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BARD1 links histone H2A Lysine-15 ubiquitination to initiation of BRCA1-dependent homologous recombination
bioRxiv - Molecular Biology Pub Date : 2020-06-01 , DOI: 10.1101/2020.06.01.127951
Jordan R. Becker , Clara Bonnet , Gillian Clifford , Anja Groth , Marcus D. Wilson , J. Ross Chapman

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 damage- dependent 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.

中文翻译:

BARD1连接组蛋白H2A赖氨酸15泛素化与BRCA1依赖的同源重组的启动

RNF168募集的DNA双链断裂(DSB)部位的蛋白质泛素化分别是BRCA1和53BP1,它们是同源重组(HR)和非同源末端连接(NHEJ)DSB修复途径的介体。尽管NHEJ依赖于HBP依赖的H2A型组蛋白(H2AK15ub)上泛素化赖氨酸15的53BP1结合,但在HR期间将RNF168与BRCA1募集联系的机制仍不清楚。在这里,我们在BARD1(BRCA1的专职伴侣蛋白)BARD1中鉴定了串联的BRCT域泛素依赖性募集基序(BUDR),该蛋白直接结合H2AK15ub,从而将BRCA1募集到DSBs。BARD1 BUDR突变会损害HR,并使细胞对PARP抑制和顺铂治疗高度敏感。我们发现,BARD1-核小体相互作用需要BUDR结合到H2AK15ub和锚蛋白重复域介导的组蛋白H4尾部结合,特别是在赖氨酸20(H4K20me0)未甲基化时,这种状态仅限于复制后的染色质。最后,我们证明,通过在DNA损伤位点整合依赖DNA损伤的H2AK15ub和依赖DNA复制的H4K20me0信号,BARD1与53BP1途径拮抗BRCA1依赖的HR,为DSB修复途径选择的治理建立了简单的范例。
更新日期:2020-06-01
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