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J. Biol. Chem., Vol. 281, Issue 17, 11649-11657, April 28, 2006

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Recombination Mediator and Rad51 Targeting Activities of a Human BRCA2 Polypeptide^*

From the Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520

BRCA2 likely exerts its tumor suppressor function by enhancing the efficiency of the homology-directed repair of injured chromosomes. To help define the DNA repair role of BRCA2, we expressed and purified a polypeptide, BRC3/4-DBD, that harbors its BRC3 and BRC4 repeats and DNA binding domain. BRC3/4-DBD interacted with hRad51 and bound DNA with a distinct preference for single-stranded (ss) DNA. Importantly we demonstrated by biochemical means and electron microscopy that BRC3/4-DBD nucleates hRad51 onto ssDNA and acts as a recombination mediator in enabling hRad51 to utilize replication protein A-coated ssDNA as recombination substrate. These functions of BRC3/4-DBD required both the BRC repeats and the BRCA2 DNA binding domain. The results thus clarify the role of BRCA2 in Rad51-dependent DNA recombination and repair, and the experimental strategies described herein should be valuable for systematically deciphering this BRCA2 function.

Received for publication, February 8, 2006 , and in revised form, March 1, 2006.

^* This work was supported by National Institutes of Health Research Grants RO1CA110415 and RO1ES07061, Wellcome Trust Fund GR076476, Department of Defense Postdoctoral Fellowship DAMD17-03-1-0586, and Susan G. Komen Breast Cancer Foundation Research Grant BCTR503471 and Postdoctoral Fellowship PDF0503471. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: National Centre for Biomolecular Research, Masaryk University, Kamenice 5/A4, Brno 625 00, Czech Republic.

² To whom correspondence should be addressed: Dept. of Molecular Biophysics and Biochemistry, Yale University School of Medicine, 333 Cedar St., C130 Sterling Hall of Medicine, New Haven, CT 06520. Tel.: 203-785-4553; Fax: 203-785-6404; E-mail: Patrick.Sung{at}yale.edu.

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