BARD1 reads H2A Lys-15 ubiquitination to direct homologous recombination

Jordan R. Becker, Gillian Clifford, Clara Bonnet, Anja Groth, Marcus D Wilson, J Ross Chapman

Research output: Contribution to journalArticlepeer-review

Abstract

Protein ubiquitination at sites of DNA double-strand breaks (DSBs) by RNF168 recruits BRCA1 and 53BP11,2, mediators of the homologous recombination (HR) and non-homologous end joining (NHEJ) DSB repair pathways, respectively3. While NHEJ relies on 53BP1 binding directly to ubiquitinated Lysine 15 on H2A-type histones (H2AK15ub)4,5 - an RNF168- dependent modification6 - how RNF168 promotes BRCA1 recruitment and function remains unclear. Here, we identify a tandem BRCT domain-associated ubiquitin-dependent recruitment motif (BUDR) in BARD1 – BRCA1’s obligate partner protein – that by engaging H2AK15ub, recruits BRCA1 to DSBs. BARD1 BUDR disruption compromises HR and renders cells hypersensitive to PARP inhibition and cisplatin. We further show that BARD1 binds nucleosomes through multivalent interactions: coordinated binding of H2AK15ub and unmethylated H4 Lys20 (H4K20me0) by its adjacent BUDR and ankyrin repeat domains, respectively, provides high-affinity recognition of DNA lesions in replicated chromatin and promotes HR activities of the BRCA1-BARD1 complex. Finally, genetic epistasis experiments confirm that the need for BARD1-chromatin binding activities can be entirely relieved upon deletion of RNF168 or 53BP1. Thus, our results demonstrate that by sensing DNA damage dependent and post-replication histone PTM states, BRCA1-BARD1 complexes coordinate 53BP1 pathway antagonization with HR promotion, establishing a simple paradigm for the governance of DSB repair pathway choice.
Original languageEnglish
Number of pages33
JournalNature
DOIs
Publication statusPublished - 28 Jul 2021

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