BRCA2 is required for homology-directed repair of chromosomal breaks

The BRCA2 tumor suppressor has been implicated in the maintenance of chromo somal stability through a function in DNA repair. In this report, we examin e human and mouse cell lines containing different BRCA2 mutations for their ability to repair chromosomal breaks by homologous recombination. Using th e I-Scel endonuclease to introduce a double-strand break at a specific chro mosomal locus, we find that BRCA2 mutant cell lines are recombination defic ient, such that homology-directed repair is reduced 6- to >100-fold, depend ing on the cell line. Thus, BRCA2 is essential for efficient homology-direc ted repair, presumably in conjunction with the Rad51 recombinase. We propos e that impaired homology-directed repair caused by BRCA2 deficiency leads t o chromosomal instability and, possibly, tumorigenesis, through lack of rep air or misrepair of DNA damage.