Semisynthesis of site-specifically succinylated histone reveals that succinylation regulates nucleosome unwrapping rate and DNA accessibility.
Semisynthesis of site-specifically succinylated histone reveals that succinylation regulates nucleosome unwrapping rate and DNA accessibility.
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DOI：
10.1093/nar/gkaa663
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发表时间：
2020-09-25
影响因子：
14.9
通讯作者：
Li XD
中科院分区：
文献类型：
--
作者：
Jing Y;Ding D;Tian G;Kwan KCJ;Liu Z;Ishibashi T;Li XD
组蛋白的翻译后修饰（PTMs）是多种基于DNA的细胞过程（如复制、转录和DNA损伤修复）中核小体和染色质动力学的重要调控机制。赖氨酸琥珀酰化（Lysine succinylation, ksuc）是一种新发现的组蛋白PTM，但其在染色质中的调控和功能尚不清楚。在这里，我们利用表达蛋白连接（EPL）策略合成具有位点特异性琥珀酰化的组蛋白H4， K77残基（H4K77succ）是核小体dna -组蛋白界面上的一个进化保守的琥珀酰化位点。然后，我们在体外用半合成的H4K77succ组装单核小体。我们证明这种琥珀酰化影响核小体动力学并促进DNA从组蛋白表面展开，这使得转录因子等蛋白质能够快速进入核小体DNA的隐藏区域。在出芽酵母中，H4K77位点的赖氨酸-谷氨酸突变（模仿Ksucc）降低了核小体的稳定性，导致体内DNA损伤修复缺陷和端粒沉默。我们的研究结果表明，这种未表征的组蛋白修饰在核小体和染色质动力学中具有重要作用。
Posttranslational modifications (PTMs) of histones represent a crucial regulatory mechanism of nucleosome and chromatin dynamics in various of DNA-based cellular processes, such as replication, transcription and DNA damage repair. Lysine succinylation (Ksucc) is a newly identified histone PTM, but its regulation and function in chromatin remain poorly understood. Here, we utilized an expressed protein ligation (EPL) strategy to synthesize histone H4 with site-specific succinylation at K77 residue (H4K77succ), an evolutionarily conserved succinylation site at the nucleosomal DNA-histone interface. We then assembled mononucleosomes with the semisynthetic H4K77succ in vitro. We demonstrated that this succinylation impacts nucleosome dynamics and promotes DNA unwrapping from the histone surface, which allows proteins such as transcription factors to rapidly access buried regions of the nucleosomal DNA. In budding yeast, a lysine-to-glutamic acid mutation, which mimics Ksucc, at the H4K77 site reduced nucleosome stability and led to defects in DNA damage repair and telomere silencing in vivo. Our findings revealed this uncharacterized histone modification has important roles in nucleosome and chromatin dynamics.
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影响因子：
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作者：
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通讯作者：
Li XD