Abstract
BRCA2 is the product of a breast cancer susceptibility gene in humans and the founding member of an emerging family of proteins present throughout the eukaryotic domain that serve in homologous recombination. The function of BRCA2 in recombination is to control RAD51, a protein that catalyzes homologous pairing and DNA strand exchange. By physically interacting with both RAD51 and single-stranded DNA, BRCA2 mediates delivery of RAD51 preferentially to sites of single-stranded DNA (ssDNA) exposed as a result of DNA damage or replication problems. Through its action, BRCA2 helps restore and maintain integrity of the genome. This review highlights recent studies on BRCA2 and its orthologs that have begun to illuminate the molecular mechanisms by which these proteins control homologous recombination.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Budzowska, M. & Kanaar, R. Mechanisms of dealing with DNA damage-induced replication problems. Cell Biochem. Biophys. 53, 17–31 (2009).
Heyer, W.D., Ehmsen, K.T. & Liu, J. Regulation of homologous recombination in eukaryotes. Annu. Rev. Genet. 44, 113–139 (2010).
Mimitou, E.P. & Symington, L.S. Nucleases and helicases take center stage in homologous recombination. Trends Biochem. Sci. 34, 264–272 (2009).
Moynahan, M.E. & Jasin, M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat. Rev. Mol. Cell Biol. 11, 196–207 (2010).
San Filippo, J., Sung, P. & Klein, H. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem. 77, 229–257 (2008).
Thorslund, T. & West, S.C. BRCA2: a universal recombinase regulator. Oncogene 26, 7720–7730 (2007).
Venkitaraman, A.R. Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Annu. Rev. Pathol. 4, 461–487 (2009).
Holthausen, J.T., Wyman, C. & Kanaar, R. Regulation of DNA strand exchange in homologous recombination. DNA Repair (Amst.) 9, 1264–1272 (2010).
Bugreev, D.V., Hanaoka, F. & Mazin, A.V. Rad54 dissociates homologous recombination intermediates by branch migration. Nat. Struct. Mol. Biol. 14, 746–753 (2007).
McIlwraith, M.J. & West, S.C. DNA repair synthesis facilitates RAD52-mediated second-end capture during DSB repair. Mol. Cell 29, 510–516 (2008).
Sugiyama, T., Kantake, N., Wu, Y. & Kowalczykowski, S.C. Rad52-mediated DNA annealing after Rad51-mediated DNA strand exchange promotes second ssDNA capture. EMBO J. 25, 5539–5548 (2006).
Lao, J.P., Oh, S.D., Shinohara, M., Shinohara, A. & Hunter, N. Rad52 promotes postinvasion steps of meiotic double-strand-break repair. Mol. Cell 29, 517–524 (2008).
Krogh, B.O. & Symington, L.S. Recombination proteins in yeast. Annu. Rev. Genet. 38, 233–271 (2004).
Rijkers, T. et al. Targeted inactivation of mouse RAD52 reduces homologous recombination but not resistance to ionizing radiation. Mol. Cell. Biol. 18, 6423–6429 (1998).
Yamaguchi-Iwai, Y. et al. Homologous recombination, but not DNA repair, is reduced in vertebrate cells deficient in RAD52. Mol. Cell. Biol. 18, 6430–6435 (1998).
Stark, J.M., Pierce, A.J., Oh, J., Pastink, A. & Jasin, M. Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Mol. Cell. Biol. 24, 9305–9316 (2004).
Sung, P. & Klein, H. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat. Rev. Mol. Cell Biol. 7, 739–750 (2006).
Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995).
Tavtigian, S.V. et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat. Genet. 12, 333–337 (1996).
Bork, P., Blomberg, N. & Nilges, M. Internal repeats in the BRCA2 protein sequence. Nat. Genet. 13, 22–23 (1996).
Bignell, G., Micklem, G., Stratton, M.R., Ashworth, A. & Wooster, R. The BRC repeats are conserved in mammalian BRCA2 proteins. Hum. Mol. Genet. 6, 53–58 (1997).
Sharan, S.K. et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804–810 (1997).
Mizuta, R. et al. RAB22 and RAB163/mouse BRCA2: proteins that specifically interact with the RAD51 protein. Proc. Natl. Acad. Sci. USA 94, 6927–6932 (1997).
Lim, D.S. & Hasty, P. 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 (1996).
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).
Tsuzuki, T. et al. Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc. Natl. Acad. Sci. USA 93, 6236–6240 (1996).
Chen, J. et al. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol. Cell 2, 317–328 (1998).
Wong, A.K., Pero, R., Ormonde, P.A., Tavtigian, S.V. & Bartel, P.L. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J. Biol. Chem. 272, 31941–31944 (1997).
Chen, C.F., Chen, P.L., Zhong, Q., Sharp, Z.D. & Lee, W.H. 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 (1999).
Patel, K.J. et al. Involvement of Brca2 in DNA repair. Mol. Cell 1, 347–357 (1998).
Connor, F. et al. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat. Genet. 17, 423–430 (1997).
Morimatsu, M., Donoho, G. & Hasty, P. Cells deleted for Brca2 COOH terminus exhibit hypersensitivity to gamma-radiation and premature senescence. Cancer Res. 58, 3441–3447 (1998).
Tutt, A. et al. Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr. Biol. 9, 1107–1110 (1999).
Yu, V.P. et al. Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev. 14, 1400–1406 (2000).
German, J. Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine (Baltimore) 72, 393–406 (1993).
Goggins, M. et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 56, 5360–5364 (1996).
Abbott, D.W., Freeman, M.L. & Holt, J.T. Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J. Natl. Cancer Inst. 90, 978–985 (1998).
Yuan, S.S. et al. BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res. 59, 3547–3551 (1999).
Moynahan, M.E., Pierce, A.J. & Jasin, M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7, 263–272 (2001).
Xia, F. et al. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc. Natl. Acad. Sci. USA 98, 8644–8649 (2001).
Warren, M. et al. Structural analysis of the chicken BRCA2 gene facilitates identification of functional domains and disease causing mutations. Hum. Mol. Genet. 11, 841–851 (2002).
Lo, T., Pellegrini, L., Venkitaraman, A.R. & Blundell, T.L. Sequence fingerprints in BRCA2 and RAD51: implications for DNA repair and cancer. DNA Repair (Amst.) 2, 1015–1028 (2003).
Kojic, M., Kostrub, C.F., Buchman, A.R. & Holloman, W.K. BRCA2 homolog required for proficiency in DNA repair, recombination, and genome stability in Ustilago maydis. Mol. Cell 10, 683–691 (2002).
Yang, H. et al. BRCA2 function in DNA binding and recombination from a BRCA2–DSS1-ssDNA structure. Science 297, 1837–1848 (2002).
Marston, N.J. et al. 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, 4633–4642 (1999).
Bochkarev, A. & Bochkareva, E. From RPA to BRCA2: lessons from single-stranded DNA binding by the OB-fold. Curr. Opin. Struct. Biol. 14, 36–42 (2004).
San Filippo, J. et al. Recombination mediator and Rad51 targeting activities of a human BRCA2 polypeptide. J. Biol. Chem. 281, 11649–11657 (2006).
Kojic, M., Zhou, Q., Lisby, M. & Holloman, W.K. Brh2-Dss1 interplay enables properly controlled recombination in Ustilago maydis. Mol. Cell. Biol. 25, 2547–2557 (2005).
Zhou, Q., Kojic, M. & Holloman, W.K. DNA-binding domain within the Brh2 N terminus Is the primary interaction site for association with DNA. J. Biol. Chem. 284, 8265–8273 (2009).
Edwards, S.L. et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111–1115 (2008).
Bryant, H.E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Saeki, H. et al. Suppression of the DNA repair defects of BRCA2-deficient cells with heterologous protein fusions. Proc. Natl. Acad. Sci. USA 103, 8768–8773 (2006).
Pellegrini, L. et al. Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 420, 287–293 (2002).
Rajendra, E. & Venkitaraman, A.R. Two modules in the BRC repeats of BRCA2 mediate structural and functional interactions with the RAD51 recombinase. Nucleic Acids Res. 38, 82–96 (2010).
Carreira, A. et al. The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Cell 136, 1032–1043 (2009).
Shivji, M.K. et al. The BRC repeats of human BRCA2 differentially regulate RAD51 binding on single- versus double-stranded DNA to stimulate strand exchange. Proc. Natl. Acad. Sci. USA 106, 13254–13259 (2009).
Bugreev, D.V. & Mazin, A.V. Ca2+ activates human homologous recombination protein Rad51 by modulating its ATPase activity. Proc. Natl. Acad. Sci. USA 101, 9988–9993 (2004).
Petalcorin, M.I., Sandall, J., Wigley, D.B. & Boulton, S.J. CeBRC-2 stimulates D-loop formation by RAD-51 and promotes DNA single-strand annealing. J. Mol. Biol. 361, 231–242 (2006).
Esashi, F. et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434, 598–604 (2005).
Davies, O.R. & Pellegrini, L. Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly by BRC repeats. Nat. Struct. Mol. Biol. 14, 475–483 (2007).
Esashi, F., Galkin, V.E., Yu, X., Egelman, E.H. & West, S.C. Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2. Nat. Struct. Mol. Biol. 14, 468–474 (2007).
Ayoub, N. et al. The carboxyl terminus of Brca2 links the disassembly of Rad51 complexes to mitotic entry. Curr. Biol. 19, 1075–1085 (2009).
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).
Hashimoto, Y., Chaudhuri, A.R., 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).
Thorslund, T., Esashi, F. & West, S.C. Interactions between human BRCA2 protein and the meiosis-specific recombinase DMC1. EMBO J. 26, 2915–2922 (2007).
Kojic, M., Zhou, Q., Fan, J. & Holloman, W.K. Mutational analysis of Brh2 reveals requirements for compensating mediator functions. Mol. Microbiol. 79, 180–191 (2011).
Yang, H., Li, Q., Fan, J., Holloman, W.K. & Pavletich, N.P. The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction. Nature 433, 653–657 (2005).
Mazloum, N., Zhou, Q. & Holloman, W.K. DNA binding, annealing, and strand exchange activities of Brh2 protein from Ustilago maydis. Biochemistry 46, 7163–7173 (2007).
Mazloum, N., Zhou, Q. & Holloman, W.K. D-loop formation by Brh2 protein of Ustilago maydis. Proc. Natl. Acad. Sci. USA 105, 524–529 (2008).
Wu, Y., Kantake, N., Sugiyama, T. & Kowalczykowski, S.C. Rad51 protein controls Rad52-mediated DNA annealing. J. Biol. Chem. 283, 14883–14892 (2008).
Mazloum, N. & Holloman, W.K. Brh2 promotes a template-switching reaction enabling recombinational bypass of lesions during DNA synthesis. Mol. Cell 36, 620–630 (2009).
Jensen, R.B., Carreira, A. & Kowalczykowski, S.C. Purified human BRCA2 stimulates RAD51-mediated recombination. Nature 467, 678–683 (2010).
Thorslund, T. et al. The breast cancer tumor suppressor BRCA2 promotes the specific targeting of RAD51 to single-stranded DNA. Nat. Struct. Mol. Biol. 17, 1263–1265 (2010).
Liu, J., Doty, T., Gibson, B. & Heyer, W.D. Human BRCA2 protein promotes RAD51 filament formation on RPA-covered single-stranded DNA. Nat. Struct. Mol. Biol. 17, 1260–1262 (2010).
Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006).
Buisson, R. et al. Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination. Nat. Struct. Mol. Biol. 17, 1247–1254 (2010).
Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat. Genet. 39, 165–167 (2007).
Tischkowitz, M. et al. Analysis of PALB2/FANCN-associated breast cancer families. Proc. Natl. Acad. Sci. USA 104, 6788–6793 (2007).
Dray, E. et al. Enhancement of RAD51 recombinase activity by the tumor suppressor PALB2. Nat. Struct. Mol. Biol. 17, 1255–1259 (2010).
Liu, J. & Heyer, W.D. Who's who in human recombination: BRCA2 and RAD52. Proc. Natl. Acad. Sci. USA 108, 441–442 (2011).
Kojic, M., Mao, N., Zhou, Q., Lisby, M. & Holloman, W.K. Compensatory role for Rad52 during recombinational repair in Ustilago maydis. Mol. Microbiol. 67, 1156–1168 (2008).
de Vries, F.A. et al. Inactivation of RAD52 aggravates RAD54 defects in mice but not in Schizosaccharomyces pombe. DNA Repair (Amst.) 4, 1121–1128 (2005).
Fujimori, A. et al. Rad52 partially substitutes for the Rad51 paralog XRCC3 in maintaining chromosomal integrity in vertebrate cells. EMBO J. 20, 5513–5520 (2001).
Feng, Z. et al. Rad52 inactivation is synthetically lethal with BRCA2 deficiency. Proc. Natl. Acad. Sci. USA 108, 686–691 (2011).
Benson, F.E., Baumann, P. & West, S.C. Synergistic actions of Rad51 and Rad52 in recombination and DNA repair. Nature 391, 401–404 (1998).
Jackson, D., Dhar, K., Wahl, J.K., Wold, M.S. & Borgstahl, G.E. Analysis of the human replication protein A:Rad52 complex: evidence for crosstalk between RPA32, RPA70, Rad52 and DNA. J. Mol. Biol. 321, 133–148 (2002).
Acknowledgements
The author is grateful to L. Symington (Columbia University) and laboratory members M. Kojic, Q. Zhou and N. Mazloum for stimulating conversations. Apologies are extended to colleagues whose work was not cited because of space limitations. Research in the author's laboratory is supported by grants GM042482 and GM079859 from the US National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The author declares no competing financial interests.
Rights and permissions
About this article
Cite this article
Holloman, W. Unraveling the mechanism of BRCA2 in homologous recombination. Nat Struct Mol Biol 18, 748–754 (2011). https://doi.org/10.1038/nsmb.2096
Published:
Issue Date:
DOI: https://doi.org/10.1038/nsmb.2096
This article is cited by
-
Case report of penile squamous cell carcinoma continuous treatment with BRCA2 mutation
World Journal of Surgical Oncology (2024)
-
Expression of human BRCA2 in Saccharomyces cerevisiae complements the loss of RAD52 in double-strand break repair
Current Genetics (2023)
-
Molecular contribution of BRCA1 and BRCA2 to genome instability in breast cancer patients: review of radiosensitivity assays
Biological Procedures Online (2020)
-
The novel quinolizidine derivate IMB-HDC inhibits STAT5a phosphorylation at 694 and 780 and promotes DNA breakage and cell apoptosis via blocking STAT5a nuclear translocation
Acta Pharmacologica Sinica (2020)
-
Structurally distinct telomere-binding proteins in Ustilago maydis execute non-overlapping functions in telomere replication, recombination, and protection
Communications Biology (2020)