Regulation of DNA Methylation Patterns by CK2-Mediated Phosphorylation of Dnmt3a

被引：72

作者：

Deplus, Rachel ^{[1
]}

Blanchon, Loic ^{[1
]}

Rajavelu, Arumugam ^{[2
]}

Boukaba, Abdelhalim ^{[1
]}

Defrance, Matthieu ^{[1
]}

Luciani, Judith ^{[1
]}

Rothe, Francoise ^{[3
]}

Dedeurwaerder, Sarah ^{[1
]}

Denis, Helene ^{[1
]}

Brinkman, Arie B. ^{[4
]}

Simmer, Femke ^{[4
]}

Mueller, Fabian ^{[7
]}

Bertin, Benjamin ^{[1
]}

Berdasco, Maria

Putmans, Pascale ^{[1
]}

Calonne, Emilie ^{[1
]}

Litchfield, David W. ^{[9
]}

de Launoit, Yvan ^{[10
,11
]}

Jurkowski, Tomasz P. ^{[2
]}

Stunnenberg, Hendrik G. ^{[4
]}

Bock, Christoph ^{[5
,6
,7
]}

Sotiriou, Christos ^{[3
]}

Fraga, Mario F. ^{[12
,13
]}

Esteller, Manel ^{[8
,14
,15
]}

Jeltsch, Albert ^{[2
]}

Fuks, Francois ^{[1
]}

机构：

[1] Univ Libre Bruxelles, Fac Med, Lab Canc Epigenet, B-1070 Brussels, Belgium

[2] Univ Stuttgart, Inst Biochem, D-70569 Stuttgart, Germany

[3] Univ Libre Bruxelles, Inst Jules Bordet, Breast Canc Translat Res Lab JC Heuson, B-1000 Brussels, Belgium

[4] Radboud Univ Nijmegen, Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands

[5] Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria

[6] Med Univ Vienna, Dept Lab Med, A-1090 Vienna, Austria

[7] Max Planck Inst Informat, D-66123 Saarbrucken, Germany

[8] Hosp Llobregat, Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona 08907, Catalonia, Spain

[9] Univ Western Ontario, Schulich Sch Med & Dent, Dept Biochem, London, ON N6A 5C1, Canada

[10] Univ Lille 1, Inst Pasteur Lille, CNRS, UMR 8161, F-59021 Lille, France

[11] Univ Lille 2, Inst Biol Lille, F-59021 Lille, France

[12] Inst Univ Oncol Principado Asturias, CSIC, CNB, Oviedo 33006, Spain

[13] Inst Univ Oncol Principado Asturias, Unidad Epigenet Canc, Oviedo 33006, Spain

[14] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona 08036, Catalonia, Spain

[15] ICREA, Barcelona 08010, Catalonia, Spain

来源：

CELL REPORTS | 2014年 / 8卷 / 03期

关键词：

PROTEIN-KINASE CK2; DE-NOVO METHYLATION; METHYLTRANSFERASE DNMT3A; HUMAN GENOME; PWWP DOMAIN; EXPRESSION; IMPACT; TRIMETHYLATION; TRANSCRIPTION; PREFERENCE;

D O I：

10.1016/j.celrep.2014.06.048

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

DNA methylation is a central epigenetic modification that is established by de novo DNA methyl-transferases. 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.

引用

页码：743 / 753

页数：11

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