Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions

School of Medicine, University of Tasmania, Hobart, TAS, Australia
Blood (Impact Factor: 10.45). 02/2013; 121(20). DOI: 10.1182/blood-2012-09-456897
Source: PubMed


Twenty-five years ago, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells ATM is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high molecular weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell signaling pathways involved in cell cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients -- children and adults alike -- which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. Most exciting recently is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.

8 Reads
    • "However, the cause of the most serious manifestation of this disease – the progressive cerebellar degeneration – is still being debated [74] [75] [76] [77] [78]. This debate is fueled by evidence that ATM's capacity as a protein kinase is also exploited in signaling pathways that are not associated with DNA damage, some of which are even cytoplasmic [64] [66] [68] [71] [79]. Investigators have suggested that the ATM functions whose loss is responsible for the cerebellar atrophy in A-T could be those that are associated with ATM's non-DDR roles [64,68,76,79–81]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: •The ATM protein kinase mobilizes the cellular response to DNA double-strand breaks.•Evidence is presented that ATM also regulates other aspects of genome stability.•ATM may have a more general role in maintaining genome integrity than previously thought.
    Experimental Cell Research 09/2014; 329(1). DOI:10.1016/j.yexcr.2014.09.002 · 3.25 Impact Factor
  • Source
    • "Interestingly, in patients who received either anthracycline-based or CMF adjuvant chemotherapy , low ATM level was associated with poor survival, implying that ATM may also predict response to chemotherapy. The data appear to be counterintuitive in that several preclinical studies have suggested that ATM-deficient cells are sensitive to cytotoxic chemotherapy and radiotherapy [1] [2] [3] [4]. However, our data would concur with a recent report in breast cancers that showed a poor survival in patients with low ATM who received adjuvant/ neoadjuvant chemotherapy [31]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: ATM-Chk2 network is critical for genomic stability and its deregulation may influence breast cancer pathogenesis. We investigated ATM and Chk2 protein levels in two cohorts [cohort 1 (n=1650) and cohort 2 (n= 252)]. ATM and Chk2 mRNA expression was evaluated in the Metabric cohort (n=1950). Low nuclear ATM protein level was significantly associated with aggressive breast cancer including larger size tumours, higher tumour grade, higher mitotic index, pleomorphism , tumour type , lymphovascular invasion, ER- , PR-, AR-, triple negative and basal-like phenotypes (ps<0.05). BRCA1 negative, low XRCC1, low SMUG1, high FEN1, high MIB1, p53 mutants, low MDM2, low Bcl-2, low p21, low Bax, high CDK1 and low Chk2 were also more frequent in tumours with low nuclear ATM level (ps<0.05). Low ATM protein level was significantly associated with poor survival including in patients with ER- negative tumours who received adjuvant anthracycline or CMF based adjuvant chemotherapy (ps<0.05). Low nuclear Chk2 protein was likely in ER-/PR-/AR-, HER- 2 positive, BRCA1 negative, low XRCC1, low SMUG1, low APE1, low polβ, low DNA-PKcs, low ATM, low Bcl-2 and low TOPO2A tumours (p<0.05). In patients with ER+ tumours who received endocrine therapy or ER- negative tumours who received chemotherapy, nuclear Chk2 levels did not significantly influence survival. In p53 mutant tumours, low ATM (p<0.000001) or high Chk2 (p<0.01) was associated with poor survival. When investigated together, low ATM/high Chk2 tumours have the worst survival (p=0.0033). Our data suggests that ATM-Chk2 levels in sporadic breast cancer may have prognostic and predictive significance.
    Neoplasia 09/2014; 16(11). DOI:10.1016/j.neo.2014.09.009 · 4.25 Impact Factor
  • Source
    • "Mitochondria are crucial to metabolism, cell-cycle progression, signaling, and apoptosis. One of the striking aspects of the ATMdependent pathology is that the mitochondria leads to inefficient respiration and energy metabolism plus the increased generation of free radicals that are able to create life-threatening DNA lesions (Ambrose and Gatti 2013). We have observed an apparent discrepancy between the increased mitochondrial copy number in the A. nidulans DatmA mutant and defects in glucose uptake and oxygen consumption in this mutant. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The coordination of cell growth and division with nutrient availability is crucial for all microorganisms to successfully proliferate in a heterogeneous environment. Mitochondria supply cellular energy but also perform a role in the adaptation to metabolic stress and the cross-talk between prosurvival and prodeath pathways. In mammalian cells the ATM kinases acts as a redox sensor controlling mitochondrial function. Subsequently, transcriptomic and genetic studies were utilised to elucidate the role played by a fungal ATM homologue during carbon starvation. The present study of Aspergillus nidulans demonstrates that AtmA also controlled mitochondrial mass, function and oxidative phosphorylation, which directly or indirectly influenced glucose uptake. Carbon-starvation responses, including autophagy, shifting metabolism to the glyoxylate cycle and the secretion of carbon scavenging enzymes were AtmA-dependent. Transcriptomic profiling of the carbon starvation response demonstrated how TOR signalling and the retrograde response, which signals mitochondrial dysfunction, were directly or indirectly influenced by AtmA. The AtmA kinase was also shown to influence a p53-like transcription factor, inhibiting starvation induced XprG-dependent protease secretion and cell death. Therefore, in response to metabolic stress AtmA appears to perform a role in the regulation of TOR signalling, involving the retrograde and SnfA pathways. Thus AtmA may represent a link between mitochondrial function and cell cycle or growth, possibly through the influence of the TOR and XprG function.
    G3-Genes Genomes Genetics 11/2013; 4(1). DOI:10.1534/g3.113.008607 · 3.20 Impact Factor
Show more

Similar Publications


8 Reads
Available from