Cell Reports (Aug 2014)
Regulation of DNA Methylation Patterns by CK2-Mediated Phosphorylation of Dnmt3a
- Rachel Deplus,
- Loïc Blanchon,
- Arumugam Rajavelu,
- Abdelhalim Boukaba,
- Matthieu Defrance,
- Judith Luciani,
- Françoise Rothé,
- Sarah Dedeurwaerder,
- Hélène Denis,
- Arie B. Brinkman,
- Femke Simmer,
- Fabian Müller,
- Benjamin Bertin,
- Maria Berdasco,
- Pascale Putmans,
- Emilie Calonne,
- David W. Litchfield,
- Yvan de Launoit,
- Tomasz P. Jurkowski,
- Hendrik G. Stunnenberg,
- Christoph Bock,
- Christos Sotiriou,
- Mario F. Fraga,
- Manel Esteller,
- Albert Jeltsch,
- François Fuks
Affiliations
- Rachel Deplus
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- Loïc Blanchon
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- Arumugam Rajavelu
- Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, 70569 Stuttgart, Germany
- Abdelhalim Boukaba
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- Matthieu Defrance
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- Judith Luciani
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- Françoise Rothé
- Breast Cancer Translational Research Laboratory J.C. Heuson, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium
- Sarah Dedeurwaerder
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- Hélène Denis
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- Arie B. Brinkman
- Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, the Netherlands
- Femke Simmer
- Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, the Netherlands
- Fabian Müller
- Max Planck Institute for Informatics, 66123 Saarbrücken, Germany
- Benjamin Bertin
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- Maria Berdasco
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona 08907, Catalonia, Spain
- Pascale Putmans
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- Emilie Calonne
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- David W. Litchfield
- Department of Biochemistry, Schulich School of Medicine & Dentistery, University of Western Ontario, London ON N6A 5C1, Canada
- Yvan de Launoit
- UMR 8161, CNRS, Institut Pasteur de Lille, Universités de Lille 1 et 2, Institut de Biologie de Lille, 1 rue Calmette, 59021 Lille, France
- Tomasz P. Jurkowski
- Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, 70569 Stuttgart, Germany
- Hendrik G. Stunnenberg
- Nijmegen Centre for Molecular Life Sciences, Radboud University, 6500 HB Nijmegen, the Netherlands
- Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria
- Christos Sotiriou
- Breast Cancer Translational Research Laboratory J.C. Heuson, Jules Bordet Institute, Université Libre de Bruxelles, 1000 Brussels, Belgium
- Mario F. Fraga
- Centro Nacional de Biotecnología (CNB-CSIC) and Unidad de Epigenética del Cáncer, Instituto Universitario de Oncología del Principado de Asturias, 33006-Oviedo, Spain
- Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona 08907, Catalonia, Spain
- Albert Jeltsch
- Institute of Biochemistry, Stuttgart University, Pfaffenwaldring 55, 70569 Stuttgart, Germany
- François Fuks
- Laboratory of Cancer Epigenetics, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium
- DOI
- https://doi.org/10.1016/j.celrep.2014.06.048
- Journal volume & issue
-
Vol. 8,
no. 3
pp. 743 – 753
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.
