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.

  • Review
  • Published:

BRCA2: a universal recombinase regulator

Oncogene volume 26, pages 7720–7730 (2007)Cite this article

Abstract

Homologous recombination has a dual role in eukaryotic organisms. Firstly, it is responsible for the creation of genetic variability during meiosis by directing the formation of reciprocal crossovers that result in random combinations of alleles and traits. Secondly, in mitotic cells, it maintains the integrity of the genome by promoting the faithful repair of DNA double-strand breaks (DSBs). In vertebrates, it therefore plays a key role in tumour avoidance. Mutations in the tumour suppressor protein BRCA2 are associated with predisposition to breast and ovarian cancers, and loss of BRCA2 function leads to genetic instability. BRCA2 protein interacts directly with the RAD51 recombinase and regulates recombination-mediated DSB repair, accounting for the high levels of spontaneous chromosomal aberrations seen in BRCA2-defective cells. Recent observations indicate that BRCA2 also plays a critical role in meiotic recombination, this time through direct interactions with the meiosis-specific recombinase DMC1. The interactions of BRCA2 with RAD51 and DMC1 lead us to suggest that the BRCA2 tumour suppressor is a universal regulator of recombinase actions.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Atanassov BS, Barrett JC, Davis BJ . (2005). Homozygous germ-line mutation in exon 27 of murine BRCA2 disrupts the FANCD2-BRCA2 pathway in the homologous recombination-mediated DNA interstrand cross-link repair but does not affect meiosis. Genes Chromosomes Cancer 44: 429–437.

    Article  CAS  Google Scholar 

  • Barlow AL, Benson FE, West SC, Hultén MA . (1997). Distribution of RAD51 recombinase in human and mouse spermatocytes. EMBO J 16: 5207–5215.

    Article  CAS  Google Scholar 

  • Bennett CB, Lewis AL, Baldwin KK, Resnick MA . (1993). Lethality induced by a single site-specific double-strand break in a dispensable yeast plasmid. Proc Natl Acad Sci USA 90: 5613–5617.

    Article  CAS  Google Scholar 

  • Benson FE, Stasiak A, West SC . (1994). Purification and characterisation of the human RAD51 protein, an analogue of E. coli RecA. EMBO J 13: 5764–5771.

    Article  CAS  Google Scholar 

  • Chen CF, Chen PL, Zhong Q, Sharp ZD, Lee WH . (1999). Expression of BRC repeats in breast cancer cells disrupts the BRCA2–RAD51 complex and leads to radiation hypersensitivity and loss of G(2)/M checkpoint control. J Biol Chem 274: 32931–32935.

    Article  CAS  Google Scholar 

  • Chen JJ, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G et al. (1998a). Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell 2: 317–328.

    Article  CAS  Google Scholar 

  • Chen PL, Chen CF, Chen YM, Xiao J, Sharp ZD, Lee WH . (1998b). The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci USA 95: 5287–5292.

    Article  CAS  Google Scholar 

  • Connor F, Bertwistle D, Mee PJ, Ross GM, Swift S, Grigorieva E et al. (1997). Tumorigenesis and a DNA-repair defect in mice with a truncating BRCA2 mutation. Nat Genet 17: 423–430.

    Article  CAS  Google Scholar 

  • Conway AB, Lynch TW, Zhang Y, Fortin GS, Fung CW, Symington LS et al. (2004). Crystal structure of a Rad51 filament. Nat Struct Mol Biol 11: 791–796.

    Article  CAS  Google Scholar 

  • Davies AA, Masson J-Y, McIlwraith MJ, Stasiak AZ, Stasiak A, Venkitaraman AR et al. (2001). Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell 7: 273–282.

    Article  CAS  Google Scholar 

  • Davies OR, Pellegrini L . (2007). Interaction with the BRCA2 C-terminus protects RAD51-DNA filaments from disassembly by BRC repeats. Nat Struct Mol Biol 14: 475–483.

    Article  Google Scholar 

  • Donoho G, Brenneman MA, Cui TX, Donoviel D, Vogel H, Goodwin EH et al. (2003). Deletion of BRCA2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice. Genes Chromosomes Cancer 36: 317–331.

    Article  CAS  Google Scholar 

  • Dray E, Siaud N, Dubois E, Doutriaux MP . (2006). Interaction between Arabidopsis BRCA2 and its partners RAD51, DMC1, and DSS1. Plant Physiol 140: 1059–1069.

    Article  CAS  Google Scholar 

  • Esashi F, Christ N, Gannon J, Liu Y, Hunt T, Jasin M et al. (2005). CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434: 598–604.

    Article  CAS  Google Scholar 

  • Esashi F, Galkin VE, Yu X, Egelman EH, West SC . (2007). Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2. Nat Struct Mol Biol 14: 468–474.

    Article  CAS  Google Scholar 

  • Galkin VE, Esashi F, Yu X, Yang SX, West SC, Egelman EH . (2005). BRCA2 BRC motifs bind RAD51-DNA filaments. Proc Natl Acad Sci USA 102: 8537–8542.

    Article  CAS  Google Scholar 

  • Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM et al. (1996). Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Can Res 56: 5360–5364.

    CAS  Google Scholar 

  • Haaf T, Golub EI, Reddy G, Radding CM, Ward DC . (1995). Nuclear foci of mammalian RAD51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes. Proc Natl Acad Sci USA 92: 2298–2302.

    Article  CAS  Google Scholar 

  • Hoeijmakers JH . (2001). Genome maintenance mechanisms for preventing cancer. Nature 411: 366–374.

    Article  CAS  Google Scholar 

  • Kinebuchi T, Kagawa W, Enomoto R, Tanaka K, Miyagawa K, Shibata T et al. (2004). Structural basis for octameric ring formation and DNA interaction of the human homologous-pairing protein DMC1. Mol Cell 14: 363–374.

    Article  CAS  Google Scholar 

  • Kojic M, Kostrub CF, Buchman AR, Holloman WK . (2002). BRCA2 homolog required for proficiency in DNA repair, recombination, and genome stability in Ustilago maydis. Mol Cell 10: 683–691.

    Article  CAS  Google Scholar 

  • Lim DS, Hasty P . (1996). A mutation in mouse RAD51 results in an early embryonic lethal that is suppressed by a mutation in p53. Mol Cell Biol 16: 7133–7143.

    Article  CAS  Google Scholar 

  • Lindahl T . (1993). Instability and decay of the primary structure of DNA. Nature 362: 709–715.

    Article  CAS  Google Scholar 

  • Ludwig T, Chapman DL, Papaioannou VE, Efstratiadis A . (1997). Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of BRCA1, BRCA2, BRCA1/BRCA2, BRCA1/p53, and BRCA2/p53 null zygous embryos. Genes Dev 11: 1226–1241.

    Article  CAS  Google Scholar 

  • Marmorstein LY, Ouchi T, Aaronson SA . (1998). The BRCA2 gene product functionally interacts with p53 and RAD51. Proc Natl Acad Sci USA 95: 13869–13874.

    Article  CAS  Google Scholar 

  • Martin JS, Winkelmann N, Petalcorin MIR, McIlwraith MJ, Boulton SJ . (2005). RAD-51-dependent and independent roles of a Caenorhabditis elegans BRCA2-related protein during DNA double-strand break repair. Mol Cell Biol 25: 3127–3139.

    Article  CAS  Google Scholar 

  • McAllister KA, Bennett LM, Houle CD, Ward TA, Malphurs J, Collins NK et al. (2002). Cancer susceptibility of mice with a homozygous deletion of the COOH-terminal domain of the BRCA2 gene. Cancer Res 62: 990–994.

    CAS  PubMed  Google Scholar 

  • Mizuta R, Lasalle JM, Cheng HL, Shinohara A, Ogawa H, Copeland N et al. (1997). Rab22 and Rab163/mouse BRCA2: proteins that specifically interact with the RAD51 protein. Proc Natl Acad Sci USA 94: 6927–6932.

    Article  CAS  Google Scholar 

  • Moynahan ME, Pierce AJ, Jasin M . (2001). BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 7: 263–272.

    Article  CAS  Google Scholar 

  • Neale MJ, Keeney S . (2006). Clarifying the mechanics of DNA strand exchange in meiotic recombination. Nature 442: 153–158.

    Article  CAS  Google Scholar 

  • Patel KJ, Yu VPCC, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ et al. (1998). Involvement of BRCA2 in DNA repair. Mol Cell 1: 347–357.

    Article  CAS  Google Scholar 

  • Pellegrini L, Yu DS, Lo T, Anand S, Lee MY, Blundell TL et al. (2002). Insights into DNA recombination from the structure of a RAD51–BRCA2 complex. Nature 420: 287–293.

    Article  CAS  Google Scholar 

  • Petalcorin MIR, Galkin VE, Yu X, Egelman EH, Boulton SJ . (2007). Stabilization of RAD-51-DNA filaments by a novel interaction domain in Caenorhabditis elegans BRCA2. Proc Natl Acad Sci USA 104: 8299–8304.

    Article  CAS  Google Scholar 

  • Pittman DL, Cobb J, Schimenti KJ, Wilson LA, Cooper DM, Brignull E et al. (1998). Meiotic prophase arrest with failure of chromosome synapsis in mice deficient for DMC1, a germline-specific RecA homolog. Mol Cell 1: 697–705.

    Article  CAS  Google Scholar 

  • Raderschall E, Golub EI, Haaf T . (1999). Nuclear foci of mammalian recombination proteins are located at single-stranded DNA regions formed after DNA damage. Proc Natl Acad Sci USA 96: 1921–1926.

    Article  CAS  Google Scholar 

  • Saeki H, Siaud N, Christ N, Wiegant WW, van BPPW, Han MG et al. (2006). Suppression of the DNA repair defects of BRCA2-deficient cells with heterologous protein fusions. Proc Natl Acad Sci USA 103: 8768–8773.

    Article  CAS  Google Scholar 

  • Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J et al. (1997). Association of BRCA1 with RAD51 in mitotic and meiotic cells. Cell 88: 265–275.

    Article  CAS  Google Scholar 

  • Sehorn MG, Sigurdsson S, Bussen W, Unger VM, Sung P . (2004). Human meiotic recombinase DMC1 promotes ATP-dependent homologous DNA strand exchange. Nature 429: 433–437.

    Article  CAS  Google Scholar 

  • Sharan SK, Morimatsu M, Albrecht U, Lim SS, Regel E, Dinh C et al. (1997). Embryonic lethality and radiation hypersensitivity mediated by RAD51 in mice lacking BRCA2. Nature 386: 804–810.

    Article  CAS  Google Scholar 

  • Sharan SK, Pyle A, Coppola V, Babus J, Swaminathan S, Benedict J et al. (2004). BRCA2 deficiency in mice leads to meiotic impairment and infertility. Development 131: 131–142.

    Article  CAS  Google Scholar 

  • Shin DS, Pellegrini L, Daniels DS, Yelent B, Craig L, Bates D et al. (2003). Full-length archaeal RAD51 structure and mutants: mechanisms for RAD51 assembly and control by BRCA2. EMBO J 22: 4566–4576.

    Article  CAS  Google Scholar 

  • Shinohara M, Gasior SL, Bishop DK, Shinohara A . (2000). Tid1/Rdh54 promotes colocalization of Rad51 and Dmc1 during meiotic recombination. Proc Natl Acad Sci USA 97: 10814–10819.

    Article  CAS  Google Scholar 

  • Shivji MKK, Davies OR, Savill JM, Bates DL, Pellegrini L, Venkitaraman AR . (2006). A region of human BRCA2 containing multiple BRC repeats promotes RAD51-mediated strand exchange. Nucl Acids Res 34: 4000–4011.

    Article  CAS  Google Scholar 

  • Siaud N, Dray E, Gy I, Gerard E, Takvorian N, Doutriaux MP . (2004). BRCA2 is involved in meiosis in Arabidopsis thaliana as suggested by its interaction with DMC1. EMBO J 23: 1392–1401.

    Article  CAS  Google Scholar 

  • Sung P, Klein H . (2006). Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 7: 739–750.

    Article  CAS  Google Scholar 

  • Suzuki A, Delapompa JL, Hakem R, Elia A, Yoshida R, Mo R et al. (1997). BRCA2 is required for embryonic cellular proliferation in the mouse. Genes Dev 11: 1242–1252.

    Article  CAS  Google Scholar 

  • Takanami T, Mori A, Takahashi H, Higashitani A . (2000). Hyper-resistance of meiotic cells to radiation due to a strong expression of a single recA-like gene in Caenorhabditis elegans. Nucl Acids Res 28: 4232–4236.

    Article  CAS  Google Scholar 

  • Takata M, Tachiiri S, Fujimori A, Thompson LH, Miki F, Hiraoka M et al. (2002). Conserved domains in the chicken homologue of BRCA2. Oncogene 21: 1130–1134.

    Article  CAS  Google Scholar 

  • Tarsounas M, Davies AA, West SC . (2004). RAD51 localization and activation following DNA damage. Phil Trans R Soc Lond B 359: 87–93.

    Article  CAS  Google Scholar 

  • Tarsounas M, Morita T, Pearlman RE, Moens PB . (1999). RAD51 and DMC1 form mixed complexes associated with mouse meiotic chromosome cores and synaptonemal complexes. J Cell Biol 147: 207–219.

    Article  CAS  Google Scholar 

  • Thorslund T, Esashi F, West SC . (2007). Interactions between human BRCA2 protein and the meiosis-specific recombinase DMC1. EMBO J 26: 2915–2922.

    Article  CAS  Google Scholar 

  • Tsuzuki T, Fujii Y, Sakuma K, Tominaga Y, Nakao K, Sekiguchi M et al. (1996). Targeted disruption of the RAD51 gene leads to lethality in embryonic mice. Proc Natl Acad Sci USA 93: 6236–6240.

    Article  CAS  Google Scholar 

  • Tutt A, Bertwistle D, Valentine J, Gabriel A, Swift S, Ross G et al. (2001). Mutation in BRCA2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J 20: 4704–4716.

    Article  CAS  Google Scholar 

  • West SC . (2003). Molecular views of recombination proteins and their control. Nat Rev Mol Cell Biol 4: 435–445.

    Article  CAS  Google Scholar 

  • Wong AKC, Pero R, Ormonde PA, Tavtigian SV, Bartel PL . (1997). RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene BRCA2. J Biol Chem 272: 31941–31944.

    Article  CAS  Google Scholar 

  • Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J et al. (1995). Identification of the breast cancer susceptibility gene BRCA2. Nature 378: 789–792.

    Article  CAS  Google Scholar 

  • Yang H, Li Q, Holloman WK, Pavletich NP . (2005). The BRCA2 homologue BRH2 nucleates RAD51 filament formation at a dsDNS–ssDNA junction. Nature 433: 653–657.

    Article  CAS  Google Scholar 

  • Yang HJ, Jeffrey PD, Miller J, Kinnucan E, Sun YT, Thoma NH et al. (2002). BRCA2 function in DNA binding and recombination from a BRCA2–DSS1–ssDNA structure. Science 297: 1837–1848.

    Article  CAS  Google Scholar 

  • Yoshida K, Kondoh G, Matsuda Y, Habu T, Nishimune Y, Morita T . (1998). The mouse recA-like gene DMC1 is required for homologous chromosome synapsis during meiosis. Mol Cell 1: 707–718.

    Article  CAS  Google Scholar 

  • Yu VPCC, Köehler M, Steinlein C, Schmid M, Hanakahi LA, van Gool AJ et al. (2000). Gross chromosomal rearrangements and genetic exchange between non-homologous chromosomes following BRCA2 inactivation. Genes Dev 14: 1400–1406.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan S-SF, Lee S-Y, 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: 3547–3551.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Uli Rass for critical reading of the manuscript. This work was supported by Cancer Research UK, the EU DNA Repair Consortium, the Breast Cancer Campaign, and the Louis-Jeantet Foundation. TT is a recipient of a post-doctoral fellowship from the Carlsberg foundation.

Author information

Authors and Affiliations

  1. London Research Institute, Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts, UK

    T Thorslund & S C West

Authors
  1. T Thorslund
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S C West
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S C West.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thorslund, T., West, S. BRCA2: a universal recombinase regulator. Oncogene 26, 7720–7730 (2007). https://doi.org/10.1038/sj.onc.1210870

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210870

Keywords

This article is cited by

Search

Advanced search

Quick links