Exp Mol Med.  2010 Mar;42(3):195-204. 10.3858/emm.2010.42.3.020.

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

• Jang ER
• Choi JD
• Park MA
• Jeong G
• Cho H
• Lee JS

• KMID: 946652
• DOI: http://doi.org/10.3858/emm.2010.42.3.020

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 Gadd45alpha 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 Gadd45alpha 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.

Keyword

ataxia telangiectasia mutated protein; chromatin; GADD45 protein; histone deacetylases; myeloid cell leukemia sequence 1 protein; transcription, genetic; trichostatin A

MeSH Terms

Cell Cycle Proteins/genetics/*metabolism
DNA Damage/*genetics
DNA-Binding Proteins/*metabolism
E2F1 Transcription Factor/metabolism
Gene Expression Regulation/drug effects
Histone Deacetylase Inhibitors/*pharmacology
Histone Deacetylases/*metabolism
Humans
Hydroxamic Acids/pharmacology
Nuclear Proteins/genetics/metabolism
Promoter Regions, Genetic/genetics
Protein Binding/drug effects
Protein-Serine-Threonine Kinases/*metabolism
Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
RNA, Messenger/genetics/metabolism
*Transcription, Genetic/drug effects
Tumor Suppressor Proteins/*metabolism