1932

Abstract

Mutations in the and genes predispose afflicted individuals to breast, ovarian, and other cancers. The BRCA-encoded products form complexes with other tumor suppressor proteins and with the recombinase enzyme RAD51 to mediate chromosome damage repair by homologous recombination and also to protect stressed DNA replication forks against spurious nucleolytic attrition. Understanding how the BRCA tumor suppressor network executes its biological functions would provide the foundation for developing targeted cancer therapeutics, but progress in this area has been greatly hampered by the challenge of obtaining purified BRCA complexes for mechanistic studies. In this article, we review how recent effort begins to overcome this technical challenge, leading to functional and structural insights into the biochemical attributes of these complexes and the multifaceted roles that they fulfill in genome maintenance. We also highlight the major mechanistic questions that remain.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-013118-111058
2019-06-20
2024-12-07
Loading full text...

Full text loading...

/deliver/fulltext/biochem/88/1/annurev-biochem-013118-111058.html?itemId=/content/journals/10.1146/annurev-biochem-013118-111058&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Lindahl T, Barnes DE. 2000. Repair of endogenous DNA damage. Cold Spring Harb. Symp. Quant. Biol. 65:127–33
    [Google Scholar]
  2. 2. 
    Hoeijmakers JH. 2009. DNA damage, aging, and cancer. N. Engl. J. Med. 361:1475–85
    [Google Scholar]
  3. 3. 
    Garaycoechea JI, Crossan GP, Langevin F, Mulderrig L, Louzada S et al. 2018. Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells. Nature 553:171–77
    [Google Scholar]
  4. 4. 
    Prakash R, Zhang Y, Feng W, Jasin M 2015. Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harb. Perspect. Biol. 7:a016600
    [Google Scholar]
  5. 5. 
    Ashworth A, Lord CJ. 2018. Synthetic lethal therapies for cancer: What's next after PARP inhibitors?. Nat. Rev. Clin. Oncol. 15:564–76
    [Google Scholar]
  6. 6. 
    Her J, Bunting SF. 2018. How cells ensure correct repair of DNA double-strand breaks. J. Biol. Chem. 293:10502–11
    [Google Scholar]
  7. 7. 
    Pannunzio NR, Watanabe G, Lieber MR 2018. Nonhomologous DNA end-joining for repair of DNA double-strand breaks. J. Biol. Chem. 293:10512–23
    [Google Scholar]
  8. 8. 
    Wright WD, Shah SS, Heyer WD 2018. Homologous recombination and the repair of DNA double-strand breaks. J. Biol. Chem. 293:10524–35
    [Google Scholar]
  9. 9. 
    Zickler D, Kleckner N. 2015. Recombination, pairing, and synapsis of homologs during meiosis. Cold Spring Harb. Perspect. Biol. 7:a016626
    [Google Scholar]
  10. 10. 
    Sallmyr A, Tomkinson AE. 2018. Repair of DNA double-strand breaks by mammalian alternative end-joining pathways. J. Biol. Chem. 293:10536–46
    [Google Scholar]
  11. 11. 
    Pasero P, Vindigni A. 2017. Nucleases acting at stalled forks: how to reboot the replication program with a few shortcuts. Annu. Rev. Genet. 51:477–99
    [Google Scholar]
  12. 12. 
    Vaisman A, Woodgate R. 2017. Translesion DNA polymerases in eukaryotes: What makes them tick?. Crit. Rev. Biochem. Mol. Biol. 52:274–303
    [Google Scholar]
  13. 13. 
    Lomonosov M, Anand S, Sangrithi M, Davies R, Venkitaraman AR 2003. Stabilization of stalled DNA replication forks by the BRCA2 breast cancer susceptibility protein. Genes Dev 17:3017–22
    [Google Scholar]
  14. 14. 
    Hashimoto Y, Chaudhuri AR, Lopes M, Costanzo V 2010. Rad51 protects nascent DNA from Mre11-dependent degradation and promotes continuous DNA synthesis. Nat. Struct. Mol. Biol. 17:1305–11
    [Google Scholar]
  15. 15. 
    Schlacher K, Christ N, Siaud N, Egashira A, Wu H, Jasin M 2011. Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145:529–42
    [Google Scholar]
  16. 16. 
    Schlacher K, Wu H, Jasin M 2012. A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22:106–16
    [Google Scholar]
  17. 17. 
    Wang AT, Kim T, Wagner JE, Conti BA, Lach FP et al. 2015. A dominant mutation in human RAD51 reveals its function in DNA interstrand crosslink repair independent of homologous recombination. Mol. Cell 59:478–90
    [Google Scholar]
  18. 18. 
    Clauson C, Scharer OD, Niedernhofer L 2013. Advances in understanding the complex mechanisms of DNA interstrand cross-link repair. Cold Spring Harb. Perspect. Biol. 5:a012732
    [Google Scholar]
  19. 19. 
    Zhang J, Walter JC. 2014. Mechanism and regulation of incisions during DNA interstrand cross-link repair. DNA Repair 19:135–42
    [Google Scholar]
  20. 20. 
    Michl J, Zimmer J, Tarsounas M 2016. Interplay between Fanconi anemia and homologous recombination pathways in genome integrity. EMBO J 35:909–23
    [Google Scholar]
  21. 21. 
    Hashimoto S, Anai H, Hanada K 2016. Mechanisms of interstrand DNA crosslink repair and human disorders. Genes Environ 38:9
    [Google Scholar]
  22. 22. 
    Wood RD. 2010. Mammalian nucleotide excision repair proteins and interstrand crosslink repair. Environ. Mol. Mutagen 51:520–26
    [Google Scholar]
  23. 23. 
    Amunugama R, Willcox S, Wu RA, Abdullah UB, El-Sagheer AH et al. 2018. Replication fork reversal during DNA interstrand crosslink repair requires CMG unloading. Cell Rep 23:3419–28
    [Google Scholar]
  24. 24. 
    Mutreja K, Krietsch J, Hess J, Ursich S, Berti M et al. 2018. ATR-mediated global fork slowing and reversal assist fork traverse and prevent chromosomal breakage at DNA interstrand cross-links. Cell Rep 24:2629–42
    [Google Scholar]
  25. 25. 
    Nalepa G, Clapp DW. 2018. Fanconi anaemia and cancer: an intricate relationship. Nat. Rev. Cancer 18:168–85
    [Google Scholar]
  26. 26. 
    Game JC, Mortimer RK. 1974. A genetic study of X-ray sensitive mutants in yeast. Mutat. Res. 24:281–92
    [Google Scholar]
  27. 27. 
    Game JC. 1993. DNA double-strand breaks and the RAD50-RAD57 genes in Saccharomyces. Semin. . Cancer Biol 4:73–83
    [Google Scholar]
  28. 28. 
    Bai Y, Symington LS. 1996. A Rad52 homolog is required for RAD51-independent mitotic recombination in Saccharomyces cerevisiae. . Genes Dev 10:2025–37
    [Google Scholar]
  29. 29. 
    Klein HL. 1997. RDH54, a RAD54 homologue in Saccharomyces cerevisiae, is required for mitotic diploid-specific recombination and repair and for meiosis. Genetics 147:1533–43
    [Google Scholar]
  30. 30. 
    Shor E, Weinstein J, Rothstein R 2005. A genetic screen for top3 suppressors in Saccharomyces cerevisiae identifies SHU1, SHU2,. PSY3 and CSM2: four genes involved in error-free DNA repair. Genetics 169:1275–89
    [Google Scholar]
  31. 31. 
    Symington LS. 2002. Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair. Microbiol. Mol. Biol. Rev. 66:630–70
    [Google Scholar]
  32. 32. 
    Symington LS, Rothstein R, Lisby M 2014. Mechanisms and regulation of mitotic recombination in Saccharomyces cerevisiae. . Genetics 198:795–835
    [Google Scholar]
  33. 33. 
    Xia B, Sheng Q, Nakanishi K, Ohashi A, Wu J et al. 2006. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22:719–29
    [Google Scholar]
  34. 34. 
    Tischkowitz M, Xia B. 2010. PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res 70:7353–59
    [Google Scholar]
  35. 35. 
    Nepomuceno TC, De Gregoriis G, Bastos de Oliveira FM, Suarez-Kurtz G, Monteiro AN, Carvalho MA 2017. The role of PALB2 in the DNA damage response and cancer predisposition. Int. J. Mol. Sci. 18:E1886
    [Google Scholar]
  36. 36. 
    Dray E, Etchin J, Wiese C, Saro D, Williams GJ et al. 2010. Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nat. Struct. Mol. Biol. 17:1255–59
    [Google Scholar]
  37. 37. 
    Buisson R, Dion-Cote AM, Coulombe Y, Launay H, Cai H et al. 2010. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat. Struct. Mol. Biol. 17:1247–54
    [Google Scholar]
  38. 38. 
    Gowen LC, Johnson BL, Latour AM, Sulik KK, Koller BH 1996. Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nat. Genet. 12:191–94
    [Google Scholar]
  39. 39. 
    Hakem R, de la Pompa JL, Sirard C, Mo R, Woo M et al. 1996. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 85:1009–23
    [Google Scholar]
  40. 40. 
    Liu CY, Flesken-Nikitin A, Li S, Zeng Y, Lee WH 1996. Inactivation of the mouse Brca1 gene leads to failure in the morphogenesis of the egg cylinder in early postimplantation development. Genes Dev 10:1835–43
    [Google Scholar]
  41. 41. 
    Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E et al. 1997. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. . Nature 386:804–10
    [Google Scholar]
  42. 42. 
    McCarthy EE, Celebi JT, Baer R, Ludwig T 2003. Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. Mol. Cell. Biol. 23:5056–63
    [Google Scholar]
  43. 43. 
    Rantakari P, Nikkila J, Jokela H, Ola R, Pylkas K et al. 2010. Inactivation of Palb2 gene leads to mesoderm differentiation defect and early embryonic lethality in mice. Hum. Mol. Genet. 19:3021–29
    [Google Scholar]
  44. 44. 
    Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q et al. 2002. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297:606–9
    [Google Scholar]
  45. 45. 
    Reid S, Schindler D, Hanenberg H, Barker K, Hanks S et al. 2007. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat. Genet. 39:162–64
    [Google Scholar]
  46. 46. 
    Sawyer SL, Tian L, Kahkonen M, Schwartzentruber J, Kircher M et al. 2015. Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov 5:135–42
    [Google Scholar]
  47. 47. 
    Golmard L, Castera L, Krieger S, Moncoutier V, Abidallah K et al. 2017. Contribution of germline deleterious variants in the RAD51 paralogs to breast and ovarian cancers. Eur. J. Hum. Genet. 25:1345–53
    [Google Scholar]
  48. 48. 
    Brosh RM Jr., Cantor SB. 2014. Molecular and cellular functions of the FANCJ DNA helicase defective in cancer and in Fanconi anemia. Front. Genet. 5:372
    [Google Scholar]
  49. 49. 
    Martino J, Bernstein KA. 2016. The Shu complex is a conserved regulator of homologous recombination. FEMS Yeast Res 16:fow073
    [Google Scholar]
  50. 50. 
    Taylor MRG, Spirek M, Chaurasiya KR, Ward JD, Carzaniga R et al. 2015. Rad51 paralogs remodel pre-synaptic Rad51 filaments to stimulate homologous recombination. Cell 162:271–86
    [Google Scholar]
  51. 51. 
    Gaines WA, Godin SK, Kabbinavar FF, Rao T, VanDemark AP et al. 2015. Promotion of presynaptic filament assembly by the ensemble of S. cerevisiae Rad51 paralogues with Rad52. Nat. Commun. 6:7834
    [Google Scholar]
  52. 52. 
    Jensen RB, Ozes A, Kim T, Estep A, Kowalczykowski SC 2013. BRCA2 is epistatic to the RAD51 paralogs in response to DNA damage. DNA Repair 12:306–11
    [Google Scholar]
  53. 53. 
    Symington LS. 2016. Mechanism and regulation of DNA end resection in eukaryotes. Crit. Rev. Biochem. Mol. Biol. 51:195–212
    [Google Scholar]
  54. 54. 
    Nimonkar AV, Genschel J, Kinoshita E, Polaczek P, Campbell JL et al. 2011. BLM–DNA2–RPA–MRN and EXO1–BLM–RPA–MRN constitute two DNA end resection machineries for human DNA break repair. Genes Dev 25:350–62
    [Google Scholar]
  55. 55. 
    Cejka P. 2015. DNA end resection: nucleases team up with the right partners to initiate homologous recombination. J. Biol. Chem. 290:22931–38
    [Google Scholar]
  56. 56. 
    Cannavo E, Cejka P, Kowalczykowski SC 2013. Relationship of DNA degradation by Saccharomyces cerevisiae exonuclease 1 and its stimulation by RPA and Mre11-Rad50-Xrs2 to DNA end resection. PNAS 110:E1661–68
    [Google Scholar]
  57. 57. 
    Sturzenegger A, Burdova K, Kanagaraj R, Levikova M, Pinto C et al. 2014. DNA2 cooperates with the WRN and BLM RecQ helicases to mediate long-range DNA end resection in human cells. J. Biol. Chem. 289:27314–26
    [Google Scholar]
  58. 58. 
    Pinto C, Kasaciunaite K, Seidel R, Cejka P 2016. Human DNA2 possesses a cryptic DNA unwinding activity that functionally integrates with BLM or WRN helicases. eLife 5:e19574
    [Google Scholar]
  59. 59. 
    Wu Y, Lee SH, Williamson EA, Reinert BL, Cho JH et al. 2015. EEPD1 rescues stressed replication forks and maintains genome stability by promoting end resection and homologous recombination repair. PLOS Genet 11:e1005675
    [Google Scholar]
  60. 60. 
    Thangavel S, Berti M, Levikova M, Pinto C, Gomathinayagam S et al. 2015. DNA2 drives processing and restart of reversed replication forks in human cells. J. Cell Biol. 208:545–62
    [Google Scholar]
  61. 61. 
    Panier S, Boulton SJ. 2014. Double-strand break repair: 53BP1 comes into focus. Nat. Rev. Mol. Cell Biol. 15:7–18
    [Google Scholar]
  62. 62. 
    Bunting SF, Callen E, Wong N, Chen HT, Polato F et al. 2010. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell 141:243–54
    [Google Scholar]
  63. 63. 
    Dev H, Chiang TW, Lescale C, de Krijger I, Martin AG et al. 2018. Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells. Nat. Cell Biol.20:954–65
    [Google Scholar]
  64. 64. 
    Gupta R, Somyajit K, Narita T, Maskey E, Stanlie A et al. 2018. DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity. Cell 173:972–88
    [Google Scholar]
  65. 65. 
    Mirman Z, Lottersberger F, Takai H, Kibe T, Gong Y et al. 2018. 53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. Nature 560:112–16
    [Google Scholar]
  66. 66. 
    Noordermeer SM, Adam S, Setiaputra D, Barazas M, Pettitt SJ et al. 2018. The shieldin complex mediates 53BP1-dependent DNA repair. Nature560:117–21
    [Google Scholar]
  67. 67. 
    Barazas M, Annunziato S, Pettitt SJ, de Krijger I, Ghezraoui H et al. 2018. The CST complex mediates end protection at double-strand breaks and promotes PARP inhibitor sensitivity in BRCA1-deficient cells. Cell Rep 23:2107–18
    [Google Scholar]
  68. 68. 
    Sung P. 1994. Catalysis of ATP-dependent homologous DNA pairing and strand exchange by yeast RAD51 protein. Science 265:1241–43
    [Google Scholar]
  69. 69. 
    San Filippo J, Sung P, Klein H 2008. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem. 77:229–57
    [Google Scholar]
  70. 70. 
    Kowalczykowski SC. 2015. An overview of the molecular mechanisms of recombinational DNA repair. Cold Spring Harb. Perspect. Biol. 7:a016410
    [Google Scholar]
  71. 71. 
    Yu X, Jacobs SA, West SC, Ogawa T, Egelman EH 2001. Domain structure and dynamics in the helical filaments formed by RecA and Rad51 on DNA. PNAS 98:8419–24
    [Google Scholar]
  72. 72. 
    VanLoock MS, Yu X, Yang S, Lai AL, Low C et al. 2003. ATP-mediated conformational changes in the RecA filament. Structure 11:187–96
    [Google Scholar]
  73. 73. 
    Short JM, Liu Y, Chen S, Soni N, Madhusudhan MS et al. 2016. High-resolution structure of the presynaptic RAD51 filament on single-stranded DNA by electron cryo-microscopy. Nucleic Acids Res 44:9017–30
    [Google Scholar]
  74. 74. 
    Xu J, Zhao L, Xu Y, Zhao W, Sung P, Wang HW 2017. Cryo-EM structures of human RAD51 recombinase filaments during catalysis of DNA-strand exchange. Nat. Struct. Mol. Biol. 24:40–46
    [Google Scholar]
  75. 75. 
    Chen Z, Yang H, Pavletich NP 2008. Mechanism of homologous recombination from the RecA–ssDNA/dsDNA structures. Nature 453:489–94
    [Google Scholar]
  76. 76. 
    Zelensky A, Kanaar R, Wyman C 2014. Mediators of homologous DNA pairing. Cold Spring Harb. Perspect. Biol. 6:a016451
    [Google Scholar]
  77. 77. 
    Zhao W, Vaithiyalingam S, San Filippo J, Maranon DG, Jimenez-Sainz J et al. 2015. Promotion of BRCA2-dependent homologous recombination by DSS1 via RPA targeting and DNA mimicry. Mol. Cell 59:176–87
    [Google Scholar]
  78. 78. 
    Sung P. 1997. Yeast Rad55 and Rad57 proteins form a heterodimer that functions with replication protein A to promote DNA strand exchange by Rad51 recombinase. Genes Dev 11:1111–21
    [Google Scholar]
  79. 79. 
    Sigurdsson S, Van Komen S, Bussen W, Schild D, Albala JS, Sung P 2001. Mediator function of the human Rad51B–Rad51C complex in Rad51/RPA-catalyzed DNA strand exchange. Genes Dev 15:3308–18
    [Google Scholar]
  80. 80. 
    Krejci L, Van Komen S, Li Y, Villemain J, Reddy MS et al. 2003. DNA helicase Srs2 disrupts the Rad51 presynaptic filament. Nature 423:305–9
    [Google Scholar]
  81. 81. 
    Liu J, Renault L, Veaute X, Fabre F, Stahlberg H, Heyer WD 2011. Rad51 paralogues Rad55–Rad57 balance the antirecombinase Srs2 in Rad51 filament formation. Nature 479:245–48
    [Google Scholar]
  82. 82. 
    Takata M, Sasaki MS, Tachiiri S, Fukushima T, Sonoda E et al. 2001. Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. Mol. Cell. Biol. 21:2858–66
    [Google Scholar]
  83. 83. 
    Renkawitz J, Lademann CA, Jentsch S 2014. Mechanisms and principles of homology search during recombination. Nat. Rev. Mol. Cell Biol. 15:369–83
    [Google Scholar]
  84. 84. 
    Bianchi M, DasGupta C, Radding CM 1983. Synapsis and the formation of paranemic joints by E. coli RecA protein. Cell 34:931–39
    [Google Scholar]
  85. 85. 
    Qi Z, Redding S, Lee JY, Gibb B, Kwon Y et al. 2015. DNA sequence alignment by microhomology sampling during homologous recombination. Cell 160:856–69
    [Google Scholar]
  86. 86. 
    Zhao W, Sung P. 2015. Significance of ligand interactions involving Hop2-Mnd1 and the RAD51 and DMC1 recombinases in homologous DNA repair and XX ovarian dysgenesis. Nucleic Acids Res 43:4055–66
    [Google Scholar]
  87. 87. 
    Ito K, Murayama Y, Takahashi M, Iwasaki H 2018. Two three-strand intermediates are processed during Rad51-driven DNA strand exchange. Nat. Struct. Mol. Biol. 25:29–36
    [Google Scholar]
  88. 88. 
    Liang F, Longerich S, Miller AS, Tang C, Buzovetsky O et al. 2016. Promotion of RAD51-mediated homologous DNA pairing by the RAD51AP1-UAF1 complex. Cell Rep 15:2118–26
    [Google Scholar]
  89. 89. 
    Zhao W, Steinfeld JB, Liang F, Chen X, Maranon DG et al. 2017. BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing. Nature 550:360–65
    [Google Scholar]
  90. 90. 
    Lee JY, Terakawa T, Qi Z, Steinfeld JB, Redding S et al. 2015. Base triplet stepping by the Rad51/RecA family of recombinases. Science 349:977–81
    [Google Scholar]
  91. 91. 
    Prindle MJ, Loeb LA. 2012. DNA polymerase delta in DNA replication and genome maintenance. Environ. Mol. Mutagen 53:666–82
    [Google Scholar]
  92. 92. 
    Szostak JW, Orr-Weaver TL, Rothstein RJ, Stahl FW 1983. The double-strand-break repair model for recombination. Cell 33:25–35
    [Google Scholar]
  93. 93. 
    West SC, Blanco MG, Chan YW, Matos J, Sarbajna S, Wyatt HD 2015. Resolution of recombination intermediates: mechanisms and regulation. Cold Spring Harb. Symp. Quant. Biol. 80:103–9
    [Google Scholar]
  94. 94. 
    Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA et al. 1990. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684–89
    [Google Scholar]
  95. 95. 
    Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K et al. 1994. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71
    [Google Scholar]
  96. 96. 
    Friedman LS, Ostermeyer EA, Szabo CI, Dowd P, Lynch ED 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
    [Google Scholar]
  97. 97. 
    Petrucelli N, Daly MB, Pal T 1993–2018. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. GeneReviews® MP Adam, HH Ardinger, RA Pagon, SE Wallace, LJH Bean et al. Seattle: University of Washington, updated Dec 15 2016.
    [Google Scholar]
  98. 98. 
    Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A et al. 1996. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat. Genet. 14:430–40
    [Google Scholar]
  99. 99. 
    Hashizume R, Fukuda M, Maeda I, Nishikawa H, Oyake D et al. 2001. The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J. Biol. Chem. 276:14537–40
    [Google Scholar]
  100. 100. 
    Christou CM, Kyriacou K. 2013. BRCA1 and its network of interacting partners. Biology 2:40–63
    [Google Scholar]
  101. 101. 
    Zhang F, Ma J, Wu J, Ye L, Cai H et al. 2009. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19:524–29
    [Google Scholar]
  102. 102. 
    Zhang F, Fan Q, Ren K, Andreassen PR 2009. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol. Cancer Res. 7:1110–18
    [Google Scholar]
  103. 103. 
    Paull TT, Cortez D, Bowers B, Elledge SJ, Gellert M 2001. Direct DNA binding by Brca1. PNAS 98:6086–91
    [Google Scholar]
  104. 104. 
    Simons AM, Horwitz AA, Starita LM, Griffin K, Williams RS et al. 2006. BRCA1 DNA-binding activity is stimulated by BARD1. Cancer Res 66:2012–18
    [Google Scholar]
  105. 105. 
    Scully R, Chen J, Plug A, Xiao Y, Weaver D et al. 1997. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88:265–75
    [Google Scholar]
  106. 106. 
    Densham RM, Morris JR. 2017. The BRCA1 ubiquitin ligase function sets a new trend for remodelling in DNA repair. Nucleus 8:116–25
    [Google Scholar]
  107. 107. 
    Irminger-Finger I, Ratajska M, Pilyugin M 2016. New concepts on BARD1: regulator of BRCA pathways and beyond. Int. J. Biochem. Cell Biol. 72:1–17
    [Google Scholar]
  108. 108. 
    Thai TH, Du F, Tsan JT, Jin Y, Phung A et al. 1998. Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Hum. Mol. Genet. 7:195–202
    [Google Scholar]
  109. 109. 
    Shakya R, Szabolcs M, McCarthy E, Ospina E, Basso K et al. 2008. The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. PNAS 105:7040–45
    [Google Scholar]
  110. 110. 
    Shen SX, Weaver Z, Xu X, Li C, Weinstein M et al. 1998. A targeted disruption of the murine Brca1 gene causes γ-irradiation hypersensitivity and genetic instability. Oncogene 17:3115–24
    [Google Scholar]
  111. 111. 
    Cortez D, Wang Y, Qin J, Elledge SJ 1999. Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks. Science 286:1162–66
    [Google Scholar]
  112. 112. 
    Moynahan ME, Cui TY, Jasin M 2001. Homology-directed DNA repair, mitomycin-C resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 61:4842–50
    [Google Scholar]
  113. 113. 
    Moynahan ME, Chiu JW, Koller BH, Jasin M 1999. Brca1 controls homology-directed DNA repair. Mol. Cell 4:511–18
    [Google Scholar]
  114. 114. 
    Laufer M, Nandula SV, Modi AP, Wang S, Jasin M et al. 2007. Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair. J. Biol. Chem. 282:34325–33
    [Google Scholar]
  115. 115. 
    Bhattacharyya A, Ear US, Koller BH, Weichselbaum RR, Bishop DK 2000. 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. 275:23899–903
    [Google Scholar]
  116. 116. 
    Densham RM, Garvin AJ, Stone HR, Strachan J, Baldock RA et al. 2016. Human BRCA1-BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection. Nat. Struct. Mol. Biol. 23:647–55
    [Google Scholar]
  117. 117. 
    Ferretti LP, Lafranchi L, Sartori AA 2013. Controlling DNA-end resection: a new task for CDKs. Front. Genet. 4:99
    [Google Scholar]
  118. 118. 
    Xu G, Chapman JR, Brandsma I, Yuan J, Mistrik M et al. 2015. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 521:541–44
    [Google Scholar]
  119. 119. 
    Boersma V, Moatti N, Segura-Bayona S, Peuscher MH, van der Torre J et al. 2015. MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection. Nature 521:537–40
    [Google Scholar]
  120. 120. 
    Kalb R, Mallery DL, Larkin C, Huang JT, Hiom K 2014. BRCA1 is a histone-H2A-specific ubiquitin ligase. Cell Rep 8:999–1005
    [Google Scholar]
  121. 121. 
    Yu X, Wu LC, Bowcock AM, Aronheim A, Baer R 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. 273:25388–92
    [Google Scholar]
  122. 122. 
    Cruz-Garcia A, Lopez-Saavedra A, Huertas P 2014. BRCA1 accelerates CtIP-mediated DNA-end resection. Cell Rep 9:451–59
    [Google Scholar]
  123. 123. 
    Yang H, Jeffrey PD, Miller J, Kinnucan E, Sun Y et al. 2002. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297:1837–48
    [Google Scholar]
  124. 124. 
    Santos-Pereira JM, Aguilera A. 2015. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16:583–97
    [Google Scholar]
  125. 125. 
    Hatchi E, Skourti-Stathaki K, Ventz S, Pinello L, Yen A et al. 2015. BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair. Mol. Cell 57:636–47
    [Google Scholar]
  126. 126. 
    Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D et al. 1994. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265:2088–90
    [Google Scholar]
  127. 127. 
    Wooster R, Bignell G, Lancaster J, Swift S, Seal S et al. 1995. Identification of the breast cancer susceptibility gene BRCA2. . Nature 378:789–92
    [Google Scholar]
  128. 128. 
    Bork P, Blomberg N, Nilges M 1996. Internal repeats in the BRCA2 protein sequence. Nat. Genet. 13:22–23
    [Google Scholar]
  129. 129. 
    Chen PL, Chen CF, Chen Y, Xiao J, Sharp ZD, Lee WH 1998. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. PNAS 95:5287–92
    [Google Scholar]
  130. 130. 
    Chatterjee G, Jimenez-Sainz J, Presti T, Nguyen T, Jensen RB 2016. Distinct binding of BRCA2 BRC repeats to RAD51 generates differential DNA damage sensitivity. Nucleic Acids Res 44:5256–70
    [Google Scholar]
  131. 131. 
    von Nicolai C, Ehlen A, Martin C, Zhang X, Carreira A 2016. A second DNA binding site in human BRCA2 promotes homologous recombination. Nat. Commun. 7:12813
    [Google Scholar]
  132. 132. 
    Marston NJ, Richards WJ, Hughes D, Bertwistle D, Marshall CJ, Ashworth A 1999. Interaction between the product of the breast cancer susceptibility gene BRCA2 and DSS1, a protein functionally conserved from yeast to mammals. Mol. Cell. Biol. 19:4633–42
    [Google Scholar]
  133. 133. 
    Moynahan ME, Pierce AJ, Jasin M 2001. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7:263–72
    [Google Scholar]
  134. 134. 
    Bhatia V, Barroso SI, Garcia-Rubio ML, Tumini E, Herrera-Moyano E, Aguilera A 2014. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature 511:362–65
    [Google Scholar]
  135. 135. 
    Kolinjivadi AM, Sannino V, de Antoni A, Techer H, Baldi G, Costanzo V 2017. Moonlighting at replication forks—a new life for homologous recombination proteins BRCA1, BRCA2 and RAD51. FEBS Lett 591:1083–100
    [Google Scholar]
  136. 136. 
    Yuan SS, Lee SY, Chen G, Song M, Tomlinson GE, Lee EY 1999. BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res 59:3547–51
    [Google Scholar]
  137. 137. 
    Yang H, Li Q, Fan J, Holloman WK, Pavletich NP 2005. The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA–ssDNA junction. Nature 433:653–57
    [Google Scholar]
  138. 138. 
    San Filippo J, Chi P, Sehorn MG, Etchin J, Krejci L, Sung P 2006. Recombination mediator and Rad51 targeting activities of a human BRCA2 polypeptide. J. Biol. Chem. 281:11649–57
    [Google Scholar]
  139. 139. 
    Carreira A, Hilario J, Amitani I, Baskin RJ, Shivji MK et al. 2009. The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Cell 136:1032–43
    [Google Scholar]
  140. 140. 
    Jensen RB, Carreira A, Kowalczykowski SC 2010. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 467:678–83
    [Google Scholar]
  141. 141. 
    Liu J, Doty T, Gibson B, Heyer WD 2010. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat. Struct. Mol. Biol. 17:1260–62
    [Google Scholar]
  142. 142. 
    Thorslund T, McIlwraith MJ, Compton SA, Lekomtsev S, Petronczki M et al. 2010. The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat. Struct. Mol. Biol. 17:1263–65
    [Google Scholar]
  143. 143. 
    Shahid T, Soroka J, Kong E, Malivert L, McIlwraith MJ et al. 2014. Structure and mechanism of action of the BRCA2 breast cancer tumor suppressor. Nat. Struct. Mol. Biol. 21:962–68
    [Google Scholar]
  144. 144. 
    Carreira A, Kowalczykowski SC. 2011. Two classes of BRC repeats in BRCA2 promote RAD51 nucleoprotein filament function by distinct mechanisms. PNAS 108:10448–53
    [Google Scholar]
  145. 145. 
    Saeki H, Siaud N, Christ N, Wiegant WW, van Buul PP et al. 2006. Suppression of the DNA repair defects of BRCA2-deficient cells with heterologous protein fusions. PNAS 103:8768–73
    [Google Scholar]
  146. 146. 
    Siaud N, Barbera MA, Egashira A, Lam I, Christ N et al. 2011. Plasticity of BRCA2 function in homologous recombination: genetic interactions of the PALB2 and DNA binding domains. PLOS Genet 7:e1002409
    [Google Scholar]
  147. 147. 
    Kragelund BB, Schenstrom SM, Rebula CA, Panse VG, Hartmann-Petersen R 2016. DSS1/Sem1, a multifunctional and intrinsically disordered protein. Trends Biochem. Sci. 41:446–59
    [Google Scholar]
  148. 148. 
    Gudmundsdottir K, Lord CJ, Witt E, Tutt AN, Ashworth A 2004. DSS1 is required for RAD51 focus formation and genomic stability in mammalian cells. EMBO Rep 5:989–93
    [Google Scholar]
  149. 149. 
    Li J, Zou C, Bai Y, Wazer DE, Band V, Gao Q 2006. DSS1 is required for the stability of BRCA2. Oncogene 25:1186–94
    [Google Scholar]
  150. 150. 
    Wu K, Hinson SR, Ohashi A, Farrugia D, Wendt P et al. 2005. Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res 65:417–26
    [Google Scholar]
  151. 151. 
    Jeyasekharan AD, Liu Y, Hattori H, Pisupati V, Jonsdottir AB et al. 2013. A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nat. Struct. Mol. Biol. 20:1191–98
    [Google Scholar]
  152. 152. 
    Riaz N, Blecua P, Lim RS, Shen R, Higginson DS et al. 2017. Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes. Nat. Commun. 8:857
    [Google Scholar]
  153. 153. 
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA et al. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–21
    [Google Scholar]
  154. 154. 
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D et al. 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–17
    [Google Scholar]
/content/journals/10.1146/annurev-biochem-013118-111058
Loading
/content/journals/10.1146/annurev-biochem-013118-111058
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error