JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity.
JMJD-5/KDM8 regulates H3K36me2 and is required for late steps of homologous recombination and genome integrity.
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DOI：
10.1371/journal.pgen.1006632
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发表时间：
2017-02
期刊：
影响因子：
4.5
通讯作者：
Salcini AE
中科院分区：
文献类型：
--
作者：
Amendola PG;Zaghet N;Ramalho JJ;Vilstrup Johansen J;Boxem M;Salcini AE
真核生物的基因组以三维结构组织，称为染色质，由DNA和相关蛋白质组成，其中大多数是组蛋白。组蛋白的翻译后修饰极大地影响染色质结构并调节许多基于DNA的生物学过程。组蛋白3的赖氨酸36甲基化（H3 K36）是在DNA损伤修复的早期步骤中功能相关的翻译后修饰。在这里，我们表明，JMJD-5调节H3 K36二甲基化，它是必需的同源重组介导的双链断裂修复的后期阶段。jmjd-5的缺失导致对电离辐射的超敏反应和减数分裂缺陷，并且其与RAD-51在双链断裂位点的异常保留相关。jmjd-5与解析重组中间体（rtel-1）或促进RAD-51双链DNA丝（rfs-1和helq-1）解析所需基因的遗传相互作用分析表明，jmjd-5阻止了停滞的突触后重组中间体的形成，并有利于RAD-51的去除。由于这些表型都是由一个催化失活的jmjd-5突变体重演，我们提出了一个新的作用H3 K36 me 2调节在后期步骤的同源重组至关重要，以保持基因组的完整性。DNA损伤修复发生在染色质的背景下，它受到组蛋白翻译后修饰的影响。组蛋白3（H3 K36）赖氨酸36位甲基化水平在DNA损伤修复的早期阶段起着重要作用，通过在位点断裂处募集早期修复因子和调节RAD-51灶的形成。在这里，我们认为，由JMJD-5的H3 K36 me 2水平的调节也是相关的DNA修复的后期阶段。利用C. elegans作为模型系统，我们表明，jmjd-5的损失，导致H3 K36 me 2水平的增加，损害重组中间体的分辨率和RAD-51的释放，在电离辐射后的DNA修复过程和减数分裂重组的后果。因此，我们的工作提供了对调节H3 K36甲基化的机制及其在修复双链断裂和基因组稳定性中的核心作用的进一步见解。
The eukaryotic genome is organized in a three-dimensional structure called chromatin, constituted by DNA and associated proteins, the majority of which are histones. Post-translational modifications of histone proteins greatly influence chromatin structure and regulate many DNA-based biological processes. Methylation of lysine 36 of histone 3 (H3K36) is a post-translational modification functionally relevant during early steps of DNA damage repair. Here, we show that the JMJD-5 regulates H3K36 di-methylation and it is required at late stages of double strand break repair mediated by homologous recombination. Loss of jmjd-5 results in hypersensitivity to ionizing radiation and in meiotic defects, and it is associated with aberrant retention of RAD-51 at sites of double strand breaks. Analyses of jmjd-5 genetic interactions with genes required for resolving recombination intermediates (rtel-1) or promoting the resolution of RAD-51 double stranded DNA filaments (rfs-1 and helq-1) suggest that jmjd-5 prevents the formation of stalled postsynaptic recombination intermediates and favors RAD-51 removal. As these phenotypes are all recapitulated by a catalytically inactive jmjd-5 mutant, we propose a novel role for H3K36me2 regulation during late steps of homologous recombination critical to preserve genome integrity. DNA damage repair occurs in the context of chromatin and it is influenced by post-translational modifications of histone proteins. The level of methylation at lysine 36 of histone 3 (H3K36) plays an important role in early phases of DNA damage repair by recruiting early repair factors at the site breaks and regulating the formation of RAD-51 foci. Here, we suggest that the regulation of H3K36me2 levels by JMJD-5 is also relevant at later stages of DNA repair. By using C. elegans as model system, we show that loss of jmjd-5, resulting in increased levels of H3K36me2, impairs the resolution of recombination intermediates and the release of RAD-51, with consequences in the DNA repair process after ionizing radiation and in meiotic recombination. Thus, our work provides further insights into the mechanism regulating H3K36 methylation and its central role in repair of double strand breaks and in genome stability.