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Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a.

par Deplus, Rachel ;Blanchon, Loïc ;Rajavelu, Arumugam;Boukaba, Abdel Halim ;Defrance, Matthieu ;Luciani, Judith ;Rothé, Françoise ;Dedeurwaerder, Sarah ;Denis, Hélène ;Brinkman, Arie B;Simmer, Femke;Müller, Fabian;Bertin, Benjamin ;Berdasco, Maria;Putmans, Pascale ;Calonne, Emilie ;Litchfield, David DW;De Launoit, Yvan ;Jurkowski, Tomasz Piotr;Stunnenberg, Hendrik HG;Bock, Christoph;Sotiriou, Christos ;Fraga, Mario F;Esteller, Manel;Jeltsch, Albert;Fuks, François
Référence Cell reports, 8, 3, page (743-753)
Publication Publié, 2014-08

Article révisé par les pairs

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Résumé :

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.