Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States
Amy Leung
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States
Kevin R Costello
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, United States
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States
Hiroyuki Kato
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States
Roger E Moore
Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center Duarte, Duarte, United States
Michael Lee
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, United States
Dimitri Lin
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States
Xiaofang Tang
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States
Patrick Pirrotte
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States; Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center Duarte, Duarte, United States; Cancer & Cell Biology Division, Translational Genomics Research Institute, Phoenix, United States
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, United States
Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, United States; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, United States
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-GlcNAcylated 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.
