SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability.
SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability.
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DOI：
10.1016/j.celrep.2014.05.026
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发表时间：
2014-06-26
期刊：
影响因子：
8.8
通讯作者：
Humphrey TC
中科院分区：
文献类型：
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作者：
Pfister SX;Ahrabi S;Zalmas LP;Sarkar S;Aymard F;Bachrati CZ;Helleday T;Legube G;La Thangue NB;Porter AC;Humphrey TC
通过组蛋白甲基化调节染色质协调许多细胞过程。组蛋白H3 K36的依赖SETD 2的三甲基化与转录活性相关。在这里，我们定义了H3 K36三甲基化在人类细胞同源重组（HR）修复中的作用。我们发现，耗尽SETD 2产生类似于在I-SceI诱导的DNA双链断裂（DSB）位点的RAD 51耗尽的突变签名，通过微同源介导的末端连接产生显着增加的缺失。我们建立了一个突触前的作用，为SETD 2甲基转移酶在HR，在那里它有利于招聘的C-末端结合蛋白相互作用蛋白（CtIP），并促进DSB切除，允许复制蛋白A（RPA）和RAD 51结合到DNA损伤位点。此外，通过过表达KDM 4A/JMJD 2A、癌基因和H3 K36 me 3/2脱甲基酶或H3.3K36M转基因来降低H3 K36 me 3水平也减少了HR修复事件。我们提出，在H3 K36 me 3修饰的转录活性基因组区域内的无错误HR修复促进细胞内稳态。此外，这些发现提供了关于为什么致癌突变聚集在H3 K36 me 3轴内的见解。SETD 2在DSB切除和同源重组修复中的作用组蛋白H3 K36 me 3是同源重组所必需的SETD 2和RAD 51抑制由微同源介导的末端连接引起的突变影响H3 K36 me 3水平的突变可能促进肿瘤发生SETD 2基因编码组蛋白H3 K36三甲基转移酶。Pfister等人现在显示，人SETD 2依赖性H3 K36 me 3通过同源重组（HR）促进无错误DNA修复来维持基因组稳定性。在DNA损伤后，SETD 2缺失的细胞表现出DNA切除减少，早期HR因子的募集受损，以及易错微同源介导的末端连接修复途径的利用增加。通过过度表达癌基因KDM 4A消除H3 K36 me 3也会损害HR。因此，H3 K36 me 3通过促进准确的DNA修复来抑制肿瘤发生。
Modulating chromatin through histone methylation orchestrates numerous cellular processes. SETD2-dependent trimethylation of histone H3K36 is associated with active transcription. Here, we define a role for H3K36 trimethylation in homologous recombination (HR) repair in human cells. We find that depleting SETD2 generates a mutation signature resembling RAD51 depletion at I-SceI-induced DNA double-strand break (DSB) sites, with significantly increased deletions arising through microhomology-mediated end-joining. We establish a presynaptic role for SETD2 methyltransferase in HR, where it facilitates the recruitment of C-terminal binding protein interacting protein (CtIP) and promotes DSB resection, allowing Replication Protein A (RPA) and RAD51 binding to DNA damage sites. Furthermore, reducing H3K36me3 levels by overexpressing KDM4A/JMJD2A, an oncogene and H3K36me3/2 demethylase, or an H3.3K36M transgene also reduces HR repair events. We propose that error-free HR repair within H3K36me3-decorated transcriptionally active genomic regions promotes cell homeostasis. Moreover, these findings provide insights as to why oncogenic mutations cluster within the H3K36me3 axis. A role for SETD2 in DSB resection and homologous recombination repair Histone H3K36me3 is required for homologous recombination SETD2 and RAD51 suppress mutations arising from microhomology-mediated end-joining Mutations affecting H3K36me3 levels may promote tumorigenesis The SETD2 gene encodes the histone H3K36 trimethyltransferase. Pfister et al. now show that human SETD2-dependent H3K36me3 maintains genome stability by promoting error-free DNA repair through homologous recombination (HR). Upon DNA damage, SETD2-depleted cells exhibit reduced DNA resection, impaired recruitment of early HR factors, and increased utilization of the error-prone microhomology-mediated end-joining repair pathway. Eliminating H3K36me3 by overexpressing the oncogene KDM4A also impairs HR. Thus, H3K36me3 suppresses tumorigenesis by promoting accurate DNA repair.
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影响因子：
3.7
作者：
Gordon WR;Vardar-Ulu D;L'Heureux S;Ashworth T;Malecki MJ;Sanchez-Irizarry C;McArthur DG;Histen G;Mitchell JL;Aster JC;Blacklow SC
通讯作者：
Blacklow SC
DOI：
10.1016/j.tig.2008.08.007
发表时间：
2008-11
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
McVey M;Lee SE
通讯作者：
Lee SE
影响因子：
16.8
作者：
Daugaard, Mads;Baude, Annika;Jaattela, Marja
通讯作者：
Jaattela, Marja
影响因子：
16.8
作者：
Couture, Jean-Francois;Collazo, Evys;Trievel, Raymond C.
通讯作者：
Trievel, Raymond C.
影响因子：
64.8
作者：
通讯作者：
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