Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing 100048, China.
Guangdong Key Laboratory for Genome Stability and Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering, China Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, China.
Nucleic Acids Res. 2022 Sep 23;50(17):9873-9892. doi: 10.1093/nar/gkac734.
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.
蛋白质的可逆翻译后修饰（PTM）在许多细胞过程中起着重要作用。赖氨酸丁酰化（Kcr）是一种新发现的 PTM，但它的功能意义尚不清楚。在这里，我们发现 Kcr 参与复制应激反应。我们表明，组蛋白 H2A 赖氨酸 119 （H2AK119）的丁酰化和 H2AK119 的泛素化可被复制应激可逆调节。SIRT1 的去丁酰化是随后由 BMI1 对 H2AK119 进行泛素化的前提。在反转复制叉处积累的泛素化 H2AK119 导致 RNA 聚合酶 II 在停滞复制叉附近的释放和转录抑制。这些效应减弱了转录-复制冲突（TRCs）和与 TRC 相关的 R 环形成和 DNA 双链断裂。这些发现表明，H2A 赖氨酸 119 的去丁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。
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