A histone mimic within DNA Ligase 1 links DNA replication and DNA remethylation: a revised model for the maintenance of DNA methylation by UHRF (RRBS)

DNA methylation is an essential epigenetic mark in mammals, and its pattern has to be re-established after each round of DNA replication. The protein UHRF1 is known to be necessary for this process, but its mode of action is unclear. Using proteomics, we havefound that a replication factor, DNA Ligase 1 (LIG1), is a direct interactor of UHRF1. The interaction is mediated bythe Tudor domain of UHRF1 and an H3K9-like histone mimic within LIG1. This mimic ismethylated on a conserved lysine by the enzymes G9a and GLP, and outcompetes H3K9me3 for UHRF1 binding. Lastly, the interaction with LIG1 promotes the recruitment of UHRF1 to sites of DNA replication and is required for DNA methylation maintenance. These results clarify UHRF1 activity, identify a new non-histone target of G9a and GLP, and provide the first example of a histone mimic that coordinates DNA replication and DNA remethylation

DNA甲基化（DNA methylation）是哺乳动物体内至关重要的表观遗传修饰标记，其修饰图谱需在每一轮DNA复制完成后重新建立。已知蛋白UHRF1是该过程的必需调控因子，但其具体作用机制尚未阐明。本研究通过蛋白质组学分析发现，复制因子DNA连接酶1（DNA Ligase 1, LIG1）是UHRF1的直接互作蛋白。二者的互作由UHRF1的Tudor结构域与LIG1内部的类H3K9组蛋白模拟序列所介导。该模拟序列的保守赖氨酸可被G9a与GLP催化甲基化，并在与UHRF1的结合竞争中优于三甲基化组蛋白H3赖氨酸9（H3K9me3）。最后，与LIG1的互作可促进UHRF1被招募至DNA复制位点，且该互作是DNA甲基化维持过程所必需的。本研究结果阐明了UHRF1的作用机制，鉴定出G9a与GLP的一类新型非组蛋白靶标，并首次提供了可协同DNA复制与DNA再甲基化的组蛋白模拟物实例。