title: Acetylation Enhances TET2 Function in Protecting against Abnormal DNA Methylation during Oxidative Stress.
abstract: TET proteins, by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), are hypothesized, but not directly shown, to protect promoter CpG islands (CGIs) against abnormal DNA methylation (DNAm) in cancer. We define such a protective role linked to DNA damage from oxidative stress (OS) known to induce this abnormality. TET2 removes aberrant DNAm during OS through interacting with DNA methyltransferases (DNMTs) in a "Yin-Yang" complex targeted to chromatin and enhanced by p300 mediated TET2 acetylation. Abnormal gains of DNAm and 5hmC occur simultaneously in OS, and knocking down TET2 dynamically alters this balance by enhancing 5mC and reducing 5hmC. TET2 reduction results in hypermethylation of promoter CGIs and enhancers in loci largely overlapping with those induced by OS. Thus, TET2 indeed may protect against abnormal, cancer DNAm in a manner linked to DNA damage.
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Yang W
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, University of the Sciences, Philadelphia, PA 19104, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Hariharan
authors.initials: H
authors.lastname: Easwaran
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Ray-Whay Chiu
authors.initials: RC
authors.lastname: Yen
authors.affiliation: Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Yana
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: sbaylin@jhmi.edu.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D000107:Acetylation; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D045325:HCT116 Cells; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination
chemical_list: D002843:Chromatin; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D049308:Dioxygenases; C541081:TET2 protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
keywords: 5hmC; DNA demethylation; DNA methylation; TET2; acetylation; cancer; oxidative stress