Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining

Carriers of BRCA2 germline mutations are at high risk to develop early-onse t breast cancer. The underlying mechanisms of how BRCA2 inactivation predis poses to malignant transformation have not been established. Here, we provi de direct functional evidence that human BRCA2 promotes homologous recombin ation (HR), which comprises one major pathway of DNA double-strand break re pair. We found that up-regulated HR after transfection of wildtype (wt) BRC A2 into a human tumor line with mutant BRCA2 was linked to increased radior esistance. In addition, BRCA2-mediated enhancement of HR depended on the in teraction with Rad51. In contrast to the tumor suppressor BRCA1, which is i nvolved in multiple DNA repair pathways, BRCA2 status had no impact on the other principal double-strand break repair pathway, nonhomologous end joini ng. Thus, there exists a specific regulation of HR by BRCA2, which may func tion to maintain genomic integrity and suppress tumor development in prolif erating cells.