The versatile functions of ATM kinase

G enetic diseases with cancer predisposition phenotypes provide insights into essential roles of the involved genes and their products in the maintenance of genome stability, as genome instability is one of the hallmarks of cancer. Ataxia-telangiectasia (A-T), a rare autosomal recessive disorder, is such an example. A-T is caused by mutations in the ataxia-telangiectasia mutated (ATM) gene, located on human chromosome 11q22.3. Depending on the extent of the mutation, the resultant loss of ATM protein expression or function can lead to pleiotropic clinical phenotypes, including a characteristic lack of coordination in limbs due to progressive neurodegeneration, predisposition to hematological malignancies (typically leukemia and lymphoma), immunodeficiency, as well as hypersensitivity to ionizing irradiation. The classical presentation of A-T is the result of two truncation mutations in ATM, subsequently leading to a loss of function in the ATM protein, with a less severe form of A-T that is usually associated with missense mutations or leaky splice sites within the ATM gene. This is typically attributed to defects on both alleles resulting in compound heterozygosity for a truncating mutation. The resulting translated ATM protein is not stable and, therefore, not functional. This type of loss of function is the main contributor to the radiosensitive phenotype in the patients.