BRCA1/BARD1 is a nucleosome reader and writer

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 47; no. 7; pp. 582 - 595
• Main Authors: Witus, Samuel R., Zhao, Weixing, Brzovic, Peter S., Klevit, Rachel E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2022
• Subjects: BRCA1 Protein - genetics; BRCA1 Protein - metabolism; chromatin regulation; DNA Breaks, Double-Stranded; DNA damage repair; DNA Repair; homologous recombination; Nucleosomes; transcriptional regulation; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; ubiquitin ligase; Ubiquitin-Protein Ligases - metabolism; ubiquitin ligase; DNA damage repair; homologous recombination; transcriptional regulation; chromatin regulation
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2022.03.001

Mutations in BRCA1 and BARD1 predispose carriers to breast and ovarian cancers. The BRCA1 and BARD1 proteins form a heterodimeric complex (BRCA1/BARD1) that regulates many biological processes, including transcription and DNA double-stranded break repair. These functions are mediated by the only known enzymatic activity of BRCA1/BARD1 in its capacity as an E3 ubiquitin ligase and its role as a central hub for many large protein complexes. But the mechanisms by which BRCA1/BARD1 interfaces with chromatin, where it exerts its major functions, have remained unknown. Here, we review recent advancements in structural and cellular biology that have provided critical insights into how BRCA1/BARD1 serves as both a nucleosome reader and writer to facilitate transcriptional regulation and DNA repair by homologous recombination. BRCA1/BARD1 binds directly to nucleosomes in chromatin via multiple interaction sites to regulate transcription and DNA double-stranded break repair.BRCA1/BARD1 functions as a ubiquitin (ub) ligase to promote site-specific ubiquitylation of residues in the unstructured C‐terminal tail of H2A (K125/127/129), a unique and novel histone modification.The BARD1 C‐terminal Ank-BRCT domains recognize nucleosomes carrying H2A K13/15-Ub and H4K20me0, hallmarks of damaged chromatin in S/G2 phases when a newly replicated sister chromatid can be used as a template for homologous recombination.Redundant BRCA1/BARD1 nucleosome-based recruitment pathways reveal specific requirements for BRCA1/BARD1 RING function and Ub ligase activity in DNA double-stranded break repair.