TY - JOUR
T1 - Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a
AU - Deplus, Rachel
AU - Blanchon, Loïc
AU - Rajavelu, Arumugam
AU - Boukaba, Abdelhalim
AU - Defrance, Matthieu
AU - Luciani, Judith
AU - Rothé, Françoise
AU - Dedeurwaerder, Sarah
AU - Denis, Hélène
AU - Brinkman, Arie B.
AU - Simmer, Femke
AU - Müller, Fabian
AU - Bertin, Benjamin
AU - Berdasco, Maria
AU - Putmans, Pascale
AU - Calonne, Emilie
AU - Litchfield, David W.
AU - De Launoit, Yvan
AU - Jurkowski, Tomasz P.
AU - Stunnenberg, Hendrik G.
AU - Bock, Christoph
AU - Sotiriou, Christos
AU - Fraga, Mario F.
AU - Esteller, Manel
AU - Jeltsch, Albert
AU - Fuks, François
N1 - Publisher Copyright:
© 2014 The Authors.
PY - 2014/8/7
Y1 - 2014/8/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84919776252&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2014.06.048
DO - 10.1016/j.celrep.2014.06.048
M3 - Article
C2 - 25066127
AN - SCOPUS:84919776252
SN - 2211-1247
VL - 8
SP - 743
EP - 753
JO - Cell Reports
JF - Cell Reports
IS - 3
ER -