, J. et al. 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. 15, 852–861 (2014).

    Article  CAS  PubMed  Google Scholar 

  180. Litton, J. K. et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N. Engl. J. Med. 379, 753–763 (2018).

    Article  CAS  PubMed  Google Scholar 

  181. Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).

    Article  CAS  PubMed  Google Scholar 

  182. Mirza, M. R. et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N. Engl. J. Med. 375, 2154–2164 (2016).

    Article  CAS  PubMed  Google Scholar 

  183. Swisher, E. M. et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 18, 75–87 (2017).

    Article  CAS  PubMed  Google Scholar 

  184. Turner, N., Tutt, A. & Ashworth, A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat. Rev. Cancer 4, 814–819 (2004).

    Article  CAS  PubMed  Google Scholar 

  185. Mateo, J. et al. DNA-repair defects and olaparib in metastatic prostate cancer. N. Engl. J. Med. 373, 1697–1708 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  186. Jaspers, J. E. et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 3, 68–81 (2013).

    Article  CAS  PubMed  Google Scholar 

  187. Tomida, J. et al. FAM35A associates with REV7 and modulates DNA damage responses of normal and BRCA1-defective cells. EMBO J. 37, e99543 (2018).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  188. Dev, H. et al. Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat. Cell Biol. 20, 954–965 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  189. Barazas, M. et al. Radiosensitivity is an acquired vulnerability of PARPi-resistant BRCA1-deficient tumors. Cancer Res. 79, 452–460 (2019).

    Article  CAS  PubMed  Google Scholar 

  190. Tacconi, E. M. et al. Chlorambucil targets BRCA1/2-deficient tumours and counteracts PARP inhibitor resistance. EMBO Mol. Med. 11, e9982 (2019).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  191. Cruz, C. et al. RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer. Ann. Oncol. 29, 1203–1210 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  192. Ang, J. E. et al. Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study. Clin. Cancer Res. 19, 5485–5493 (2013).

    Article  CAS  PubMed  Google Scholar 

  193. Rottenberg, S. et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl Acad. Sci. USA 104, 12117–12122 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Rottenberg, S. 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. USA 105, 17079–17084 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Gogola, E. et al. Selective loss of PARG restores PARylation and counteracts PARP inhibitor-mediated synthetic lethality. Cancer Cell 33, 1078–1093 (2018).

    Article  CAS  PubMed  Google Scholar 

  196. Michelena, J. et al. Analysis of PARP inhibitor toxicity by multidimensional fluorescence microscopy reveals mechanisms of sensitivity and resistance. Nat. Commun. 9, 2678 (2018).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  197. Wang, J. et al. PTIP associates with Artemis to dictate DNA repair pathway choice. Genes Dev. 28, 2693–2698 (2014).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  198. Callen, E. et al. 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. Cell 153, 1266–1280 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  199. Swisher, E. M. et al. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 68, 2581–2586 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  201. Castroviejo-Bermejo, M. et al. A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. EMBO Mol. Med. 10, e9172 (2018).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  202. Ter Brugge, P. et al. Mechanisms of therapy resistance in patient-derived xenograft models of BRCA1-deficient breast cancer. J. Natl Cancer Inst. 108, djw148 (2016).

    Article  CAS  Google Scholar 

  203. Zoppoli, G. et al. Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. Proc. Natl Acad. Sci. USA 109, 15030–15035 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Zimmermann, M. et al. CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions. Nature 559, 285–289 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  205. Tomimatsu, N. et al. Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice. Nat. Commun. 5, 3561 (2014).

    Article  PubMed  CAS  Google Scholar 

  206. Densham, R. M. & Morris, J. R. Moving mountains-the BRCA1 promotion of DNA resection. Front. Mol. Biosci. 6, 79 (2019).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  207. Minchom, A., Aversa, C. & Lopez, J. Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies. Ther. Adv. Med. Oncol. 10, 1758835918786658 (2018).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  208. Brandsma, I., Fleuren, E. D. G., Williamson, C. T. & Lord, C. J. Directing the use of DDR kinase inhibitors in cancer treatment. Expert. Opin. Investig. Drugs 26, 1341–1355 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  209. Drean, A. et al. Modeling therapy resistance in BRCA1/2-mutant cancers. Mol. Cancer Ther. 16, 2022–2034 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  210. Blackford, A. N. & Jackson, S. P. ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response. Mol. Cell 66, 801–817 (2017).

    Article  CAS  PubMed  Google Scholar 

  211. Matos, J. & West, S. C. Holliday junction resolution: regulation in space and time. DNA Repair 19, 176–181 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  212. Scully, R., Panday, A., Elango, R. & Willis, N. A. DNA double-strand break repair-pathway choice in somatic mammalian cells. Nat. Rev. Mol. Cell Biol. 20, 698–714 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Orthwein, A. et al. A mechanism for the suppression of homologous recombination in G1 cells. Nature 528, 422–426 (2015).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  214. Her, J. & Bunting, S. F. How cells ensure correct repair of DNA double-strand breaks. J. Biol. Chem. 293, 10502–10511 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  215. Zimmermann, M., Lottersberger, F., Buonomo, S. B., Sfeir, A. & de Lange, T. 53BP1 regulates DSB repair using Rif1 to control 5’ end resection. Science 339, 700–704 (2013).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  216. Gupta, R. et al. DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity. Cell 173, 972–988 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Noordermeer, S. M. et al. The shieldin complex mediates 53BP1-dependent DNA repair. Nature 560, 117–121 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  218. Mirman, Z. et al. 53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polalpha-dependent fill-in. Nature 560, 112–116 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  219. Barazas, M. et al. The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells. Cell Rep. 23, 2107–2118 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  220. Ghezraoui, H. et al. 53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Nature 560, 122–127 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  221. Stewart, J. A., Wang, Y., Ackerson, S. M. & Schuck, P. L. Emerging roles of CST in maintaining genome stability and human disease. Front. Biosci. 23, 1564–1586 (2018).

    Article  CAS  Google Scholar 

  222. He, Y. J. et al. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells. Nature 563, 522–526 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  223. Becker, J. R. et al. The ASCIZ-DYNLL1 axis promotes 53BP1-dependent non-homologous end joining and PARP inhibitor sensitivity. Nat. Commun. 9, 5406 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  224. Zgheib, O., Pataky, K., Brugger, J. & Halazonetis, T. D. An oligomerized 53BP1 tudor domain suffices for recognition of DNA double-strand breaks. Mol. Cell Biol. 29, 1050–1058 (2009).

    Article  CAS  PubMed  Google Scholar 

  225. Lottersberger, F., Bothmer, A., Robbiani, D. F., Nussenzweig, M. C. & de Lange, T. Role of 53BP1 oligomerization in regulating double-strand break repair. Proc. Natl Acad. Sci. USA 110, 2146–2151 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Wilson, M. D. et al. The structural basis of modified nucleosome recognition by 53BP1. Nature 536, 100–103 (2016).

    Article  CAS  PubMed  Google Scholar 

  227. Cortez, D. Replication-coupled DNA repair. Mol. Cell 74, 866–876 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Ait Saada, A., Lambert, S. A. E. & Carr, A. M. Preserving replication fork integrity and competence via the homologous recombination pathway. DNA Repair 71, 135–147 (2018).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  229. Pasero, P. & Vindigni, A. Nucleases acting at stalled forks: how to reboot the replication program with a few shortcuts. Annu. Rev. Genet. 51, 477–499 (2017).

    Article  CAS  PubMed  Google Scholar 

  230. Wong, A. K. et al. Characterization of a carboxy-terminal BRCA1 interacting protein. Oncogene 17, 2279–2285 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  232. Folias, A. et al. BRCA1 interacts directly with the Fanconi anemia protein FANCA. Hum. Mol. Genet. 11, 2591–2597 (2002).

    Article  CAS  PubMed  Google Scholar 

  233. Davis, A. J. et al. BRCA1 modulates the autophosphorylation status of DNA-PKcs in S phase of the cell cycle. Nucleic Acids Res. 42, 11487–11501 (2014).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  234. Wang, Q. et al. Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1. Oncogene 20, 4640–4649 (2001).

    Article  CAS  PubMed  Google Scholar 

  235. Batenburg, N. L. et al. CSB interacts with BRCA1 in late S/G2 to promote MRN- and CtIP-mediated DNA end resection. Nucleic Acids Res. 47, 10678–10692 (2019).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  236. Cortez, D., Wang, Y., Qin, J. & Elledge, S. J. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 286, 1162–1166 (1999).

    Article  CAS  PubMed  Google Scholar 

  237. Venere, M., Snyder, A., Zgheib, O. & Halazonetis, T. D. Phosphorylation of ATR-interacting protein on Ser239 mediates an interaction with breast-ovarian cancer susceptibility 1 and checkpoint function. Cancer Res. 67, 6100–6105 (2007).

    Article  CAS  PubMed  Google Scholar 

  238. Chen, J. Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage. Cancer Res. 60, 5037–5039 (2000).

    CAS  PubMed  Google Scholar 

  239. Gatei, M. et al. 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. 276, 17276–17280 (2001).

    Article  CAS  PubMed  Google Scholar 

  240. Verma, S. et al. BRCA1/BARD1-dependent ubiquitination of NF2 regulates Hippo-YAP1 signaling. Proc. Natl Acad. Sci. USA 116, 7363–7370 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  243. Ruffner, H., Jiang, W., Craig, A. G., Hunter, T. & Verma, I. M. BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Mol. Cell Biol. 19, 4843–4854 (1999).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  244. Wang, H. et al. BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases. Oncogene 15, 143–157 (1997).

    Article  CAS  PubMed  Google Scholar 

  245. Liu, Y., Virshup, D. M., White, R. L. & Hsu, L. C. Regulation of BRCA1 phosphorylation by interaction with protein phosphatase 1alpha. Cancer Res. 62, 6357–6361 (2002).

    CAS  PubMed  Google Scholar 

  246. Dubrovska, A. et al. TGFbeta1/Smad3 counteracts BRCA1-dependent repair of DNA damage. Oncogene 24, 2289–2297 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Schlegel, B. P., Green, V. J., Ladias, J. A. & Parvin, J. D. BRCA1 interaction with RNA polymerase II reveals a role for hRPB2 and hRPB10alpha in activated transcription. Proc. Natl Acad. Sci. USA 97, 3148–3153 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Chai, Y. L. et al. The second BRCT domain of BRCA1 proteins interacts with p53 and stimulates transcription from the p21WAF1/CIP1 promoter. Oncogene 18, 263–268 (1999).

    Article  CAS  PubMed  Google Scholar 

  250. Pao, G. M., Janknecht, R., Ruffner, H., Hunter, T. & Verma, I. M. CBP/p300 interact with and function as transcriptional coactivators of BRCA1. Proc. Natl Acad. Sci. USA 97, 1020–1025 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Nair, S. J. et al. Genetic suppression reveals DNA repair-independent antagonism between BRCA1 and COBRA1 in mammary gland development. Nat. Commun. 7, 10913 (2016).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  252. Jensen, D. E. et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097–1112 (1998).

    Article  CAS  PubMed  Google Scholar 

  253. Aprelikova, O. N. et al. BRCA1-associated growth arrest is RB-dependent. Proc. Natl Acad. Sci. USA 96, 11866–11871 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Kais, Z. et al. KIAA0101 interacts with BRCA1 and regulates centrosome number. Mol. Cancer Res. 9, 1091–1099 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  256. Lou, Z., Minter-Dykhouse, K. & Chen, J. BRCA1 participates in DNA decatenation. Nat. Struct. Mol. Biol. 12, 589–593 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  258. Harte, M. T. et al. BRD7, a subunit of SWI/SNF complexes, binds directly to BRCA1 and regulates BRCA1-dependent transcription. Cancer Res. 70, 2538–2547 (2010).

    Article  CAS  PubMed  Google Scholar 

  259. Yarden, R. I. & Brody, L. C. BRCA1 interacts with components of the histone deacetylase complex. Proc. Natl Acad. Sci. USA 96, 4983–4988 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Magnard, C. et al. BRCA1 interacts with acetyl-CoA carboxylase through its tandem of BRCT domains. Oncogene 21, 6729–6739 (2002).

    Article  CAS  PubMed  Google Scholar 

  261. Chen, C. F. et al. The nuclear localization sequences of the BRCA1 protein interact with the importin-alpha subunit of the nuclear transport signal receptor. J. Biol. Chem. 271, 32863–32868 (1996).

    Article  CAS  PubMed  Google Scholar 

  262. Sato, K. et al. A DNA-damage selective role for BRCA1 E3 ligase in claspin ubiquitylation, CHK1 activation, and DNA repair. Curr. Biol. 22, 1659–1666 (2012).

    Article  CAS  PubMed  Google Scholar 

  263. Kim, B. J. et al. The histone variant MacroH2A1 is a BRCA1 ubiquitin ligase substrate. Cell Rep. 19, 1758–1766 (2017).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  264. Kleiman, F. E. et al. BRCA1/BARD1 inhibition of mRNA 3′ processing involves targeted degradation of RNA polymerase II. Genes Dev. 19, 1227–1237 (2005).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  265. Starita, L. M. et al. BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II. J. Biol. Chem. 280, 24498–24505 (2005).

    Article  CAS  PubMed  Google Scholar 

  266. Velimezi, G. et al. Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48. Nat. Commun. 9, 2280 (2018).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  267. Uckelmann, M. et al. USP48 restrains resection by site-specific cleavage of the BRCA1 ubiquitin mark from H2A. Nat. Commun. 9, 229 (2018).

    Article  PubMed Central  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The studies in the laboratories of the authors were supported by Cancer Research UK, the UK Medical Research Council, the University of Oxford and the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 722729 (M.T.), and by Cancer Prevention and Research Institute of Texas (CPRIT) REI award RR180029, a Grey Foundation Team Science award and US National Institutes of Health research grant awards R35 CA241801, RO1 CA168635 and RO1 ES007061 (to P.S.). P.S. is a CPRIT Scholar of Cancer Research and the Robert A. Welch Distinguished Chair in Chemistry (AQ-0012). The authors are grateful to Y. Kwon for help with artwork and to W. Zhao and J. Daley for providing valuable feedback on the manuscript.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Madalena Tarsounas or Patrick Sung.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks Joanna Morris and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

R-loops

Three-stranded nucleic acid structures that arise during transcription, consisting of an RNA–DNA hybrid formed by annealing of the nascent transcript with its DNA template. The non-template DNA is displaced as single-stranded DNA.

Synthetic lethality

Induction of cell death (lethality) by simultaneously inactivating two different biological pathways or genes, which normally do not affect cell viability inactivated individually.

Ionizing radiation-induced nuclear foci

Subnuclear domains into which factors needed for DNA damage signalling and repair concentrate on exposure to ionizing radiation. Their formation and resolution reflect the robustness of the cellular response to ionizing radiation.

G-quadruplexes

Non-canonical DNA (or RNA) structures consisting of stacks of two or more guanine quartets, each stabilized by a monovalent cation. G-quadruplexes form spontaneously on guanine-rich single-stranded DNA during DNA replication and transcription.

Radial chromosomes

Fused chromosomes that arise from aberrant repair of DNA double-strand breaks or stalled replication forks, or from incomplete resolution of repair intermediates.

Fanconi anaemia

A multigenic disorder characterized by bone marrow failure and cancer predisposition, owing to an inability to properly process DNA interstrand crosslinks and other DNA lesions.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tarsounas, M., Sung, P. The antitumorigenic roles of BRCA1–BARD1 in DNA repair and replication. Nat Rev Mol Cell Biol 21, 284–299 (2020). https://doi.org/10.1038/s41580-020-0218-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41580-020-0218-z

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer