ATM, the gene product mutated in the cancer susceptibility syndrome ataxia?telangiectasia, is related to proteins involved in DNA repair and cell-cycle control. It encodes a nuclear 350 kDa phosphoprotein containing a carboxy terminus phosphatidylinositol 3-kinase (Pl-3 kinase) catalytic domain shared by members of a superfamily of large eukaryotic proteins involved in intracellular signaling, DNA-damage induced cell cycle checkpoints, DNA repair and recombination. It was discovered as mutated proteins in patients with ataxia-telagiectasia (A-T), a severe genetic disorder characterized by cerebellar degeneration, neuromotor dysfunction, chromosomal instability, immune system defects, cancer predisposition, and acute sensitivity to ionizing radiations. In undamaged cells it is present as a dimer or oligomer molecule in which the kinase domain is silent because associated with the FAT region of another ATM monomer. Following DSB formation, it rapidly autophosphorylates on residue Serine 1981, and the inactive ATM dimers are converted (dissociated) into active ATM monomers. Active phosphorylated ATM molecules interact and phosphorylate downstream proteins that affect one or more of the cell cycle checkpoints. Some of the known substrates are the p53 protein and its ubiquitin ligase, MDM2; the Nbs1 protein; the Brca1 protein, which interacts with other repair proteins; the checkpoint kinase 2, Chk2; the Rad17 protein and the chromatin remodeling protein SMC1. Phylogenetic analyses reveal that the ATM protein is most closely related to several very large proteins that define a subgroup of the PI 3-kinase family which include the Schizosaccharomyces pombe Rad3 protein and its probable Saccharomyces cerevisiae homologue, Mec1p/Esr1p. Other proteins in the ATM family are S. cerevisiae Tor1p and Tor2p and their mammalian counterpart FRAP, which function, at least in part, by controlling progression through the G1 phase of the cell cycle. The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide and also assists cells in recognizing damaged or broken strands of DNA. It has been suggested that it acts as a lipid kinase, and feeds the phosphorylated lipids into signaling pathways to regulate cell-cycle progression or the activity of DNA-repair components. It regulates NF-κB activity and control the transcription of many genes that play important roles in the development and function of the immune system. In the DNA-damage response pathway, it acts upstream of p53 to induce cell cycle arrest at the G1/S and G2/M boundaries and a slowing of the S-phase. Signalling by ATM involves interactions with and phosphorylation of critical molecules, including the mitotic checkpoints Chk1 and Chk2. Apart from its role in ataxia telangiectasia (AT), ATM gene mutations have also been found in T-cell prolymphocytic leukaemia patients with no family history of AT and in non-Hodgkin's lymphomas.