The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA–ssDNA junction

Haijuan Yang, Qiubai Li, Jie Fan, William K. Holloman and Nikola P. Pavletich ()
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Haijuan Yang: Structural Biology Program, Memorial Sloan-Kettering Cancer Center
Qiubai Li: Structural Biology Program, Memorial Sloan-Kettering Cancer Center
Jie Fan: Structural Biology Program, Memorial Sloan-Kettering Cancer Center
William K. Holloman: Cornell University Weill Medical College
Nikola P. Pavletich: Structural Biology Program, Memorial Sloan-Kettering Cancer Center

Nature, 2005, vol. 433, issue 7026, 653-657

Abstract: Abstract The BRCA2 tumour suppressor1 is essential for the error-free repair of double-strand breaks (DSBs) in DNA by homologous recombination2,3. This is mediated by RAD51, which forms a nucleoprotein filament with the 3′ overhanging single-stranded DNA (ssDNA) of the resected DSB, searches for a homologous donor sequence, and catalyses strand exchange with the donor DNA4. The 3,418-amino-acid BRCA2 contains eight ∼30-amino-acid BRC repeats that bind RAD51 (refs 5, 6) and a ∼700-amino-acid DBD domain that binds ssDNA7. The isolated BRC and DBD domains have the opposing effects of inhibiting8,9 and stimulating recombination7, respectively, and the role of BRCA2 in repair has been unclear. Here we show that a full-length BRCA2 homologue (Brh2) stimulates Rad51-mediated recombination at substoichiometric concentrations relative to Rad51. Brh2 recruits Rad51 to DNA and facilitates the nucleation of the filament, which is then elongated by the pool of free Rad51. Brh2 acts preferentially at a junction between double-stranded DNA (dsDNA) and ssDNA, with strict specificity for the 3′ overhang polarity of a resected DSB. These results establish a BRCA2 function in RAD51-mediated DSB repair and explain the loss of this repair capacity in BRCA2-associated cancers.

Date: 2005
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DOI: 10.1038/nature03234

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