ATM: a mediator of multiple responses to genotoxic stress.
The ATM protein kinase is the product of the gene responsible for the pleiotropic recessive disorder ataxia-telangiectasia. ATM-deficient cells show enhanced sensitivity and greatly reduced responses to genotoxic agents that generate DNA double strand breaks (DSBs), such as ionizing radiation and radiomimetic chemicals, but exhibit normal responses to DNA adducts and base modifications induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identification of the ATM gene triggered extensive research aimed at elucidating the numerous functions of its large multifaceted protein product. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in the nucleus where it plays a central role in the very early stages of damage detection and serves as a master controller of cellular responses to DSBs. By activating key regulators of multiple signal transduction pathways, ATM mediates the efficient induction of a signaling network responsible for repair of the damage, and for cellular recovery and survival.
Rotman
G
G
Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
Shiloh
Y
Y
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000502:physiology / Q000528:radiation effects; D018797:Cell Cycle Proteins; D002470:Cell Survival; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics* / Q000502:physiology* / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases