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- Title
Inhibition of DNMT1 methyltransferase activity via glucose-regulated O-GlcNAcylation alters the epigenome.
- Authors
Heon Shin; Leung, Amy; Costello, Kevin R.; Senapati, Parijat; Hiroyuki Kato; Moore, Roger E.; Lee, Michael; Lin, Dimitri; Xiaofang Tang; Pirrotte, Patrick; Zhen Bouman Chen; Schones, Dustin E.
- Abstract
The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-Glc-NAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that preferentially occurs at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.
- Subjects
METHYLTRANSFERASES; DNA methylation; GLUCOSE metabolism; MASS spectrometry; GLUCOSE-regulated proteins; DNA damage; GLYCANS
- Publication
eLife, 2023, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.85595