Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences

Mutation of BRCA2 causes familial early onset breast and ovarian cancer. BR CA2 has been suggested to be important for the maintenance of genome integr ity and to have a role in DNA repair by homology-directed double-strand bre ak (DSB) repair. By studying the repair of a specific induced chromosomal D SB we show that loss of Brca2 leads to a substantial increase in error-pron e repair by homology-directed single-strand annealing and a reduction in DS B repair by conservative gene conversion. These data demonstrate that loss of Brca2 causes misrepair of chromosomal DSBs occurring between repeated se quences by stimulating use of an error-prone homologous recombination pathw ay. Furthermore, loss of Brca2 causes a large increase in genome-wide error -prone repair of both spontaneous DNA damage and mitomycin C-induced DNA cr oss-links at the expense of error-free repair by sister chromatid recombina tion. This provides insight into the mechanisms that induce genome instabil ity in tumour cells lacking BRCA2.