title: O-linked N-acetylglucosamine transferase (OGT) interacts with the histone chaperone HIRA complex and regulates nucleosome assembly and cellular senescence.
abstract: The histone chaperone HIRA complex, consisting of histone cell cycle regulator (HIRA), Ubinuclein1 (UBN1), and calcineurin binding protein 1 (CABIN1), deposits histone variant H3.3 to genic regions and regulates gene expression in various cellular processes, including cellular senescence. How HIRA-mediated nucleosome assembly of H3.3-H4 is regulated remains not well understood. Here, we show that O-linked N-acetylglucosamine (GlcNAc) transferase (OGT), an enzyme that catalyzes O-GlcNAcylation of serine or threonine residues, interacts with UBN1, modifies HIRA, and promotes nucleosome assembly of H3.3. Depletion of OGT or expression of the HIRA S231A O-GlcNAcylation-deficient mutant compromises formation of the HIRA-H3.3 complex and H3.3 nucleosome assembly. Importantly, OGT depletion or expression of the HIRA S231A mutant delays premature cellular senescence in primary human fibroblasts, whereas overexpression of OGT accelerates senescence. Taken together, these results support a model in which OGT modifies HIRA to regulate HIRA-H3.3 complex formation and H3.3 nucleosome assembly and reveal the mechanism by which OGT functions in cellular senescence.
authors.affiliation: Mayo Graduate School, Biochemistry and Molecular Biology Track, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Jong-Sun
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Mayo Graduate School, Biochemistry and Molecular Biology Track, Mayo Clinic College of Medicine, Rochester, MN 55905; Epigenomics Developmental Program, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905 zhang.zhiguo@mayo.edu.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence / Q000502:physiology*; D057809:HEK293 Cells; D056488:Histone Chaperones / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D018797:Cell Cycle Proteins; C086057:HIRA protein, human; D056488:Histone Chaperones; D006657:Histones; D009687:Nuclear Proteins; D009707:Nucleosomes; D014157:Transcription Factors; C406814:UBN1 protein, human; D017351:N-Acetylglucosaminyltransferases; C063057:UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase
keywords: HIRA; OGT; cellular senescence; histone H3.3; nucleosome assembly