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Author Notes:

To whom correspondence should be addressed: Sriharsa Pradhan. Tel: +1 978 380 7227; Fax: +1 978 921 1350; Email: pradhan@neb.com

Pierre-Olivier Estève and Guoqiang Zhang contributed equally to the paper as first authors.

We would like to thank Donald Comb, James V. Ellard, Rich Roberts, William Jack and Clotilde Carlow at New England Biolabs Inc., for research support and encouragement.

Conflict of interest statement: None declared.

RRBS data and RNA-seq data are available at Gene Expression Omnibus (GSE72860).

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Research Funding:

New England Biolabs Inc.; Cancer Prevention Research Institute of Texas [RP130432 to M.T.B.]; Center for Environmental and Molecular Carcinogenesis at MD Anderson; X.C.'s laboratory was supported by NIH [GM049245-22].

Funding for open access charge: New England Biolabs Inc.

Binding of 14-3-3 reader proteins to phosphorylated DNMT1 facilitates aberrant DNA methylation and gene expression

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Journal Title:

Nucleic Acids Research

Volume:

Volume 44, Number 4

Publisher:

, Pages 1642-1656

Type of Work:

Article | Final Publisher PDF

Abstract:

Mammalian DNA (cytosine-5) methyltransferase 1 (DNMT1) is essential for maintenance methylation. Phosphorylation of Ser143 (pSer143) stabilizes DNMT1 during DNA replication. Here, we show 14-3-3 is a reader protein of DNMT1pSer143. In mammalian cells 14-3-3 colocalizes and binds DNMT1pSer143 post-DNA replication. The level of DNMT1pSer143 increased with overexpression of 14-3-3 and decreased by its depletion. Binding of 14-3-3 proteins with DNMT1pSer143 resulted in inhibition of DNA methylation activity in vitro. In addition, overexpression of 14-3-3 in NIH3T3 cells led to decrease in DNMT1 specific activity resulting in hypomethylation of the genome that was rescued by transfection of DNMT1. Genes representing cell migration, mobility, proliferation and focal adhesion pathway were hypomethylated and overexpressed. Furthermore, overexpression of 14-3-3 also resulted in enhanced cell invasion. Analysis of TCGA breast cancer patient data showed significant correlation for DNA hypomethylation and reduced patient survival with increased 14-3-3 expressions. Therefore, we suggest that 14-3-3 is a crucial reader of DNMT1pSer143 that regulates DNA methylation and altered gene expression that contributes to cell invasion.

Copyright information:

© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).

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