Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a.
Cell Rep, 2014/8/07;8(3):743-53.
Deplus R[1], Blanchon L[1], Rajavelu A[2], Boukaba A[1], Defrance M[1], Luciani J[1], Rothé F[3], Dedeurwaerder S[1], Denis H[1], Brinkman AB[4], Simmer F[4], Müller F[5], Bertin B[1], Berdasco M[6], Putmans P[1], Calonne E[1], Litchfield DW[7], de Launoit Y[8], Jurkowski TP[2], Stunnenberg HG[4], Bock C[9], Sotiriou C[3], Fraga MF[10], Esteller M[11], Jeltsch A[12], Fuks F[13]
Affiliations
PMID: 25066127
Impact factor: 9.995
Abstract
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.
MeSH terms
3T3 Cells; Animals; Casein Kinase II; Cell Line, Tumor; CpG Islands; DNA (Cytosine-5-)-Methyltransferases; DNA Methylation; DNA Methyltransferase 3A; Down-Regulation; Heterochromatin; Humans; Mice; Phosphorylation; Protein Processing, Post-Translational; Protein Structure, Tertiary; Short Interspersed Nucleotide Elements
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