Ataxia-telangiectasia: future prospects

Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive multi-system disorder caused by mutation in the ataxia-telangiectasia mutated gene (ATM). ATM is a large serine/threonine protein kinase, a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) family whose best-studied function is as master controller of signal transduction for the DNA damage response (DDR) in the event of double strand breaks (DSBs). The DDR rapidly recognizes DNA lesions and initiates the appropriate cellular programs to maintain genome integrity. This includes the coordination of cell-cycle checkpoints, transcription, translation, DNA repair, metabolism, and cell fate decisions, such as apoptosis or senescence. DSBs can be generated by exposure to ionizing radiation (IR) or various chemical compounds, such as topoisomerase inhibitors, or can be part of programmed generation and repair of DSBs via cellular enzymes needed for the generation of the antibody repertoire as well as the maturation of germ cells. AT patients have immunodeficiency, and are sterile with gonadal dysgenesis as a result of defect in meiotic recombination. In the cells of nervous system ATM has additional role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Moderate levels of ATM are associated with prolonged lifespan through resistance to oxidative stress. ATM inhibitors are being viewed as potential radiosensitizers as part of cancer radiotherapy. Though there is no cure for the disease at present, glucocorticoids have been shown to induce alternate splicing site in the gene for ATM partly restoring its activity, but their most effective timing in the disease natural history is not yet known. Gene therapy is promising but large size of the gene makes it technically difficult to be delivered across the blood-brain barrier at present. As of now, apart from glucocorticoids, use of histone deacetylase inhibitors/EZH2 to minimize effect of the absence of ATM, looks more promising.

Keywords: ATM; double-stranded DNA breaks; neurodegeneration.

Figure 1

PIKK family members, Notes: The PIKK family members have a C-terminal protein kinase domain flanked on either side by an N-terminal FAT-domain and a C-terminal FAT-C domain with PIKK regulatory domain (PRD). The N-termini are largely composed of HEAT repeats. Abbreviations: ATM, ataxia-telangiectasia mutated gene; FAT, FRAP, ATM, TRRAP; HEAT, Huntingtin, elongation factor 3, protein phosphatase 2A, and yeast kinase TOR.

Figure 2

Activation of ATM. Notes: (A) Schematic of the ATM protein with domain organization. (B) Activation of ATM by DNA damage or hypotonic stress requires the Mre11 complex, or ATMIN, respectively. Activated ATM is monomeric, phosphorylated and acetylated. Alternatively, ATM is activated directly by ROS to form disulfide bridge-mediated dimer. Abbreviations: Ac, acetylation; ATM, ataxia-telangiectasia mutated gene; ATMIN, ATM interacting protein-acting as mediator of ATM activation in response to hypotonic stress or chloroquine treatment; FAT, FRAP, ATM, TRRAP; HEAT, Huntingtin, elongation factor 3, protein phosphatase 2A, and yeast kinase TOR; P, phosphorylation; ROS, Reactive Oxygen Species; SS, disulfide bridge between the two monomeric ATM protein molecules.