The role of DNA replication machinery in maintenance of DNA methylation

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Faithful propagation of DNA methylation patterns during DNA replication is critical for maintaining cellular phenotypes of individual differentiated cells. However, it is unclear how the maintenance of DNA methylation and DNA replication is coordinated. Using Xenopus egg extracts, we successfully reproduce maintenance DNA methylation in vitro. We found that Uhrf1 has an activity to ubiquitylate histone H3. Dnmt1, which converts hemi-methyl DNA to full-methyl DNA, preferentially associates with ubiquitylated histone H3 in vitro through a region previously identified as a replication foci targeting sequence. We also show that ubiquitin ligase activity of Uhrf1 is essential for Dnmt1 recruitment to DNA replication sites and maintaining DNA methylation in mammalian cultured cells. Our finding represent the first evidence of the mechanistic link between DNA methylation and DNA replication through histone H3 ubiquitylation.