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 Overall design: Reduced representation bisulfite sequencing (RRBS) experiments performed in mouse embryonic stem cells ES-E14, WT, Np95 -/-, and CRISPR mutant clones for Ligase1