The structure of ATM. Ataxia telangiectasia, mutated (ATM) is a large protein that has carboxy-terminal similarity to other proteins of the phosphatidylinositol-3-OH-kinase (PI(3)K) family. Two other representative protein kinases—ATM-Rad3 related (ATR) and the catalytic subunit of the DNA-dependent protein kinase (DNAPK_cs)—are included for comparison. Each of these PI(3)K members contain similar domains: a FAT domain, so named because it is a common motif in other related proteins, including FRAPP/ATM/TRRAP; the PI(3)K domain that was initially used to assign ATM to the PI(3)K family; and a FATC domain that represents a common C-terminal amino-acid sequence found near the termini of the protein. The blue lines indicate nuclear localization signals and the pink line indicates a leucine zipper region within ATM.

Ataxia telangiectasia. Ataxia telangiectasia (AT) is a multisystem syndrome that results from the mutation of ATM (ataxia telangiectasia, mutated); the hallmark of clinical presentation is a debilitating progressive neurodegeneration. Other characteristics are extreme radiosensitivity, immunodeficiency, a predisposition to cancer (haematopoietic malignancy) and sterility due to defective meiotic recombination. Ocular and facial telangiectasia are also associated with AT.

ATM and DNA damage signalling. In response to a DNA double-stranded break (A) several simultaneous events occur to ultimately activate ATM signal transduction. ATM exists as an inactive multimeric complex that, in response to DNA damage, undergoes autophosphorylation to an active monomer (B). A histone variant, histone H2AX, present within chromatin, becomes phosphorylated and serves as a tethering platform for repair factors. The MRE11–RAD50–NBS1 complex locates to the DNA lesion together with BRCA1 (C). Assembly of this complex facilitates coordinated co-localization of active ATM together with other factors including MDC1/NFBD1 and 53BP1. BRCA1, MDC1 and 53BP1 are also phosphorylated in an ATM-dependent manner (D). The assembly of this multiprotein complex facilitates the cellular response to a DNA double-stranded break. 53BP1, p53-binding protein 1; ATM, ataxia telangiectasia, mutated; BRCA1, breast-cancer-associated 1; MDC1, mediator of damage checkpoint 1.