Cancer-predisposing mutations within the RING domain of BRCA1: Loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity

BRCA1 is a breast and ovarian cancer-specific tumor suppressor that seems t o be involved in transcription and DNA repair. Here we report that BRCA1 ex hibits a bona fide ubiquitin (Ub) protein ligase (E3) activity, and that ca ncer-predisposing mutations within the BRCA1 RING domain abolish its Ub lig ase activity. Furthermore, these mutants are unable to reverse gamma -radia tion hypersensitivity of BRCA1-null human breast cancer cells. HCC1937, Add itionally, these mutations within the BRCA1 RING domain are not capable of restoring a G(2) + M checkpoint in HCC1937 cells. These results establish a link between Ub protein ligase activity and gamma -radiation protection fu nction of BRCA1, and provide an explanation for why mutations within the BR CA1 RING domain predispose to cancer. Furthermore, we propose that the anal ysis of the Ub ligase activity of RING-domain mutations identified in patie nts may constitute an assay to predict predisposition to cancer.