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BARD1通过读取H2A第15位赖氨酸泛素化来直接进行同源重组
2021-07-31 23:02

英国牛津大学Chapman, J. Ross课题组发现,BARD1通过读取H2A第15位赖氨酸泛素化来直接进行同源重组。相关论文于2021年7月28日在线发表在《自然》杂志上。

研究人员表示,RNF168在DNA双链断裂(DSB)处的蛋白质泛素化会招募BRCA1和53BP1,它们分别是同源重组和非同源末端连接DSB修复途径的介导者。非同源末端连接依赖于53BP1直接与组蛋白H2A上泛素化的第15位赖氨酸(H2AK15ub)结合(这是一种RNF168依赖的修饰),但RNF168如何促进BRCA1的招募和功能仍不清楚。

研究人员在BRCA1相关的RING域蛋白1(BARD1,BRCA1的专属伴侣蛋白)中发现了一个串联的BRCT域相关的泛素依赖性招募模体(BUDR),通过参与H2AK15ub,将BRCA1招募到DSB。破坏BARD1的BUDR会损害同源重组,并使细胞对PARP抑制和顺铂的敏感性降低。结果进一步表明,BARD1通过多价相互作用结合核糖体:其相邻的BUDR和ankyrin重复结构域分别与H2AK15ub和未甲基化的H4第20位赖氨酸协调结合,为复制的染色质中的DNA病变提供高亲和力识别,促进BRCA1-BARD1复合物的同源重组活动。

最后,遗传上位实验证实,删除RNF168或53BP1后,可以完全解除对BARD1染色质结合活动的需求。因此,这些结果表明,通过感知DNA损伤依赖性和复制后组蛋白翻译后修饰状态,BRCA1-BARD1复合物协调了53BP1途径的拮抗并促进同源重组,为DSB修复途径的选择建立了一个简单的管理范式。

附:英文原文

Title: BARD1 reads H2A lysine 15 ubiquitination to direct homologous recombination

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

Issue&Volume: 2021-07-28

Abstract: Protein ubiquitination at sites of DNA double-strand breaks (DSBs) by RNF168 recruits BRCA1 and 53BP11,2, which are mediators of the homologous recombination and non-homologous end joining DSB repair pathways, respectively3. Non-homologous end joining relies on 53BP1 binding directly to ubiquitinated lysine 15 on H2A-type histones (H2AK15ub)4,5 (which is an RNF168-dependent modification6), but how RNF168 promotes BRCA1 recruitment and function remains unclear. Here we identify a tandem BRCT-domain-associated ubiquitin-dependent recruitment motif (BUDR) in BRCA1-associated RING domain protein 1 (BARD1) (the obligate partner protein of BRCA1) that, by engaging H2AK15ub, recruits BRCA1 to DSBs. Disruption of the BUDR of BARD1 compromises homologous recombination 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 lysine 20 by its adjacent BUDR and ankyrin repeat domains, respectively, provides high-affinity recognition of DNA lesions in replicated chromatin and promotes the homologous recombination activities of the BRCA1–BARD1 complex. Finally, our 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 post-translation modification states, BRCA1–BARD1 complexes coordinate the antagonization of the 53BP1 pathway with promotion of homologous recombination, establishing a simple paradigm for the governance of the choice of DSB repair pathway.

DOI: 10.1038/s41586-021-03776-w

Source: https://www.nature.com/articles/s41586-021-03776-w

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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