Graduate Center for Toxicology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40506, USA.
Cell. 2013 Apr 25;153(3):590-600. doi: 10.1016/j.cell.2013.03.025.
DNA mismatch repair (MMR) ensures replication fidelity by correcting mismatches generated during DNA replication. Although human MMR has been reconstituted in vitro, how MMR occurs in vivo is unknown. Here, we show that an epigenetic histone mark, H3K36me3, is required in vivo to recruit the mismatch recognition protein hMutSα (hMSH2-hMSH6) onto chromatin through direct interactions with the hMSH6 PWWP domain. The abundance of H3K36me3 in G1 and early S phases ensures that hMutSα is enriched on chromatin before mispairs are introduced during DNA replication. Cells lacking the H3K36 trimethyltransferase SETD2 display microsatellite instability (MSI) and an elevated spontaneous mutation frequency, characteristic of MMR-deficient cells. This work reveals that a histone mark regulates MMR in human cells and explains the long-standing puzzle of MSI-positive cancer cells that lack detectable mutations in known MMR genes.
DNA 错配修复 (MMR) 通过纠正 DNA 复制过程中产生的错配来确保复制保真度。尽管人类 MMR 已在体外重建，但 MMR 在体内如何发生尚不清楚。在这里，我们表明，一种表观遗传组蛋白标记 H3K36me3，通过与 hMSH6 的 PWWP 结构域直接相互作用，在体内被招募到染色质上，从而需要错配识别蛋白 hMutSα (hMSH2-hMSH6)。在 G1 和早期 S 期，H3K36me3 的丰度确保了在 DNA 复制过程中引入错配之前，hMutSα 富集在染色质上。缺乏 H3K36 三甲基转移酶 SETD2 的细胞显示出微卫星不稳定 (MSI) 和自发突变频率升高，这是 MMR 缺陷细胞的特征。这项工作揭示了一种组蛋白标记调节人类细胞中的 MMR，并解释了长期以来的谜题，即缺乏已知 MMR 基因中可检测到的突变的 MSI 阳性癌细胞。
