Regulation of DNA Methylation Patterns by CK2-Mediated Phosphorylation of Dnmt3a

• Dnmt3a is phosphorylated by CK2 at two residues, reducing its activity
• CK2 modulates CpG methylation of several repeats, most notably of Alu SINEs
• CK2-mediated phosphorylation of Dnmt3a favors its heterochromatic localization
• Phosphorylation of Dnmt3a by CK2 shapes the CpG methylome

SummaryDNA methylation is a central epigenetic modification that is established by de novo DNA methyltransferases. The mechanisms underlying the generation of genomic methylation patterns are still poorly understood. Using mass spectrometry and a phosphospecific Dnmt3a antibody, we demonstrate that CK2 phosphorylates endogenous Dnmt3a at two key residues located near its PWWP domain, thereby downregulating the ability of Dnmt3a to methylate DNA. Genome-wide DNA methylation analysis shows that CK2 primarily modulates CpG methylation of several repeats, most notably of Alu SINEs. This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. By revealing phosphorylation as a mode of regulation of de novo DNA methyltransferase function and by uncovering a mechanism for the regulation of methylation at repetitive elements, our results shed light on the origin of DNA methylation patterns.

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