Regulation of DNA Methylation Patterns by CK2-Mediated Phosphorylation of Dnmt3a
2014
Rachel Deplus | Loïc Blanchon | Arumugam Rajavelu | Abdelhalim Boukaba | Matthieu Defrance | Judith Luciani | Françoise Rothé | Sarah Dedeurwaerder | Hélène Denis | Arie B. Brinkman | Femke Simmer | Fabian Müller | Benjamin Bertin | Maria Berdasco | Pascale Putmans | Emilie Calonne | David W. Litchfield | Yvan de Launoit | Tomasz P. Jurkowski | Hendrik G. Stunnenberg | Christoph Bock | Christos Sotiriou | Mario F. Fraga | Manel Esteller | Albert Jeltsch | François Fuks
DNA 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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