Radiosensitivity: a role of ATM in chromatin modification

Chromatin architecture plays an important role in DNA-template based processes, including transcription, DNA damage repair, replication, and apoptosis. Post-translational modification of histones and non-histone proteins through actions of histone acetyltransferase (HAT) and histone deacetylase (HDAC) regulates chromatin conformation, resulting in the control of accessibility of proteins to target sites. Some of these proteins are involved in cell cycle regulation and DNA damage repair process (ie. Rb, E2F1, p21, p53 and BRCA 1 and 2). However, the mechanism underlying the role of chromatin modification on cellular intrinsic radiation sensitivity is poorly understood. Ataxia-telangiectasia mutated (ATM), the product of the gene mutated in cells from patients with the radiation sensitivity syndrome of ataxia-telangiectasia, has been shown to be involved in multiple DNA damage-induced signal transduction pathways. Previously, we have observed that ATM interacts with histone deacetylase HDAC1 both in vivo and in vitro and its complex exhibits deacetylase activity in response to ionizing radiation. Further studies have suggested that ATM is involved in the regulation of p53 via post-translational modification. Using isogenic AT cell lines, which show radiation sensitivity differences (Do 0.7 and 1.4 Gy), we performed microarray analyses of gene expression at various intervals following irradiation. These data provide evidence for distinctive ATM-dependent or -independent radiation-mediated gene regulation patterns