Bre1-dependent H2B ubiquitination promotes homologous recombination by stimulating histone eviction at DNA breaks.
Bre1-dependent H2B ubiquitination promotes homologous recombination by stimulating histone eviction at DNA breaks.
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Bre1 依赖性 H2B 泛素化通过刺激 DNA 断裂处的组蛋白驱逐来促进同源重组
DOI：
10.1093/nar/gky918
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发表时间：
2018-11-30
影响因子：
14.9
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Zheng S;Li D;Lu Z;Liu G;Wang M;Xing P;Wang M;Dong Y;Wang X;Li J;Zhang S;Peng H;Ira G;Li G;Chen X
摘要DNA双链断裂（DSB）的修复需要清除DNA断裂周围的组蛋白，以允许装载大量的修复和检查点蛋白。然而，对这一过程的机制和调控仍然知之甚少。在这里，我们表明，组蛋白H2 B泛素化（uH 2B）促进组蛋白驱逐在DSB独立切除或ATP依赖的染色质重塑。缺乏uH 2B或其E3泛素连接酶Bre 1的细胞由于H3 K79甲基化的丧失而表现出过度切除，该甲基化招募了Rad 9，这是一种已知的切除负调节因子。出乎意料的是，尽管产生了过量的单链DNA，但bre 1 Δ细胞显示出有缺陷的RPA和Rad 51募集以及通过同源重组和对DNA损伤的反应受损的修复。bre 1 Δ细胞中的HR缺陷与DSB中受损的组蛋白损失相关，并且可以通过消耗CAF-1（沉积组蛋白H3-H4的组蛋白伴侣）来在很大程度上挽救。过表达Rad 51可促进组蛋白排出并部分抑制bre 1 Δ突变体的重组缺陷。因此，我们建议，Bre 1介导的uH 2B促进DSB修复，通过促进组蛋白驱逐和随后的修复蛋白的加载。
Abstract Repair of DNA double-strand breaks (DSBs) requires eviction of the histones around DNA breaks to allow the loading of numerous repair and checkpoint proteins. However, the mechanism and regulation of this process remain poorly understood. Here, we show that histone H2B ubiquitination (uH2B) promotes histone eviction at DSBs independent of resection or ATP-dependent chromatin remodelers. Cells lacking uH2B or its E3 ubiquitin ligase Bre1 exhibit hyper-resection due to the loss of H3K79 methylation that recruits Rad9, a known negative regulator of resection. Unexpectedly, despite excessive single-strand DNA being produced, bre1Δ cells show defective RPA and Rad51 recruitment and impaired repair by homologous recombination and response to DNA damage. The HR defect in bre1Δ cells correlates with impaired histone loss at DSBs and can be largely rescued by depletion of CAF-1, a histone chaperone depositing histones H3-H4. Overexpression of Rad51 stimulates histone eviction and partially suppresses the recombination defects of bre1Δ mutant. Thus, we propose that Bre1 mediated-uH2B promotes DSB repair through facilitating histone eviction and subsequent loading of repair proteins.
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影响因子：
3.4
作者：
Chernikova SB;Dorth JA;Razorenova OV;Game JC;Brown JM
通讯作者：
Brown JM
影响因子：
64.8
作者：
Costelloe, Thomas;Louge, Raphael;Tomimatsu, Nozomi;Mukherjee, Bipasha;Martini, Emmanuelle;Khadaroo, Basheer;Dubois, Kenny;Wiegant, Wouter W.;Thierry, Agnes;Burma, Sandeep;van Attikum, Haico;Llorente, Bertrand
通讯作者：
Llorente, Bertrand
影响因子：
11.2
作者：
Chernikova SB;Razorenova OV;Higgins JP;Sishc BJ;Nicolau M;Dorth JA;Chernikova DA;Kwok S;Brooks JD;Bailey SM;Game JC;Brown JM
通讯作者：
Brown JM
影响因子：
3.3
作者：
Game, John C.;Williamson, Marsha S.;Brown, J. Martin
通讯作者：
Brown, J. Martin
影响因子：
4.8
作者：
Clerici, M;Mantiero, D;Longhese, MP
通讯作者：
Longhese, MP