Ataxia telangiectasia is an autosomal recessive disorder characterized by neuronal degeneration, telangiectasias, acute cancer predisposition and hypersensitivity to ionizing radiation (IR). The gene defective in this disorder, ATM (for AT-mutated), encodes a protein, pATM, that has been found to have IR-inducible kinase activity. Cells from individuals with AT exhibit severely attenuated cell cycle checkpoint function in response to IR exposure and are hypersensitive to IR-induced killing. It has been suggested that pATM acts as part of a complex that senses DNA damage and in particular DNA double-strand breaks; it has also been speculated that pATM participates in response to oxidative damage. We have been studying pATM-dependent cellular responses to various DNA-damaging agents. As part of this effort, we are investigating global gene expression changes following exposures to IR in both lymphoblast and fibroblast cells from multiple individuals with either normal or defective pATM function. We are comparing gene expression changes in both normal and pATM-deficient cells from one cell type that is predisposed to undergo apoptosis (lymphoblasts) with those in cells predisposed to undergo a prolonged cell cycle arrest (fibroblasts) following IR exposure. In addition, we are comparing these responses to IR in normal and pATM-deficient fibroblasts with responses to exposure to ultraviolet light in the 000- to 000-nm range and reactive oxygen species. These analyses are being performed using National Institute of Environmental Health Sciences Human ToxChips, with approximately 2,000 known complementary DNA clones, as well as with Human Discovery Chips, a collection of approximately 12,000 known and anonymous cDNA