BARD1 links histone H2A Lysine-15 ubiquitination to initiation of BRCA1-dependent homologous recombination
Year: 2020
Type: preprint
Abstract: Protein ubiquitination at sites of DNA double-strand breaks (DSBs) by RNF168 recruits BRCA1 and 53BP1, mediators of the homologous recombination (HR) and non-homologous end joining (NHEJ) DSB repair pathways, respectively. While NHEJ relies on 53BP1 binding to ubiquitinated Lysine 15 on H2A-type histones (H2AK15ub), an RNF168-dependent modification, the mechanism linking RNF168 to BRCA1 recruitment during HR has remained unclear. Here, we identify a tandem BRCT domain ubiquitin-dependent recruitment motif (BUDR) in BARD1 – BRCA1’s obligate partner protein – that binds H2AK15ub directly, thereby recruiting BRCA1 to DSBs. BARD1 BUDR mutations compromise HR, and render cells hypersensitive to PARP inhibition and cisplatin treatment. We find that BARD1-nucleosome interactions require BUDR binding to H2AK15ub and ankyrin repeat domain-mediated binding of the histone H4 tail, specifically when unmethylated on Lysine-20 (H4K20me0), a state limited to post replicative chromatin. Finally, we demonstrate that by integrating DNA damagedependent H2AK15ub and DNA replication-dependent H4K20me0 signals at sites of DNA damage, BARD1 coordinates BRCA1-dependent HR with 53BP1 pathway antagonization, establishing a simple paradigm for the governance of DSB repair pathway choice.
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Wellcome Trust, Cancer Research UK, British Heart Foundation, University of Edinburgh, Lundbeckfonden, Novo Nordisk, BHF Centre of Research Excellence, Oxford, Novo Nordisk Fonden, H. Lundbeck A/S, National Institutes of Health, Medical Research Council, Erasmus+, National Cancer Institute, H2020 European Research Council
Awards: G1076064052, G1219506134, G1260843, G1271970818, G1303691827, G1325498775, G1606511277, G2284999390, G2444928821, G2521130840, G3693516624, Research Excellence (renewal), G4282887365, G4617978461, New and Old Histones in Epigenetic Cell Memory, Mechanistic understanding of the reading and writing of DNA methylation, G6236472089, G6531441707, G6987710327, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G7606975397, G7760474189, Core Funding for the Wellcome Trust Centre for Cell Biology, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G8975541179, G9000309734, G95971910
OpenAlex ID: W3029419460