Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation

Cancer-causing mutations often arise from gross chromosomal rearrangements (GCRs) such as translocations, which involve genetic exchange between nonho mologous chromosomes. Here we show that murine Brca2 has an essential funct ion in suppressing GCR formation after chromosome breakage. Cells that harb or truncated Brca2 spontaneously incur GCRs and genomic DNA breaks during d ivision. They exhibit hypersensitivity to DNA damage by interstrand cross-l inkers, which even at low doses trigger aberrant genetic exchange between n onhomologous chromosomes. Therefore, genetic instability in Brca2-deficient cells results from the mutagenic processing of spontaneous or induced DNA damage into gross chromosomal rearrangements, providing a mechanistic basis for cancer predisposition.