Individuals with inherited mutations in BRCA2 are predisposed to early-onset breast cancers. In mice, loss of Brca2 function leads to defects in double-strand DNA break repair and progressively impaired growth. Tumourigenesis in these mice accompanies the inhibition of the mitotic checkpoint, suggesting a crucial interplay between the DNA repair machinery and the mitotic checkpoint in maintaining genetic integrity. Here, we describe the molecular mechanism by which BRCA2 directly regulates the mitotic checkpoint. Severe DNA breaks cause cells to arrest at prometaphase, when BRCA2 and BubR1 form a complex at the kinetochore. After DNA damage, BRCA2, in complex with P/CAF, acetylates BubR1 and inhibits ubiquitin-dependent proteolysis of BubR1. In BRCA2-deficient cells, the BubR1 level is significantly low at the kinetochore, accompanied by mis-segregation of chromosomes. Moreover, mitotic apoptosis, induced by overexpressed BubR1, is lost in the acetylation-defective mutant BubR1. Collectively, these results suggest that upon genotoxic insult, BRCA2 coordinates DNA repair with the mitotic cell cycle checkpoint and that mutation of BRCA2 precipitates defects in DNA repair and mitotic checkpoint control, resulting in chromosome instability of aneuploidy with aberrant chromosome translocations.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]