Abstract
The efficient repair of double-strand breaks in DNA is critical for the maintenance of genome stability. In response to ionizing radiation and other DNA-damaging agents, the RAD51 protein, which is essential for homologous recombination, relocalizes within the nucleus to form distinct foci that can be visualized by microscopy and are thought to represent sites where repair reactions take place. The formation of RAD51 foci in response to DNA damage is dependent upon BRCA2 and a series of proteins known as the RAD51 paralogues (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3), indicating that the components present within foci assemble in a carefully orchestrated and ordered manner. By contrast, RAD51 foci that form spontaneously as cells undergo DNA replication at S phase occur without the need for BRCA2 or the RAD51 paralogues. It is known that BRCA2 interacts directly with RAD51 through a series of degenerative motifs known as the BRC repeats. These interactions modulate the ability of RAD51 to bind DNA. Taken together, these observations indicate that BRCA2 plays a critical role in controlling the actions of RAD51 at both the microscopic (focus formation) and molecular (DNA binding) level.
Full Text
The Full Text of this article is available as a PDF (2.3 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Bork P., Blomberg N., Nilges M. Internal repeats in the BRCA2 protein sequence. Nat Genet. 1996 May;13(1):22–23. doi: 10.1038/ng0596-22. [DOI] [PubMed] [Google Scholar]
- Chen P. L., Chen C. F., Chen Y., Xiao J., Sharp Z. D., Lee W. H. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5287–5292. doi: 10.1073/pnas.95.9.5287. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 1999 Nov 5;286(5442):1162–1166. doi: 10.1126/science.286.5442.1162. [DOI] [PubMed] [Google Scholar]
- Cox M. M., Goodman M. F., Kreuzer K. N., Sherratt D. J., Sandler S. J., Marians K. J. The importance of repairing stalled replication forks. Nature. 2000 Mar 2;404(6773):37–41. doi: 10.1038/35003501. [DOI] [PubMed] [Google Scholar]
- Davies A. A., Masson J. Y., McIlwraith M. J., Stasiak A. Z., Stasiak A., Venkitaraman A. R., West S. C. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell. 2001 Feb;7(2):273–282. doi: 10.1016/s1097-2765(01)00175-7. [DOI] [PubMed] [Google Scholar]
- Essers Jeroen, Houtsmuller Adriaan B., van Veelen Lieneke, Paulusma Coen, Nigg Alex L., Pastink Albert, Vermeulen Wim, Hoeijmakers Jan H. J., Kanaar Roland. Nuclear dynamics of RAD52 group homologous recombination proteins in response to DNA damage. EMBO J. 2002 Apr 15;21(8):2030–2037. doi: 10.1093/emboj/21.8.2030. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Godthelp Barbara C., Artwert Fré, Joenje Hans, Zdzienicka Małgorzata Z. Impaired DNA damage-induced nuclear Rad51 foci formation uniquely characterizes Fanconi anemia group D1. Oncogene. 2002 Jul 25;21(32):5002–5005. doi: 10.1038/sj.onc.1205656. [DOI] [PubMed] [Google Scholar]
- Haaf T., Golub E. I., Reddy G., Radding C. M., Ward D. C. Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2298–2302. doi: 10.1073/pnas.92.6.2298. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kanaar R., Hoeijmakers J. H., van Gent D. C. Molecular mechanisms of DNA double strand break repair. Trends Cell Biol. 1998 Dec;8(12):483–489. doi: 10.1016/s0962-8924(98)01383-x. [DOI] [PubMed] [Google Scholar]
- Lisby M., Rothstein R., Mortensen U. H. Rad52 forms DNA repair and recombination centers during S phase. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8276–8282. doi: 10.1073/pnas.121006298. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu Y., Maizels N. Coordinated response of mammalian Rad51 and Rad52 to DNA damage. EMBO Rep. 2000 Jul;1(1):85–90. doi: 10.1093/embo-reports/kvd002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McGlynn Peter, Lloyd Robert G. Recombinational repair and restart of damaged replication forks. Nat Rev Mol Cell Biol. 2002 Nov;3(11):859–870. doi: 10.1038/nrm951. [DOI] [PubMed] [Google Scholar]
- Mizuta R., LaSalle J. M., Cheng H. L., Shinohara A., Ogawa H., Copeland N., Jenkins N. A., Lalande M., Alt F. W. RAB22 and RAB163/mouse BRCA2: proteins that specifically interact with the RAD51 protein. Proc Natl Acad Sci U S A. 1997 Jun 24;94(13):6927–6932. doi: 10.1073/pnas.94.13.6927. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moynahan M. E., Chiu J. W., Koller B. H., Jasin M. Brca1 controls homology-directed DNA repair. Mol Cell. 1999 Oct;4(4):511–518. doi: 10.1016/s1097-2765(00)80202-6. [DOI] [PubMed] [Google Scholar]
- Moynahan M. E., Pierce A. J., Jasin M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001 Feb;7(2):263–272. doi: 10.1016/s1097-2765(01)00174-5. [DOI] [PubMed] [Google Scholar]
- Patel K. J., Yu V. P., Lee H., Corcoran A., Thistlethwaite F. C., Evans M. J., Colledge W. H., Friedman L. S., Ponder B. A., Venkitaraman A. R. Involvement of Brca2 in DNA repair. Mol Cell. 1998 Feb;1(3):347–357. doi: 10.1016/s1097-2765(00)80035-0. [DOI] [PubMed] [Google Scholar]
- Pellegrini Luca, Yu David S., Lo Thomas, Anand Shubha, Lee MiYoung, Blundell Tom L., Venkitaraman Ashok R. Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature. 2002 Nov 10;420(6913):287–293. doi: 10.1038/nature01230. [DOI] [PubMed] [Google Scholar]
- Raderschall E., Golub E. I., Haaf T. Nuclear foci of mammalian recombination proteins are located at single-stranded DNA regions formed after DNA damage. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):1921–1926. doi: 10.1073/pnas.96.5.1921. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saintigny Y., Dumay A., Lambert S., Lopez B. S. A novel role for the Bcl-2 protein family: specific suppression of the RAD51 recombination pathway. EMBO J. 2001 May 15;20(10):2596–2607. doi: 10.1093/emboj/20.10.2596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scully R., Chen J., Ochs R. L., Keegan K., Hoekstra M., Feunteun J., Livingston D. M. Dynamic changes of BRCA1 subnuclear location and phosphorylation state are initiated by DNA damage. Cell. 1997 Aug 8;90(3):425–435. doi: 10.1016/s0092-8674(00)80503-6. [DOI] [PubMed] [Google Scholar]
- Scully R., Chen J., Plug A., Xiao Y., Weaver D., Feunteun J., Ashley T., Livingston D. M. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell. 1997 Jan 24;88(2):265–275. doi: 10.1016/s0092-8674(00)81847-4. [DOI] [PubMed] [Google Scholar]
- Takata M., Sasaki M. S., Sonoda E., Fukushima T., Morrison C., Albala J. S., Swagemakers S. M., Kanaar R., Thompson L. H., Takeda S. The Rad51 paralog Rad51B promotes homologous recombinational repair. Mol Cell Biol. 2000 Sep;20(17):6476–6482. doi: 10.1128/mcb.20.17.6476-6482.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takata M., Sasaki M. S., Tachiiri S., Fukushima T., Sonoda E., Schild D., Thompson L. H., Takeda S. Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. Mol Cell Biol. 2001 Apr;21(8):2858–2866. doi: 10.1128/MCB.21.8.2858-2866.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tan T. L., Essers J., Citterio E., Swagemakers S. M., de Wit J., Benson F. E., Hoeijmakers J. H., Kanaar R. Mouse Rad54 affects DNA conformation and DNA-damage-induced Rad51 foci formation. Curr Biol. 1999 Mar 25;9(6):325–328. doi: 10.1016/s0960-9822(99)80142-0. [DOI] [PubMed] [Google Scholar]
- Tarsounas Madalena, Davies Derek, West Stephen C. BRCA2-dependent and independent formation of RAD51 nuclear foci. Oncogene. 2003 Feb 27;22(8):1115–1123. doi: 10.1038/sj.onc.1206263. [DOI] [PubMed] [Google Scholar]
- Tashiro S., Kotomura N., Shinohara A., Tanaka K., Ueda K., Kamada N. S phase specific formation of the human Rad51 protein nuclear foci in lymphocytes. Oncogene. 1996 May 16;12(10):2165–2170. [PubMed] [Google Scholar]
- Thacker J. A surfeit of RAD51-like genes? Trends Genet. 1999 May;15(5):166–168. doi: 10.1016/s0168-9525(99)01733-3. [DOI] [PubMed] [Google Scholar]
- Tutt A., Gabriel A., Bertwistle D., Connor F., Paterson H., Peacock J., Ross G., Ashworth A. Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr Biol. 1999 Oct 7;9(19):1107–1110. doi: 10.1016/s0960-9822(99)80479-5. [DOI] [PubMed] [Google Scholar]
- WATSON J. D., CRICK F. H. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953 Apr 25;171(4356):737–738. doi: 10.1038/171737a0. [DOI] [PubMed] [Google Scholar]
- Welcsh P. L., Owens K. N., King M. C. Insights into the functions of BRCA1 and BRCA2. Trends Genet. 2000 Feb;16(2):69–74. doi: 10.1016/s0168-9525(99)01930-7. [DOI] [PubMed] [Google Scholar]
- Xia F., Taghian D. G., DeFrank J. S., Zeng Z. C., Willers H., Iliakis G., Powell S. N. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc Natl Acad Sci U S A. 2001 Jul 10;98(15):8644–8649. doi: 10.1073/pnas.151253498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Xu X., Weaver Z., Linke S. P., Li C., Gotay J., Wang X. W., Harris C. C., Ried T., Deng C. X. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell. 1999 Mar;3(3):389–395. doi: 10.1016/s1097-2765(00)80466-9. [DOI] [PubMed] [Google Scholar]
- Yu V. P., Koehler M., Steinlein C., Schmid M., Hanakahi L. A., van Gool A. J., West S. C., Venkitaraman A. R. Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev. 2000 Jun 1;14(11):1400–1406. [PMC free article] [PubMed] [Google Scholar]
- Yuan S. S., Lee S. Y., Chen G., Song M., Tomlinson G. E., Lee E. Y. BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res. 1999 Aug 1;59(15):3547–3551. [PubMed] [Google Scholar]
- Yuan Z. M., Huang Y., Ishiko T., Nakada S., Utsugisawa T., Kharbanda S., Wang R., Sung P., Shinohara A., Weichselbaum R. Regulation of Rad51 function by c-Abl in response to DNA damage. J Biol Chem. 1998 Feb 13;273(7):3799–3802. doi: 10.1074/jbc.273.7.3799. [DOI] [PubMed] [Google Scholar]