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

Cell Rep. 2014 Aug 7;8(3):743-53. doi: 10.1016/j.celrep.2014.06.048. Epub 2014 Jul 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Casein Kinase II / metabolism*
  • Cell Line, Tumor
  • CpG Islands
  • DNA (Cytosine-5-)-Methyltransferases / chemistry
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation*
  • Down-Regulation
  • Heterochromatin / metabolism
  • Humans
  • Mice
  • Phosphorylation
  • Protein Processing, Post-Translational*
  • Protein Structure, Tertiary
  • Short Interspersed Nucleotide Elements

Substances

  • Heterochromatin
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • Casein Kinase II

Associated data

  • GEO/GSE26164
  • GEO/GSE26810