In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell-cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others.

Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients—children and adults alike—which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.

Introduction Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by a broad spectrum of disease phenotypes that can be viewed from many perspectives, much like the Indian parable of the blind men probing different parts of an elephant while not seeing the entirety of the animal, because each relies on only 1 methodology—his touch. The A-T phenotype is similarly complex and includes progressive neuronal degeneration, ocular telangiectasias, variable immunodeficiency, and cancer susceptibility, - whereas the overall functions of the ataxia telangiectasia mutated (ATM) protein suggest a much broader pathology. Multivac c200 manual. Indeed, the extended phenotype can include growth retardation, premature aging, insulin resistance, manifestations of mitochondrial dysfunction, inadequate responses to oxidative stress, and adverse reactions to the DNA-damaging agents commonly used to treat cancer. Cells derived from A-T patients exhibit cytoskeletal abnormalities, requirements for serum growth factors and clastogenic factors,,, chromosomal instabilities, - chromatin changes, hypersensitivity to ionizing radiation,, and aberrant checkpoint controls.

The gene responsible for A-T was first localized to chromosome 11q22.3-23.1 by Gatti et al using mathematical analysis of cosegregation (linkage) data. During the next 7 years, the region was “fine mapped” by an international consortium, - and then identified as the ATM gene by Savitsky et al. ATM is a high-molecular-weight (350 kDa) protein kinase, and it is a member of the large phosphoinositidyl 3-kinase-related protein kinase (PIKK) family; other family members include the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), A-T and Rad3-related protein (ATR), mammalian target of rapamycin (mTOR)/FKBP-rapamycin-associated protein (mTOR/FRAP), and ATX/SMG.,, Much of the structural similarity of these proteins lies in their domains for (1) kinase activity; (2) FRAP-ATM-TRRAP (FAT); and (3) C-terminal FAT (FATC) and binding sites for p53, BLM, and other ATM-binding proteins. In steady-state cells, ATM appears to exist as an inactive dimer/tetramer that can be rapidly activated and recruited to sites of double-strand breaks (DSBs) by the Mre11-Rad50-NBS1 (MRN complex) proteins via its interaction with the C-terminal domain of NBS1.

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ATM responses to oxidative stress The DNA of eukaryotic cells is continuously exposed to reactive oxygen species (ROS) generated either by exposure to physical sources (UV light and ionizing radiation), or via the physiological functions of numerous intracellular enzymes, including NADPH oxidases, xanthine oxidase, cyclooxygenases, cytochrome P450, lipoxygenases, and those of immune cells., However, the vast majority of intracellular ROS is produced by the respiratory chain in the mitochondria. ROS are an important class of toxicants that are capable of causing damage to lipids and proteins and are able to generate a plethora of DNA lesions, including oxidized DNA bases, apurinic/apyrimidinic (AP) sites, and single- and double-strand breaks., When the damage caused by ROS exceeds the cells’ capacity for repair, a general self-perpetuating state of oxidative stress is produced. Conversely, reducing the oxidation of ATM should (1) improve the efficiency of DNA repair by increasing ATM kinase activity; and (2) reduce cancer risk. Early studies showed that A-T fibroblasts were more susceptible than normal cells to oxidative damage caused by the prooxidant, hydrogen peroxide (H 2O 2). In addition, A-T cells were hypersensitive to ROS produced by activated neutrophils and by the xanthine oxidase. Together, these observations prompted Rotman and Shiloh, to suggest that A-T is in essence a disorder of oxidative stress and that ATM might well act as a sensor for redox homeostasis. Since that time, ATM-deficient cells have consistently exhibited overwhelming sensitivity to agents that generate ROS and cause oxidative DNA damage, such as IR, t-butyl hydroperoxide, chromium IV, and nitric oxide (NO)., Moreover, the basal expression levels of several different oxidative-damage responsive pathways involving p53, p21, Gadd45, NFκB, hemeoxygenase (HO-1), and manganese superoxide dismutase (MnSOD), have been shown as constitutively elevated in A-T cells and in certain tissues from Atm −/− mice.