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.

Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome

“…ATM encodes a high molecular weight (~350 kDa) multifunctional serine/threonine nuclear kinase [5], [19] which possesses a C-terminal protein kinase domain and belongs to the large PIKK (phosphoinositide 3-kinase related kinase) family [20], [21], [22]. This group also includes ATR (ATM and Rad3-related), DNA-PKcs (DNA-dependent protein kinase catalytic subunit), mTOR (mammalian target of rapamycin), and SMG-1 (suppressor with morphological effect on genitalia family member) protein [19], [20].…”

“…A fraction of ATM is also localised in mitochondria [12] and ATM plays a crucial role in the anti-oxidative response to enhanced ROS levels and accumulated oxidative DNA damage [23], [24], [25], [26]. ATM can therefore be regarded as an important part of the cellular redox regulatory system [21], [22], [27].…”

“…bleomycin and neocarzinostatin). Importantly, in patients with A-T either the DNA repair of DSBs is defective or detection of their presence in the cell is impaired [4], [21]. Furthermore, loss or inactivation of the ATM protein kinase is associated with an inadequate response to the p53 protein or c-Abl tyrosine kinase [4], [21], [22], [27] and contributes to the development of T-cell malignancies [12].…”

“…Importantly, in patients with A-T either the DNA repair of DSBs is defective or detection of their presence in the cell is impaired [4], [21]. Furthermore, loss or inactivation of the ATM protein kinase is associated with an inadequate response to the p53 protein or c-Abl tyrosine kinase [4], [21], [22], [27] and contributes to the development of T-cell malignancies [12]. Therefore, extreme radiosensitivity, one of the main features of A-T cells, may reflect an innate susceptibility to increased oxidative stress caused by the accumulation of oxidative-damaged DNA and defects in DNA repair mechanisms [9], [27].…”

Gender-Specific Associations betweenCHGBGenetic Variants and Schizophrenia in a Korean Population

“…This result suggests that the non-synonymous variation may have a cis-acting effect on subsequent amino acid phosphorylation of CHGB, resulting in a considerable susceptibility to schizophrenia (OR=0.65 at rs910122). In addition, other protein kinases of PIKKs that were predicted to phosphorylate the motif including rs6133278 (Asp145Asn) in our in silico analysis (Table 3) have been reported to be associated with several neural activities, such as neuronal development and synaptic plasticity 3233. Among the PIKKs, the mammalian target of rapamycin kinase signaling is related to several cognitive disorders, including schizophrenia 34.…”