Nucleic Acids Research Advance Access published online on August 16, 2006
Nucleic Acids Research, doi:10.1093/nar/gkl505
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© 2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
A region of human BRCA2 containing multiple BRC repeats promotes RAD51-mediated strand exchange
Cancer Research UK Department of Oncology and The Medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge Hills Road, Cambridge CB2 2XZ, UK 1 Department of Biochemistry, University of Cambridge Tennis Court Road, Cambridge CB2 1GA, UK
*To whom correspondence should be addressed. Ashok R. Venkitaraman, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK. Tel: +44 1223 336901; Fax: +44 1223 763374; Email: arv22{at}cam.ac.uk
Received May 2, 2006. Revised June 28, 2006. Accepted July 3, 2006.
Human BRCA2, a breast and ovarian cancer suppressor, binds to the DNA recombinase RAD51 through eight conserved BRC repeats, motifs of 
30 residues, dispersed across a large region of the protein. BRCA2 is essential for homologous recombination in vivo, but isolated BRC repeat peptides can prevent the assembly of RAD51 into active nucleoprotein filaments in vitro, suggesting a model in which BRCA2 sequesters RAD51 in undamaged cells, and promotes recombinase function after DNA damage. How BRCA2 might fulfill these dual functions is unclear. We have purified a fragment of human BRCA2 (BRCA2BRC1–8) with 1127 residues spanning all 8 BRC repeats but excluding the C-terminal DNA-binding domain (BRCA2CTD). BRCA2BRC1–8 binds RAD51 nucleoprotein filaments in a ternary complex, indicating it may organize RAD51 on DNA. Human RAD51 is relatively ineffective in vitro at strand exchange between homologous DNA molecules unless non-physiological ions like 
are present. In an ionic milieu more typical of the mammalian nucleus, BRCA2BRCI–8 stimulates RAD51-mediated strand exchange, suggesting it may be an essential co-factor in vivo. Thus, the human BRC repeats, embedded within their surronding sequences as an eight-repeat unit, mediate homologous recombination independent of the BRCA2CTD through a previously unrecognized role in control of RAD51 activity.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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