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

作者：Mikaela D. Stewart, Elena Zelin, Abhinav Dhall, Tom Walsh, Esha Upadhyay, Jacob E. Corn, Champak Chatterjee, Mary‐Claire King, Rachel E. Klevit · 发表于：Proceedings of the National Academy of Sciences · 年份：2018 · DOI：10.1073/pnas.1715467115 · 被引用次数：61 · 研究领域：BRCA gene mutations in cancer、DNA Repair Mechanisms、Genomics and Chromatin Dynamics

Significance Loss-of-function mutations in BRCA1 and its protein partner BARD1 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.