Role of the breast cancer suppressor BRCA1 in the maintenance of genomic integrity (97.3)

Abstract

Homology‐directed repair (HDR) is a critical pathway for the repair of DNA double‐strand breaks (DSBs) in mammalian cells. Most mammalian HDR studies have focused on transformed and immortalized cell lines. We now report the generation of a DR‐GFP reporter‐based mouse model to study HDR in primary cell types from diverse lineages. Embryonic and adult fibroblasts as well as cells derived from mammary epithelium, ovary and neonatal brain were observed to undergo HDR at I‐SceI endonuclease‐induced DSBs at similar frequencies. When the DR‐GFP reporter was crossed into mice carrying a hypomorphic mutation in the BRCA1 tumor suppressor gene, a significant reduction in HDR was detected, demonstrating that BRCA1 is critical for HDR in somatic cell types, as previously reported in embryonic and tumor cell lines. These results indicate that the DR‐GFP mouse provides a powerful tool for dissecting the genetic requirements of HDR in a diverse array of somatic cell types in a normal, non‐transformed cellular milieu. Further studies are underway to examine the role of BRCA1 specifically in mammary epithelial cells.We previously showed that BRCA1 works upstream of the other major breast tumor suppressor BRCA2 in HDR. Recent work from other labs is consistent with this result, and suggests that BRCA1 functions in an early step of HDR to control DSB repair pathway choice. We discuss our recent results in this regard.