ATM: A mediator of multiple responses to genotoxic stress

Abstract

The ATM protein kinase is the product of the gene responsible for the pleiotropic recessive disorder ataxiatelangiectasia. ATM-de®cient 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 modi®cations induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identi®cation 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 e cient induction of a signaling network responsible for repair of the damage, and for cellular recovery and survival.

Modulation of cellular radiation responses by histone deacetylase inhibitors

“…The current paradigm suggests that ATM is activated following DSB-induced changes in chromatin structure which are recognized by sensor proteins including 53BP1, a DNA damage checkpoint protein conserved in all eukaryotes (Zgheib et al, 2005). Following activation ATM rapidly phosphorylates downstream substrates that are important in DSB response pathways including p53, which has key roles in cell-cycle control and apoptosis (Figure 1), MDM2, CHK1 and CHK2 which are involved in cell-cycle regulation, and BRCA1 and NBS1 which are important in DSB repair (Rotman and Shiloh, 1999;Khanna, 2000;Jackson, 2002).…”

Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB–IIA of cervical cancer

“…DNA-PKcs is a serine/threonine protein kinase belonging to the phosphatidylinositol-3 kinase-related kinase family, which include other large proteins involved in DNA repair signalling, such as ATM and ATR (Shiloh, 2003). Genetic mutations in the ATM or DNA-PKcs gene result in immunodeficiency, cancer susceptibility and hypersensitivity to ionising radiation (Lavin and Shiloh, 1997;Rotman and Shiloh, 1999). However, in contrast to ATM, DNAPKcs deficiency has not been described in humans, as in lower species (Blunt et al, 1995;Wiler et al, 1995;Shin et al, 1997;Meek et al, 2001;Ding et al, 2002).…”

Ataxia-Telangiectasia Mutated Is Not Required for p53 Induction and Apoptosis in Irradiated Epithelial Tissues

“…2). Cells from ataxiatelangiectasia patients have a defect in DNA double-strand break repair and show impaired cell cycle checkpoints, increased chromosome instability, and hypersensitivity to IR (3,4). The Atm gene encodes a 370-kDa protein that has serine/ threonine protein kinase activity (4).…”