title: The stress-responsive gene ATF3 regulates the histone acetyltransferase Tip60.
abstract: Tat-interactive protein 60 (Tip60) is a MYST histone acetyltransferase that catalyses acetylation of the major DNA damage kinase Ataxia telangiectasia mutated (ATM), thereby triggering cellular signalling required for the maintenance of genomic stability on genotoxic insults. The Tip60 activity is modulated by post-translational modifications that alter its stability and its interactions with substrates. Here we report that activating transcription factor 3 (ATF3), a common stress mediator and a p53 activator, is a regulator of Tip60. ATF3 directly binds Tip60 at a region adjacent to the catalytic domain to promote the protein acetyltransferase activity. Moreover, the ATF3-Tip60 interaction increases the Tip60 stability by promoting USP7-mediated deubiquitination of Tip60. Consequently, knockdown of ATF3 expression leads to decreased Tip60 expression and suppression of ATM signalling as evidenced by accumulated DNA lesions and increased cell sensitivity to irradiation. Our findings thus reveal a previously unknown function of a common stress mediator in regulating Tip60 function.
authors: 1] GRU Cancer Center, Georgia Regents University, 1120 15th Street, Augusta, Georgia 30912, USA [2] Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA.
authors: Hongmei
authors: H
authors: Cui
authors: Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA.
authors: Mingxiong
authors: M
authors: Guo
authors: Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA.
authors: Dong
authors: D
authors: Xu
authors: GRU Cancer Center, Georgia Regents University, 1120 15th Street, Augusta, Georgia 30912, USA.
authors: Zhi-Chun
authors: ZC
authors: Ding
authors: 1] GRU Cancer Center, Georgia Regents University, 1120 15th Street, Augusta, Georgia 30912, USA [2] Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, Georgia 30912, USA.
authors: Gang
authors: G
authors: Zhou
authors: 1] GRU Cancer Center, Georgia Regents University, 1120 15th Street, Augusta, Georgia 30912, USA [2] Department of Pathology, Georgia Regents University, 1120 15th Street, Augusta, Georgia 30912, USA.
authors: Han-Fei
authors: HF
authors: Ding
authors: Department of Radiation Oncology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
authors: Junran
authors: J
authors: Zhang
authors: Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA.
authors: Yi
authors: Y
authors: Tang
authors: 1] GRU Cancer Center, Georgia Regents University, 1120 15th Street, Augusta, Georgia 30912, USA [2] Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Avenue, Albany, New York 12208, USA [3] Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, 1120 15th Street, Augusta, Georgia 30912, USA.
authors: Chunhong
authors: C
authors: Yan
mesh_terms: D000107:Acetylation; D051700:Activating Transcription Factor 3 / Q000235:genetics* / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7; D054875:Ubiquitination
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7