BRCA1 and BRCA2: different roles in a common pathway of genome protection

Inherited inactivating mutations inBRCA1 or BRCA2seem to cause a similar predisposition to breast and ovarian cancer, but a closer look reveals many differences as well. This Perspective discusses the similarities and differences between BRCA1 and BRCA2 and their effects on cancer phenotypes. The proteins encoded by the two major breast cancer susceptibility genes, BRCA1 and BRCA2, work in a common pathway of genome protection. However, the two proteins work at different stages in the DNA damage response (DDR) and in DNA repair. BRCA1 is a pleiotropic DDR protein that functions in both checkpoint activation and DNA repair, whereas BRCA2 is a mediator of the core mechanism of homologous recombination. The links between the two proteins are not well understood, but they must exist to explain the marked similarity of human cancer susceptibility that arises with germline mutations in these genes. As discussed here, the proteins work in concert to protect the genome from double-strand DNA damage during DNA replication.