Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France.
Cellular Memory Laboratory, RIKEN Wako, Saitama 351-0198, Japan; Graduate School of Medicine, Diabetes, Endocrinology, and Nutrition, Kyoto University, Kyoto 606-8507, Japan.
Mol Cell. 2017 Aug 17;67(4):550-565.e5. doi: 10.1016/j.molcel.2017.07.012. Epub 2017 Aug 10.
DNA methylation is an essential epigenetic mark in mammals that has to be re-established after each round of DNA replication. The protein UHRF1 is essential for this process; it has been proposed that the protein targets newly replicated DNA by cooperatively binding hemi-methylated DNA and H3K9me2/3, but this model leaves a number of questions unanswered. Here, we present evidence for a direct recruitment of UHRF1 by the replication machinery via DNA ligase 1 (LIG1). A histone H3K9-like mimic within LIG1 is methylated by G9a and GLP and, compared with H3K9me2/3, more avidly binds UHRF1. Interaction with methylated LIG1 promotes the recruitment of UHRF1 to DNA replication sites and is required for DNA methylation maintenance. These results further elucidate the function of UHRF1, identify a non-histone target of G9a and GLP, and provide an example of a histone mimic that coordinates DNA replication and DNA methylation maintenance.
DNA 甲基化是哺乳动物中一种重要的表观遗传标记，必须在每一轮 DNA 复制后重新建立。蛋白质 UHRF1 是这个过程所必需的；有人提出，该蛋白通过协同结合半甲基化的 DNA 和 H3K9me2/3 来靶向新复制的 DNA，但该模型仍有许多问题没有解答。在这里，我们通过 DNA 连接酶 1（LIG1）提供了证据，证明 UHRF1 可以被复制机制直接招募。LIG1 内的组蛋白 H3K9 类似物被 G9a 和 GLP 甲基化，与 H3K9me2/3 相比，它更能与 UHRF1 结合。与甲基化的 LIG1 相互作用促进了 UHRF1 向 DNA 复制位点的募集，并且是维持 DNA 甲基化所必需的。这些结果进一步阐明了 UHRF1 的功能，确定了 G9a 和 GLP 的非组蛋白靶标，并提供了一个组蛋白模拟物协调 DNA 复制和 DNA 甲基化维持的例子。
