A targeted disruption of the murine Brca1 gene causes gamma-irradiation hypersensitivity and genetic instability

Germline mutations of the Brca1 gene are responsible for most cases of fami lial breast and ovarian cancers, but somatic mutations are rarely detected in sporadic events. Moreover, mouse embryos deficient for Brca1 have been s hown to die during early embryogenesis due to a proliferation defect, These findings seem incompatible with the tumor suppress function assigned to th is gene and raise questions about the mechanism by which Brca1 mutations ca use tumorigenesis. We now directly demonstrate that BRCA1 is responsible fo r the integrity of the genome, Murine embryos carrying a Brca1 null mutatio n are developmentally retarded and hypersensitive to gamma-irradiation, sug gesting a failure in DNA damage repair. This notion is supported by spectra l karyotyping (SKY) of metaphase chromosomes, which display numerical and s tructural aberrations. However, massive chromosomal abnormalities are only observed when a p53(-/-) background is introduced, Thus, a p53 dependent ce ll cycle checkpoint arrests the mutant embryos and prevents the accumulatio n of damaged DNA, Brca1(-/-) fibroblasts are not viable, nor are Brca1(-/-) :p53(-/-) fibroblasts, However, proliferative foci arise from Brca1(-/-):p5 3(-/-) cells, probably due to additional mutations that are a consequence o f the accumulating DNA damage, We believe that the increased incidence of s uch additional mutations accounts for the mechanism of tumorigenesis associ ated with Brca1 mutations in humans.