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Mol Cell. 2017 Aug 17;67(4):550-565.e5. doi: 10.1016/j.molcel.2017.07.012. Epub 2017 Aug 10.

Methylation of DNA Ligase 1 by G9a/GLP Recruits UHRF1 to Replicating DNA and Regulates DNA Methylation.

Author information

1
Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France.
2
Cellular Memory Laboratory, RIKEN Wako, Saitama 351-0198, Japan; Graduate School of Medicine, Diabetes, Endocrinology, and Nutrition, Kyoto University, Kyoto 606-8507, Japan.
3
The Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
4
Cellular Memory Laboratory, RIKEN Wako, Saitama 351-0198, Japan.
5
Department of Medical Life Sciences, Yokohama City University, Yokohama 230-0045, Japan.
6
MRC Clinical Sciences Centre (CSC), Du Cane Road, London W12 0NN, UK; Faculty of Medicine, Institute of Clinical Sciences (ICS), Imperial College London, Du Cane Road, London W12 0NN, UK.
7
Biomolecular Characterization Unit, Center for Sustainable Resource Science, RIKEN, Wako, Saitama 351-0198, Japan.
8
Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain.
9
Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
10
Institut für Biochemie, Stuttgart University, 70569 Stuttgart, Germany.
11
Cellular Memory Laboratory, RIKEN Wako, Saitama 351-0198, Japan. Electronic address: yshinkai@riken.jp.
12
Epigenetics and Cell Fate, University Paris Diderot, Sorbonne Paris Cité, UMR 7216 CNRS, 75013 Paris, France. Electronic address: pierre-antoine.defossez@univ-paris-diderot.fr.

Abstract

DNA methylation is an essential epigenetic mark in mammals that has to be re-established after each round of DNA replication. The protein UHRF1 is essential for this process; it has been proposed that the protein targets newly replicated DNA by cooperatively binding hemi-methylated DNA and H3K9me2/3, but this model leaves a number of questions unanswered. Here, we present evidence for a direct recruitment of UHRF1 by the replication machinery via DNA ligase 1 (LIG1). A histone H3K9-like mimic within LIG1 is methylated by G9a and GLP and, compared with H3K9me2/3, more avidly binds UHRF1. Interaction with methylated LIG1 promotes the recruitment of UHRF1 to DNA replication sites and is required for DNA methylation maintenance. These results further elucidate the function of UHRF1, identify a non-histone target of G9a and GLP, and provide an example of a histone mimic that coordinates DNA replication and DNA methylation maintenance.

KEYWORDS:

DNA methylation; DNA replication; G9a(Ehmt2)/GLP(Ehmt1); UHRF1; epigenetics; lysine methylation

PMID:
28803780
DOI:
10.1016/j.molcel.2017.07.012
[Indexed for MEDLINE]
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