title: Activation of ATM-dependent DNA damage signal pathway by a histone deacetylase inhibitor, trichostatin A.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Formation of H2AXgamma foci was examined in HeLa and U(2)OS 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(-)) 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 U(2)OS 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biological Sciences, College of Natural Sciences and Department of Molecular Science and Technology, Ajou University, Suwon, Korea. jsjlee@mail.ajou.ac.kr
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Lee