The tumor suppressor gene BRCA1 maintains genomic integrity by protecting
cells from the deleterious effects of DNA double-strand breaks (DSBs).
Through its interactions with the checkpoint kinase 2 (Chk2) kinase and
Rad51, BRCA1 promotes homologous recombination, which is typically an
error-free repair process. In addition, accumulating evidence implicates
BRCA1 in the regulation of nonhomologous end-joining (NHEJ), which may
involve precise religation of the DSB ends if they are compatible (i.e.,
error-free repair) or sequence alteration upon rejoining (i.e.,
error-prone or mutagenic repair). However, the precise role of BRCA1 in
regulating these different subtypes of NHEJ is not clear. We provide here
the genetic and biochemical evidence to show that BRCA1 promotes
error-free rejoining of DSBs in human breast carcinoma cells while
suppressing microhomology-mediated error-prone end-joining and restricting
sequence deletion at the break junction during repair. The repair spectrum
in BRCA1-deficient cells was characterized by an increase in the formation
of >2 kb deletions and in the usage of long microhomologies distal to the
break site, compared with wild-type (WT) cells. This error-prone repair
phenotype could also be revealed by disruption of the Chk2 phosphorylation
site of BRCA1, or by expression of a dominant-negative kinase-dead Chk2
mutant in cells with WT BRCA1. We suggest that the differential control of
NHEJ subprocesses by BRCA1, in concert with Chk2, reduces the mutagenic
potential of NHEJ, thereby contributing to the prevention of familial
breast cancers
