Is Ataxia Telangiectasia a Result of Impaired Coordination between DNA Repair and Cell Cycle Checkpoint Regulators?

Abstract

Ataxia telangiectasia (AT) is an autosomal recessive multisystem human disorder and patients are characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, chromosomal instability and radio sensitivity with an increased predisposition to lymphoid cancer in childhood. The gene responsible for AT, ataxia telangiectasia mutated (ATM), has been cloned and its protein product has been biochemically characterized as a serine/threonine kinase belonging to the family of phosphatidylinositol (PI-3) like kinases. Subsequent biochemical studies by several laboratories have identified a number of DNA repair and cell cycle proteins that are phosphorylated by ATM kinase in response to different DNA damaging agents. One intriguing question that comes to mind is whether the phenotypic features of AT stem from a DNA repair defect or a cell cycle defect or both. The scope of this review is focused on the potential functions of ATM in both DNA repair and cell cycle checkpoint regulation and how deficiencies in these overlapping functions can lead to some of the phenotypic features of AT patients.