University of New Mexico Cancer Center and Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):540-5. doi: 10.1073/pnas.1013571108. Epub 2010 Dec 27.
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.
鉴于组蛋白甲基化在维持基因组稳定性方面的重要作用，人们推测它可以调节 DNA 修复。组蛋白甲基化介导 53BP1 在同源重组修复过程中定位到 DNA 双链断裂（DSB），但在非同源末端连接（NHEJ）修复中是否发挥作用尚不清楚。通过筛选电离辐射诱导 DSB 后组蛋白甲基化，我们发现生成二甲基组蛋白 H3 赖氨酸 36（H3K36me2）是主要事件。使用一种新型的人类细胞系统，该系统可以在绝大多数细胞中快速产生一个单一的明确 DSB，我们发现 DNA 修复蛋白 Metnase（也称为 SETMAR），它具有 SET 组蛋白甲基转移酶结构域，定位于诱导的 DSB，并直接介导诱导的 DSB 附近 H3K36me2 的形成。这种 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 的结合，并增强了 DSB 修复。此外，表达 JHDM1a（一种 H3K36me2 去甲基化酶）或突变 K36 为 A36 或 R36 以防止 H3K36me2 形成的组蛋白 H3，会减少早期 NHEJ 修复成分与诱导的 DSB 的结合，并降低 DSB 修复。因此，这些实验定义了一个组蛋白甲基化事件，该事件增强了 NHEJ 的 DNA DSB 修复。
