Interactions between BRCA2 protein and the meiosis-specific recombinase DMC1

Excerpt

Homologous recombination has a dual role in eukaryotic organisms. Firstly, it is responsible for the creation of genetic variability during meiosis by directing the formation of reciprocal crossovers that result in random combinations of alleles and traits. Secondly, in mitotic cells, it maintains the integrity of the genome by promoting the faithful repair of DNA double-strand breaks. In vertebrates it therefore plays a key role in tumour avoidance. Mutations in the tumour suppressor protein BRCA2 are associated with predisposition to breast and ovarian cancers, and loss of BRCA2 function leads to genetic instability, as BRCA2 is required for regulation of double-strand break repair by homologous recombination. BRCA2 protein regulates recombinational repair by interacting directly with RAD51 recombinase via a series of degenerate BRC repeat motifs encoded by exon 11 (BRCA2996-2113), and an unrelated C-terminal domain (BRCA23265-3330). Recent observations show that BRCA2 is also required for homologous recombination at meiosis. We show that human BRCA2 binds directly to the meiosis-specific recombinase DMC1 and define the primary DMC1 interaction domain to a 26 amino acid region located at BRCA22386-2411. This region is highly conserved in BRCA2 proteins from a variety of mammalian species, but is absent in BRCA2 from Arabidopsis thaliana, Caenorhabditis elegans, and other lower eukaryotes. Within this region, we demonstrate the critical importance of Phe2406, Pro2408, and Pro2409 at the conserved motif 2404KVFVPPFK2411, and define this novel DMC1 interaction domain the PhePP motif. The PhePP motif promotes specific interactions between BRCA2 and DMC1, and no interactions take place between this region of BRCA2 and RAD51. Thus, the RAD51 and DMC1 interaction domains on BRCA2 are distinct from each other, allowing coordinated interactions of the two recombinases with BRCA2 at meiosis. These results lead us to suggest that BRCA2 is a universal regulator of RAD51/DMC1 recombinase actions. …