IGMM, CNRS, INSERM, University of Montpellier, Montpellier, France.
Equipe labellisée Ligue contre le Cancer, Paris, France.
Nat Commun. 2023 Aug 22;14(1):5104. doi: 10.1038/s41467-023-40843-4.
Histone post-translational modifications promote a chromatin environment that controls transcription, DNA replication and repair, but surprisingly few phosphorylations have been documented. We report the discovery of histone H3 serine-57 phosphorylation (H3S57ph) and show that it is implicated in different DNA repair pathways from fungi to vertebrates. We identified CHK1 as a major human H3S57 kinase, and disrupting or constitutively mimicking H3S57ph had opposing effects on rate of recovery from replication stress, 53BP1 chromatin binding, and dependency on RAD52. In fission yeast, mutation of all H3 alleles to S57A abrogated DNA repair by both non-homologous end-joining and homologous recombination, while cells with phospho-mimicking S57D alleles were partly compromised for both repair pathways, presented aberrant Rad52 foci and were strongly sensitised to replication stress. Mechanistically, H3S57ph loosens DNA-histone contacts, increasing nucleosome mobility, and interacts with H3K56. Our results suggest that dynamic phosphorylation of H3S57 is required for DNA repair and recovery from replication stress, opening avenues for investigating the role of this modification in other DNA-related processes.
组蛋白翻译后修饰促进了控制转录、DNA 复制和修复的染色质环境，但令人惊讶的是，只有少数磷酸化被记录下来。我们报告了组蛋白 H3 丝氨酸-57 磷酸化（H3S57ph）的发现，并表明它与从真菌到脊椎动物的不同 DNA 修复途径有关。我们鉴定出 CHK1 是人类 H3S57 的主要激酶，并且破坏或组成性模拟 H3S57ph 对复制压力恢复速度、53BP1 染色质结合以及对 RAD52 的依赖性具有相反的影响。在裂殖酵母中，所有 H3 等位基因突变为 S57A 可消除非同源末端连接和同源重组的 DNA 修复，而具有磷酸模拟 S57D 等位基因的细胞对两种修复途径都部分受损，呈现异常的 Rad52 焦点，并对复制压力高度敏感。从机制上讲，H3S57ph 松解了 DNA-组蛋白的接触，增加了核小体的流动性，并与 H3K56 相互作用。我们的结果表明，H3S57 的动态磷酸化是 DNA 修复和复制压力恢复所必需的，为研究这种修饰在其他与 DNA 相关过程中的作用开辟了途径。
