Activation of ATM-dependent DNA Damage Signal Pathway by a Histone Deacetylase Inhibitor, Trichostatin A.
- Author:
Jong Soo LEE
1
Author Information
1. Department of Biological Sciences, College of Natural Sciences and Department of Molecular Science and Technology, Ajou University, Suwon, Korea. jsjlee@mail.ajou.ac.kr
- Publication Type:Original Article
- Keywords:
ATM;
HDAC inhibition;
DNA damage signal pathway
- MeSH:
Acetylation;
Ataxia Telangiectasia;
DNA Damage*;
DNA*;
Gene Expression;
Genome;
Histone Deacetylase Inhibitors*;
Histone Deacetylases*;
Histones*;
Phosphorylation;
Phosphotransferases;
Serine;
Signal Transduction*
- From:Cancer Research and Treatment
2007;39(3):125-130
- CountryRepublic of Korea
- Language:English
-
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.
