Promotion of RAD51-mediated homologous DNA pairing by BRCA1-BARD1

摘要

The tumor suppressor complex BRCA1-BARD1 functions in DNA double-strand break repair by homologous recombination. Therein, BRCA1-BARD1 facilitates the nucleolytic resection of DNA ends to generate a single-stranded template for the recruitment of another tumor suppressor complex BRCA2-PALB2 and the recombinase RAD51. By examining purified BRCA1-BARD1 and mutants, we show that BRCA1 and BARD1 both bind DNA and interact with RAD51, and that BRCA1-BARD1 enhances the recombinase activity of RAD51. Mechanistically, BRCA1-BARD1 promotes the assembly of the synaptic complex, an essential intermediate in RAD51-mediated DNA joint formation. Evidence is provided that BRCA1 and BARD1 are both indispensable for RAD51 stimulation. Importantly, BRCA1-BARD1 mutants weakened for RAD51 interaction are compromised for DNA joint formation and for the mediation of homologous recombination and DNA repair in cells. Our results identify a late role of BRCA1-BARD1 in homologous recombination, a novel attribute of the tumor suppressor complex that could be targeted in cancer therapy.