Dynamic switching of crotonylation to ubiquitination of H2A at lysine 119 attenuates transcription-replication conflicts caused by replication stress.
Dynamic switching of crotonylation to ubiquitination of H2A at lysine 119 attenuates transcription-replication conflicts caused by replication stress.
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DOI：
10.1093/nar/gkac734
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发表时间：
2022-09-23
影响因子：
14.9
通讯作者：
Wang, Hailong
中科院分区：
文献类型：
--
作者：
Hao, Shuailin;Wang, Ya;Zhao, Yuqin;Gao, Wen;Cui, Wei;Li, Youhang;Cui, Jian;Liu, Yu;Lin, Lixiu;Xu, Xingzhi;Wang, Hailong
蛋白质的可逆翻译后修饰（PTM）在许多细胞过程中起着重要的作用。赖氨酸巴豆酰化（Kcr）是一种新发现的PTM，但其功能意义尚不清楚。在这里，我们发现Kcr参与复制应激反应。我们发现，巴豆酰化的组蛋白H2 A在赖氨酸119（H2 AK 119）和泛素化的H2 AK 119是可逆的复制应激调节。SIRT 1对H2 AK 119的去巴豆酰化是随后BMI 1对H2 AK 119进行泛素化的先决条件。泛素化H2 AK 119在反向复制叉处的积累导致RNA聚合酶II的释放和停滞复制叉附近的转录抑制。这些作用减弱了转录-复制冲突（TRC）和TRC相关的R环形成和DNA双链断裂。这些发现表明，H2 A在赖氨酸119处的去巴豆酰化和泛素化共同作用，以解决复制应激诱导的TRCs并保护基因组稳定性。为了响应复制应激，SIRT 1从H2 AK 119上去除巴豆酰基，这一过程是随后在该位点进行BMI 1介导的泛素化的先决条件。泛素化H2 AK 119在反向复制叉处的积累导致RNA Pol II的释放和停滞复制叉附近的转录抑制。这些效应减弱了复制-转录冲突（TRCs）。
The reversible post-translational modification (PTM) of proteins plays an important role in many cellular processes. Lysine crotonylation (Kcr) is a newly identified PTM, but its functional significance remains unclear. Here, we found that Kcr is involved in the replication stress response. We show that crotonylation of histone H2A at lysine 119 (H2AK119) and ubiquitination of H2AK119 are reversibly regulated by replication stress. Decrotonylation of H2AK119 by SIRT1 is a prerequisite for subsequent ubiquitination of H2AK119 by BMI1. Accumulation of ubiquitinated H2AK119 at reversed replication forks leads to the release of RNA Polymerase II and transcription repression in the vicinity of stalled replication forks. These effects attenuate transcription–replication conflicts (TRCs) and TRC-associated R-loop formation and DNA double-strand breaks. These findings suggest that decrotonylation and ubiquitination of H2A at lysine 119 act together to resolve replication stress-induced TRCs and protect genome stability. In response to replication stress, SIRT1 removes crotonyl groups from H2AK119 and this process is a prerequisite for subsequent BMI1-mediated ubiquitination at this site. Accumulation of ubiquitinated H2AK119 at reversed replication forks leads to the release of RNA Pol II and transcription repression in the vicinity of stalled replication forks. These effects attenuate replication–transcription conflicts (TRCs).
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影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
16
作者：
Fan, Wei;Luo, Jianyuan
通讯作者：
Luo, Jianyuan
影响因子：
14.8
作者：
Dai, Lunzhi;Peng, Chao;Zhao, Yingming
通讯作者：
Zhao, Yingming
转录复制冲突取向调节R环水平并激活不同的DNA损伤反应。
影响因子：
64.5
作者：
Hamperl S;Bocek MJ;Saldivar JC;Swigut T;Cimprich KA
通讯作者：
Cimprich KA
影响因子：
8.8
作者：
Cristini A;Groh M;Kristiansen MS;Gromak N
通讯作者：
Gromak N