Brca1 Controls Homology-Directed DNA Repair

TLDR

BRCA1 germline mutations greatly increase breast and ovarian cancer risk, and although its tumor‑suppressive mechanisms are unclear, it is linked to DNA repair through interaction with RAD51, a key homologous recombination protein. Loss of Brca1 in mouse embryonic stem cells reduces homologous recombination repair of double‑strand breaks, shifts repair toward mutagenic nonhomologous integration, and underscores BRCA1’s role in maintaining genomic integrity.

Abstract

Germline mutations in BRCA1 confer a high risk of breast and ovarian tumors. The role of BRCA1 in tumor suppression is not yet understood, but both transcription and repair functions have been ascribed. Evidence that BRCA1 is involved in DNA repair stems from its association with RAD51, a homolog of the yeast protein involved in the repair of DNA double-strand breaks (DSBs) by homologous recombination. We report here that Brca1-deficient mouse embryonic stem cells have impaired repair of chromosomal DSBs by homologous recombination. The relative frequencies of homologous and nonhomologous DNA integration and DSB repair were also altered. The results demonstrate a caretaker role for BRCA1 in preserving genomic integrity by promoting homologous recombination and limiting mutagenic nonhomologous repair processes.