Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining
Methylation of histone H3 lysine 36 enhances DNA repair by nonhomologous end-joining
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DOI：
10.1073/pnas.1013571108
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发表时间：
2011-01-11
影响因子：
11.1
通讯作者：
Hromas, Robert
中科院分区：
文献类型：
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作者：
Fnu, Sheema;Williamson, Elizabeth A.;Hromas, Robert
鉴于其在维持基因组稳定性中的重要作用，组蛋白甲基化已被假定为调节DNA修复。组蛋白甲基化介导53BP1在同源重组修复过程中定位为DNA双链断裂（DSB），但其在非同源末端连接（NHEJ）修复DSB中的作用尚未明确。通过对电离辐射诱导DSB后组蛋白甲基化的筛选，我们发现二甲基组蛋白H3赖氨酸36 （H3K36me2）的生成是主要事件。利用一种在绝大多数细胞中快速生成单一定义的DSB的新型人类细胞系统，我们发现具有SET组蛋白甲基化酶结构域的DNA修复蛋白Metnase（也称为SETMAR）定位于诱导的DSB，并直接介导H3K36me2在诱导的DSB附近的形成。H3K36的二甲基化改善了早期DNA修复成分（包括NBS1和Ku70）与诱导的DSB的关联，并增强了DSB的修复。此外，表达JHDM1a（一种H3K36me2去甲基化酶）或组蛋白H3（其中K36被突变为A36或R36以阻止H3K36me2的形成）可降低早期NHEJ修复成分与诱导DSB的关联，并减少DSB修复。因此，这些实验定义了一种组蛋白甲基化事件，可以增强NHEJ对DNA DSB的修复。
Given its significant role in the maintenance of genomic stability, histone methylation has been postulated to regulate DNA repair. Histone methylation mediates localization of 53BP1 to a DNA double-strand break (DSB) during homologous recombination repair, but a role in DSB repair by nonhomologous end-joining (NHEJ) has not been defined. By screening for histone methylation after DSB induction by ionizing radiation we found that generation of dimethyl histone H3 lysine 36 (H3K36me2) was the major event. Using a novel human cell system that rapidly generates a single defined DSB in the vast majority of cells, we found that the DNA repair protein Metnase (also SETMAR), which has a SET histone methylase domain, localized to an induced DSB and directly mediated the formation of H3K36me2 near the induced DSB. This dimethylation of H3K36 improved the association of early DNA repair components, including NBS1 and Ku70, with the induced DSB, and enhanced DSB repair. In addition, expression of JHDM1a (an H3K36me2 demethylase) or histone H3 in which K36 was mutated to A36 or R36 to prevent H3K36me2 formation decreased the association of early NHEJ repair components with an induced DSB and decreased DSB repair. Thus, these experiments define a histone methylation event that enhances DNA DSB repair by NHEJ.