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

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

Author information

1
Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
2
Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, 70569 Stuttgart, Germany.
3
Breast Cancer Translational Research Laboratory J.C. Heuson, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium.
4
Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, the Netherlands.
5
Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
6
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08907, Catalonia, Spain.
7
Department of Biochemistry, Schulich School of Medicine & Dentistery, University of Western Ontario, London ON N6A 5C1, Canada.
8
UMR 8161, CNRS, Institut Pasteur de Lille, Universités de Lille 1 et 2, Institut de Biologie de Lille, 1 rue Calmette, 59021 Lille, France.
9
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
10
Centro Nacional de Biotecnología (CNB-CSIC) and Unidad de Epigenética del Cáncer, Instituto Universitario de Oncología del Principado de Asturias, 33006-Oviedo, Spain.
11
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08907, Catalonia, Spain; Department of Physiological Sciences II, School of Medicine, University of Barcelona, 08036 Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain.
12
Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, 70569 Stuttgart, Germany. Electronic address: albert.jeltsch@ibc.uni-stuttgart.de.
13
Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium. Electronic address: ffuks@ulb.ac.be.

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.

PMID:
25066127
DOI:
10.1016/j.celrep.2014.06.048
[Indexed for MEDLINE]
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