Breast cancer susceptibility genes and DNA repair
Following the landmark discovery by Scully et al that the homologous recombinase RAD51 colocalizes at subnuclear sites with BRCA1 [9], a number of additional results have provided evidence that both BRCA1 and BRCA2 are involved in recombinational repair of DNA damage. BRCA1 and BRCA2 form discrete nuclear foci during the S phase and after exposure to DNA damaging agents [9,10,11]. These foci are probably sites of repair of spontaneous and induced DNA damage [12,13,14]. Cell lines defective in either BRCA1 or BRCA2 are sensitive to damaging agents that form double-strand breaks (DSBs), as are other cell lines defective in recombinational repair (reviewed in [15]). BRCA2 interacts with the RAD51 recombinase via direct protein-protein contacts [16,17,18,19]. Biochemical analysis also showed interaction between BRCA1 and RAD51, although these detected interactions may have been indirect [9]. The BRC repeats of BRCA2 are responsible for direct RAD51 interaction. Cells lacking BRCA1/2 fail to form damage-induced subnuclear RAD51 foci with normal efficiency, suggesting that these proteins are required for the formation of recombinase complexes at the sites of DNA damage [20,21]. Finally, genetic measurements of recombination frequency have shown that Brca1-/- embryonic stem (ES) cells are deficient in recombinational DSB repair [22,23]. The similarity between phenotypes associated with BRCA1 and BRCA2 deficiency, together with data showing a similar effect of DNA damage on distribution of BRCA1 and BRCA2 in repair-proficient cells, led to the hypothesis that BRCA2, like BRCA1, is required for efficient recombinational repair. The paper by Moynahan et al [24] provides important support for this hypothesis.