The ATM gene is mutated in individuals with ataxia telangiectasia, a human genetic disease characterized by extreme sensitivity to radiation. The ATM protein acts as a sensor of radiation-induced cellular damage and contributes to cell cycle regulation, signal transduction, and DNA repair; however, the mechanisms underlying these functions of ATM remain largely unknown. Binding and immunoprecipitation assays have now shown that ATM interacts with the histone deacetylase HDAC1 both in vitro and in vivo, and that the extent of this association is increased after exposure of MRC5CV1 human fibroblasts to ionizing radiation. Histone deacetylase activity was also detected in immunoprecipitates prepared from these cells with antibodies to ATM, and this activity was blocked by the histone deacetylase inhibitor trichostatin A. These results suggest a previously unanticipated role for ATM in the modification of chromatin components in response to ionizing radiation.The human genetic disease ataxia telangiectasia (AT), 1 which is characterized by extreme sensitivity to radiation, is caused by mutations in the ATM gene (1, 2). The protein encoded by this gene acts as a sensor of radiation-induced cellular damage and plays important roles in cell cycle regulation, signal transduction, and DNA repair (2-6). However, the mechanisms by which ATM performs these various functions remain largely uncharacterized.Exposure of cells to ionizing radiation results in the arrest of cell cycle progression, induction of the transcription of specific genes, modification of nucleosomal structure, and activation of the DNA repair machinery (3, 6). Histone acetylation and deacetylation are thought to play important roles in the modification of chromatin structure and in monitoring chromosomal integrity during the cell cycle and transcriptional regulation (7-9). Various non-histone proteins that participate in regulation of the cell cycle and transcription are associated with histone acetylation or deacetylation activities (10 -14). Certain transcriptional coactivators, including pCAF, BRCA2, and ATM-like proteins, possess intrinsic acetylation activities (15-18). Conversely, transcriptional repressors have been shown to associate with histone deacetylases (19 -24). Recent studies have shown that the product of the retinoblastoma gene (Rb) represses transcription of the E2F gene by recruiting the mammalian deacetylase proteins HDAC1 and HDAC2, to which it binds through an LXCXE motif in its pocket domain (24 -27).Sequence analysis has revealed that the NH 2 terminus of ATM contains an LXCXE motif (amino acids 115-119) (Fig. 1a). We therefore investigated whether ATM also interacts with HDAC1. We have now shown that the two proteins indeed interact both in vitro and in vivo and that the extent of the association in vivo is increased by exposure of the cells to ionizing radiation. EXPERIMENTAL PROCEDURESCell Culture and Irradiation-Human normal (MRC5CV1) and AT (AT5BIVA, AT4BIVA, and AT3BIVA) fibroblasts were maintained at 37°C under an atmosphe...