title: ATM modulates transcription in response to histone deacetylase inhibition as part of its DNA damage response.
abstract: Chromatin structure has a crucial role in a diversity of physiological processes, including development, differentiation and stress responses, via regulation of transcription, DNA replication and DNA damage repair. Histone deacetylase (HDAC) inhibitors regulate chromatin structure and activate the DNA damage checkpoint pathway involving Ataxia-telangiectasia mutated (ATM). Herein, we investigated the impact of histone acetylation/deacetylation modification on the ATM-mediated transcriptional modulation to provide a better understanding of the transcriptional function of ATM. The prototype HDAC inhibitor trichostain A (TSA) reprograms expression of the myeloid cell leukemia-1 (MCL1) and Gadd45 genes via the ATM-mediated signal pathway. Transcription of MCL1 and Gadd45alpha is enhanced following TSA treatment in ATM(+) cells, but not in isogenic ATM(-) or kinase-dead ATM expressing cells, in the ATM-activated E2F1 or BRCA1- dependent manner, respectively. These findings suggest that ATM and its kinase activity are essential for the TSA-induced regulation of gene expression. In summary, ATM controls the transcriptional upregulation of MCL1 and Gadd45 through the activation of the ATM-mediated signal pathway in response to HDAC inhibition. These findings are important in helping to design combinatory treatment schedules for anticancer radio- or chemo-therapy with HDAC inhibitors.
authors.affiliation: Department of Molecular Science and Technology, College of Natural Sciences, Ajou University, Suwon 443-749, Korea.
authors.forename: Eun Ryoung
authors.initials: ER
authors.lastname: Jang
authors.forename: Jae Duk
authors.initials: JD
authors.lastname: Choi
authors.forename: Mi Ae
authors.initials: MA
authors.lastname: Park
authors.forename: Gajin
authors.initials: G
authors.lastname: Jeong
authors.forename: Hyeseong
authors.initials: H
authors.lastname: Cho
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Lee
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C493753:E2F1 protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C012589:trichostatin A; C576324:ATM protein, human