Cancer Res Treat.  2007 Sep;39(3):125-130.

Activation of ATM-dependent DNA Damage Signal Pathway by a Histone Deacetylase Inhibitor, Trichostatin A

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

Abstract

PURPOSE: Ataxia-telangiectasia mutated (ATM) kinase regulates diverse cellular DNA damage responses, including genome surveillance, cell growth, and gene expression. While the role of histone acetylation/deacetylation in gene expression is well established, little is known as to whether this modification can activate an ATM-dependent signal pathway, and whether this modification can thereby be implicated in an ATM-mediated DNA damage response.
MATERIALS AND METHODS
Formation of H2AXgamma foci was examined in HeLa and U2OS cells following treatment with a histone deacetylase inhibitor, Trichostatin A (TSA). We determine an ATM-dependency of the TSA-induced DNA damage signal pathway using isogenic A-T (ATM square) and control (ATM+) cells. We monitored the phosphorylation of ATM, an ATM-downstream effector kinase, Chk2, and H2AXgamma to detect the activation of the ATM-dependent DNA damage signal pathway.
RESULTS
Exposure of cells to TSA results in the formation of H2AXgamma foci in HeLa and U2OS cells. The TSA-induced formation of H2AXgamma foci occurs in an ATM-dependent manner. TSA induces phosphorylation of serine 1981 of ATM, accumulation of phosphorylated H2AX and Chk2, and formation of H2AX foci, in a manner analogous to genotoxic DNA damage.
CONCLUSION
In this work, we show that TSA induces a DNA damage signaling pathway in an ATM-dependent manner. These results suggest that ATM can respond to altered histone acetylation induced by the histone deacetylase inhibitor, TSA.

Keyword

ATM; HDAC inhibition; DNA damage signal pathway

MeSH Terms

Acetylation
Ataxia Telangiectasia
DNA Damage*
DNA*
Gene Expression
Genome
Histone Deacetylase Inhibitors*
Histone Deacetylases*
Histones*
Phosphorylation
Phosphotransferases
Serine
Signal Transduction*
DNA
Histone Deacetylase Inhibitors
Histone Deacetylases
Histones
Phosphotransferases
Serine
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