ABSTRACT

ATM is a member of the phosphatidylinositol 3-kinase-like family of serine/threonine protein kinases (PIKKs). Other members of this family include the ATM-and Rad 3-related (ATR) kinase that responds to singlestranded DNA, stalled or collapsed DNA replication forks, and the DNAdependent protein kinase catalytic subunit (DNA-PKcs), which is a DNA double-strand break (DSB) repair protein. In an unperturbed cell, ATM exists as an inactive dimer (or higher-order oligomer). e introduction of DNA-DSB by ionizing radiation or other insults is sensed by the telomeric protein TRF2 and the MRE11-RAD50-NBS1 (MRN) complex causing the subsequent activation of the ATM kinase, which in turn activates signal transduction pathways essential for coordinating cell cycle progression with DNA repair. During this process, ATM, together with DNA-PKcs, phosphorylates the histone H2AX (called γ-H2AX when phosphorylated on serine residue 139) along megabase-length tracks surrounding a DNA break. Activated ATM phosphorylates several downstream substrates that contribute to the proper regulation of IR-induced arrests in G1 phase (p53, Mdm2, and Chk2), S phase (Nbs1, Smc1, Brca1, and FancD2), and G2 phase (BRCA1 and Rad17) of the cell cycle.