title: Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a.
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.
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Rachel
authors: R
authors: Deplus
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Loïc
authors: L
authors: Blanchon
authors: Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, 70569 Stuttgart, Germany.
authors: Arumugam
authors: A
authors: Rajavelu
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Abdelhalim
authors: A
authors: Boukaba
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Matthieu
authors: M
authors: Defrance
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Judith
authors: J
authors: Luciani
authors: Breast Cancer Translational Research Laboratory J.C. Heuson, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium.
authors: Françoise
authors: F
authors: Rothé
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Sarah
authors: S
authors: Dedeurwaerder
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Hélène
authors: H
authors: Denis
authors: Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, the Netherlands.
authors: Arie B
authors: AB
authors: Brinkman
authors: Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, the Netherlands.
authors: Femke
authors: F
authors: Simmer
authors: Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
authors: Fabian
authors: F
authors: Müller
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Benjamin
authors: B
authors: Bertin
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona 08907, Catalonia, Spain.
authors: Maria
authors: M
authors: Berdasco
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Pascale
authors: P
authors: Putmans
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.
authors: Emilie
authors: E
authors: Calonne
authors: Department of Biochemistry, Schulich School of Medicine & Dentistery, University of Western Ontario, London ON N6A 5C1, Canada.
authors: David W
authors: DW
authors: Litchfield
authors: UMR 8161, CNRS, Institut Pasteur de Lille, Universités de Lille 1 et 2, Institut de Biologie de Lille, 1 rue Calmette, 59021 Lille, France.
authors: Yvan
authors: Y
authors: de Launoit
authors: Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, 70569 Stuttgart, Germany.
authors: Tomasz P
authors: TP
authors: Jurkowski
authors: Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, the Netherlands.
authors: Hendrik G
authors: HG
authors: Stunnenberg
authors: 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.
authors: Christoph
authors: C
authors: Bock
authors: Breast Cancer Translational Research Laboratory J.C. Heuson, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium.
authors: Christos
authors: C
authors: Sotiriou
authors: Centro Nacional de Biotecnología (CNB-CSIC) and Unidad de Epigenética del Cáncer, Instituto Universitario de Oncología del Principado de Asturias, 33006-Oviedo, Spain.
authors: Mario F
authors: MF
authors: Fraga
authors: 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.
authors: Manel
authors: M
authors: Esteller
authors: Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, 70569 Stuttgart, Germany. Electronic address: albert.jeltsch@ibc.uni-stuttgart.de.
authors: Albert
authors: A
authors: Jeltsch
authors: Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium. Electronic address: ffuks@ulb.ac.be.
authors: François
authors: F
authors: Fuks
mesh_terms: D016475:3T3 Cells; D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism*; D045744:Cell Line, Tumor; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D020086:Short Interspersed Nucleotide Elements
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D006570:Heterochromatin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D047390:Casein Kinase II