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Significance Loss-of-function mutations inBRCA1 and its protein partnerBARD1 lead to high risks of breast and ovarian cancer. Both BRCA1 and BARD1 proteins harbor RING domains, and missense mutations in the critical residues of the BRCA1 RING domain are among those known to predispose to cancer. The BRCA1 RING domain is a ubiquitin ligase, but the function of the BARD1 RING domain and the consequences of mutations in it are unknown. Evaluation of missense mutations at evolutionarily conserved zinc-binding residues of BARD1, each identified in a family severely affected with breast cancer, revealed that BARD1 is necessary for two core functions of the BRCA1/BARD1 complex: ubiquitylation of histone 2A on nucleosomes and transcriptional regulation of genes of estrogen metabolism.

BARD1 is necessary for ubiquitylation of nucleosomal histone H2A and for transcriptional regulation of estrogen metabolism genes