Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions
ABSTRACT 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.
- SourceAvailable from: Dr Tarek MA Abdel-Fatah
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- "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    . 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 . "
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 · 5.40 Impact Factor
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- "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. "
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 · 2.51 Impact Factor
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ABSTRACT: Although the etiology for many neurodegenerative diseases is unknown, the common findings of mitochondrial defects and oxidative damage posit these events as contributing factors. The temporal conundrum of whether mitochondrial defects lead to enhanced reactive oxygen species generation, or conversely, if oxidative stress is the underlying cause of the mitochondrial defects remains enigmatic. This review focuses on evidence to show that either event can lead to the evolution of the other with subsequent neuronal cell loss. Glutathione is a major antioxidant system used by cells and mitochondria for protection and is altered in a number of neurodegenerative and neuropathological conditions. This review also addresses the multiple roles for glutathione during mitochondrial inhibition or oxidative stress. Protein aggregation and inclusions are hallmarks of a number of neurodegenerative diseases. Recent evidence that links protein aggregation to oxidative stress and mitochondrial dysfunction will also be examined. Lastly, current therapies that target mitochondrial dysfunction or oxidative stress are discussed.Antioxidants and Redox Signaling 09/2005; 7(9-10):1117-39. DOI:10.1089/ars.2005.7.1117 · 7.67 Impact Factor