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ATM modulates transcription in response to histone deacetylase inhibition as part of its DNA damage response.

Authors
Jang, ER; Choi, JD; Park, MA; Jeong, G; Cho, H; Lee, JS
Citation
Experimental & molecular medicine, 42(3):195-204, 2010
Journal Title
Experimental & molecular medicine
ISSN
1226-36132092-6413
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.
MeSH terms
Cell Cycle Proteins/geneticsCell Cycle Proteins/metabolism*DNA Damage/genetics*DNA-Binding Proteins/metabolism*E2F1 Transcription Factor/metabolismGene Expression Regulation/drug effectsHistone Deacetylase Inhibitors/pharmacology*Histone Deacetylases/metabolism*HumansHydroxamic Acids/pharmacologyNuclear Proteins/geneticsNuclear Proteins/metabolismPromoter Regions, Genetic/geneticsProtein Binding/drug effectsProtein-Serine-Threonine Kinases/metabolism*Proto-Oncogene Proteins c-bcl-2/geneticsProto-Oncogene Proteins c-bcl-2/metabolismRNA, Messenger/geneticsRNA, Messenger/metabolismTranscription, Genetic*/drug effectsTumor Suppressor Proteins/metabolism*
DOI
10.3858/emm.2010.42.3.020
PMID
20164679
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
AJOU Authors
조, 혜성
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