Cancer Res Treat.  2007 Sep;39(3):116-124.

Functional Link between DNA Damage Responses and Transcriptional Regulation by ATM in Response to a Histone Deacetylase Inhibitor TSA

Affiliations
  • 1Department of Biological Sciences, College of Natural Sciences and Department of Molecular Science and Technology, Ajou University, Suwon, Korea. jsjlee@ajou.ac.kr

Abstract

PURPOSE: Mutations in the ATM (ataxia-telangiectasia mutated) gene, which encodes a 370 kd protein with a kinase catalytic domain, predisposes people to cancers, and these mutations are also linked to ataxia-telangiectasia (A-T). The histone acetylaion/deacetylation- dependent chromatin remodeling can activate the ATM kinase-mediated DNA damage signal pathway (in an accompanying work, Lee, 2007). This has led us to study whether this modification can impinge on the ATM-mediated DNA damage response via transcriptional modulation in order to understand the function of ATM in the regulation of gene transcription.
MATERIALS AND METHODS
To identify the genes whose expression is regulated by ATM in response to histone deaceylase (HDAC) inhibition, we performed an analysis of oligonucleotide microarrays with using the appropriate cell lines, isogenic A-T (ATM square) and control (ATM+) cells, following treatment with a HDAC inhibitor TSA.
RESULTS
Treatment with TSA reprograms the differential gene expression profile in response to HDAC inhibition in ATM square cells and ATM+ cells. We analyzed the genes that are regulated by TSA in the ATM-dependent manner, and we classified these genes into different functional categories, including those involved in cell cycle/DNA replication, DNA repair, apoptosis, growth/differentiation, cell- cell adhesion, signal transduction, metabolism and transcription.
CONCLUSION
We found that while some genes are regulated by TSA without regard to ATM, the patterns of gene regulation are differentially regulated in an ATM-dependent manner. Taken together, these finding indicate that ATM can regulate the transcription of genes that play critical roles in the molecular response to DNA damage, and this response is modulated through an altered HDAC inhibition-mediated gene expression.

Keyword

ATM; HDAC inhibition; Transcriptional modulation

MeSH Terms

Apoptosis
Ataxia Telangiectasia
Catalytic Domain
Cell Adhesion
Cell Line
Chromatin Assembly and Disassembly
DNA Damage*
DNA Replication
DNA*
Gene Expression
Histone Deacetylase Inhibitors*
Histone Deacetylases*
Histones*
Metabolism
Oligonucleotide Array Sequence Analysis
Phosphotransferases
Signal Transduction
Transcriptome
DNA
Histone Deacetylase Inhibitors
Histone Deacetylases
Histones
Phosphotransferases
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