Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ATM”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 991 records · Page 55Linked to original sources
PubMed1990

Dystrophin-deficient mdx muscle fibers are preferentially vulnerable to necrosis induced by experimental lengthening contractions.

Lengthening contractions were induced in the right anterior tibialis muscles (ATM) of anaesthetized normal and mdx (dystrophic) mice by supramaximal, nonfatiguing stimulation of the sciatic nerve for 180 min. In the left ATM of the same animals identical stimulation caused shortening contractions because of a prestimulation Achilles tenotomy. The prevalence of recently necrotic fibers was determined in all stimulated ATM by demonstrating the presence of IgG in the necrotic fibers using immunoperoxidase staining of cryostat sections. The results were compared to unstimulated normal and mdx ATM. A significantly higher rate of necrosis was demonstrated after lengthening contractions in the mdx ATM than normal ATM. Unstimulated normal and mdx ATM have either no or extremely infrequent necrotic fibers. We suggest that the enhanced vulnerability of mdx muscle fibers to lengthening contractions is related to the deficiency of dystrophin, which renders the sarcolemma more susceptible to suffer focal breaks. A similar situation may occur in Duchenne muscular dystrophy.

Animals↗
PubMed1991

Effects of high hydrostatic pressure on characteristics of pork slurries and inactivation of microorganisms associated with meat and meat products.

Pork slurries inoculated with various test microorganisms were prepared and subjected to high hydrostatic pressure at 1000 to 6000 atm for 10 min at 25 degrees C to examine for the pressure effects on characteristics of the slurries and the inactivation of the microorganisms associated with meat and meat products. Pressure treatment at higher than 3000 atm caused coagulation and discoloration of the pork slurries. Harder and more white coagulants were obtained by increasing the pressure. Pressure treatment at 3000 to 6000 atm killed all the microorganisms tested by more than 6-log colony-forming units (cfu)/g except Bacillus cereus spores. Gram-negative microorganisms were more labile to pressure than Gram-positive ones. Campylobacter jejuni, Pseudomonas aeruginosa, Salmonella typhimurium and Yersinia enterocolitica were inactivated at pressures higher than 3000 atm; Escherichia coli, Saccharomyces cerevisiae and Candida utilis at pressures higher than 4000 atm; Micrococcus luteus, Staphylococcus aureus and Streptococcus faecalis at 6000 atm. Only less than one-log cfu/g of B. cereus spores were inactivated at 6000 atm. Ultraviolet absorption spectra and acridine orange staining suggested that E. coli became permeable and leaked cytoplasmic RNA at lower pressure than S. aureus. From the present findings, the authors propose high hydrostatic pressure treatment as a promising means of preparing wholesome meat and meat products.

Animals↗
PubMed2006

[Ataxia-telangiectasia: a review].

Ataxia-telangiectasia (AT) is an autosomal recessive inherited disease caused by mutational inactivation of the ATM gene. It is a multisystemic disease, characterized by progressive neurological dysfunction, especially in the cerebellum, oculo-cutaneous telangiectasia, immunodeficiency, recurrent sino-pulmonary infections and high incidence of neoplasms. The responsible gene, ATM, encodes a large protein that belongs to a family of protein kinases with a phosphatidylinositol 3-kinase (Pi3K) domain. ATM is a key regulator of cell cycle checkpoints that causes DNA repair or apoptosis. Several studies report ATM function in target cells (such as neurons, fibroblast, endothelium, germ cells, lymphocytes). The pleiotropic phenotypes of AT reflect the multifaceted activities of ATM protein. In nucleus (lymphocytes, fibroblasts, germ cells) ATM is involved in regulation of cell-cycle checkpoints; in cytoplasm ATM regulates redox state (neurons).

Adolescent↗
PubMed2006

Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability.

DNA damage response mechanisms encompass pathways of DNA repair, cell cycle checkpoint arrest and apoptosis. Together, these mechanisms function to maintain genomic stability in the face of exogenous and endogenous DNA damage. ATM is activated in response to double strand breaks and initiates cell cycle checkpoint arrest. Recent studies in human fibroblasts have shown that ATM also regulates a mechanism of end-processing that is required for a component of double strand break repair. Human fibroblasts rarely undergo apoptosis after ionising radiation and, therefore, apoptosis is not considered in our review. The dual function of ATM raises the question as to how the two processes, DNA repair and checkpoint arrest, interplay to maintain genomic stability. In this review, we consider the impact of ATM's repair and checkpoint functions to the maintenance of genomic stability following irradiation in G2. We discuss evidence that ATM's repair function plays little role in the maintenance of genomic stability following exposure to ionising radiation. ATM's checkpoint function has a bigger impact on genomic stability but strikingly the two damage response pathways co-operate in a more than additive manner. In contrast, ATM's repair function is important for survival post irradiation.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

Pressure-induced cellular senescence: a mechanism linking venous hypertension to venous ulcers.

INTRODUCTION: Slow healing of ulcers in chronic venous insufficiency (CVI) has long been thought secondary to venous hypertension. Dermal fibroblasts isolated from venous ulcers have morphologies and protein production suggestive of premature aging. In this study, we hypothesized that neonatal fibroblasts (NNF) cultured under elevated pressure will demonstrate premature aging and that this effect will be augmented by an inflammatory mediator, transforming growth factor beta (TGF-beta). MATERIALS AND METHODS: A unique pressure incubator was used to culture NNF at atmospheric pressure (ATM), ATM + 30 mmHg, ATM + 60 mmHg, and ATM +120 mmHg. Some pressure-exposed NNF were also cultured with TGF- beta (1 ng/ml). Growth rates were determined by flow cytometry. Senescent cells were identified by staining with a marker for cellular senescence, beta-galactosidase (SA-beta-Gal). Light microscopy and digital imaging were used to evaluate cell morphology. Paired linear models and comparison of the slopes were used for statistical analysis of growth. chi2 analysis was used to compare senescence rates. RESULTS: NNF cultured at ATM + 60 mmHg and ATM + 120 mmHg showed increased SA-beta-Gal activity (P <0.05), and reduced growth rates (P <0.05) at 11 days. These effects were not seen at ATM + 30 mmHg. NNF grown with TGF-beta did not show augmented SA-beta-Gal staining. CONCLUSIONS: Pressure-exposed NNF demonstrated an accelerated aging phenomenon similar to fibroblasts isolated from venous ulcers. This aging effect was directly related to the level of pressure. TGF-beta did not augment the aging effect. This study suggests that pressure elevations result in altered cell function and accelerated aging that may contribute to the slowed healing seen in patients with venous insufficiency.

Cell Culture Techniques↗
PubMed1997

An analysis of automatic teller machine usage by older adults: a structured interview approach.

It is often assumed that automatic teller machines (ATMs) are inherently easy to use and require no training. However, there is evidence to suggest that ATM users do experience difficulty when learning to use the system. The purpose of the present study was to conduct an in-depth analysis of ATM usage by older adults. Our approach consisted of telephone interviews followed by structured individual interviews. The goals were to understand the problems encountered by ATM users, to determine how ATMs might be better designed and to assess the training needs of older individuals. The phone interview data provide information about the relationships between age, sex and ATM usage within the adult sample, as well as information about why some people choose not to use ATMs. The structured interview data provide a more in-depth view of the concerns of both users and non-users, and information about training needs. The training and design implications of the results are discussed.

Aged↗
PubMed2006

[Idiopathic acute transverse myelitis: application of new diagnosis criteria to 17 patients].

INTRODUCTION: Idiopathic Acute Transverse Myelitis (ATM) is an inflammatory and immune-mediated disorder, distinct from infectious ATM, ATM of systemic lupus erythematosus or Sjögren's syndrome, and medullary manifestation of multiple sclerosis. Prognosis is not well-known. OBJECTIVE: To evaluate clinical, paraclinical and pronognosis data in patients selected with new diagnosis criteria, classically described in idiopathic ATM. METHODS: Seventeen patients with diagnosis criteria were retrospectively (1996-2005) studied. A telephone investigation was conducted in 2005 to obtained data on the clinical course. RESULTS: Seven men and 10 women, ranging in age from 15 to 75 years (mean: 39.8 years) met these new criteria. Our study showed that epidemiological and clinical findings as well as laboratory results were in agreement with those presented in the literature. Conversely, prognosis was better since 76p.cent of the patients could walk without assistance. The clinical presentation of some of our patients and/or their progression towards other multifocal inflammatory disorders, suggests there might be links between ATM, neuromyelitis optica (NMO) and Acute Dissemined Encephalomyelitis (ADEM). CONCLUSION: Patients with idiopathic ATM, selected with new criteria, have a rather good prognosis. ATM seems to be part of a continuum of neuroimmunologic disorders including NMO or ADEM although reasons explaining distinct focal disorders remain unclear.

Adolescent↗
PubMed1998

Radiosensitivity and oxidative signalling in ataxia telangiectasia: an update.

Radiosensitivity is a major hallmark of the human genetic disorder ataxia telangiectasia. This hypersensitivity to ionizing radiation has been demonstrated in vivo after exposure of patients to therapeutic doses of radiation and in cells in culture. Clearly an understanding of the nature of the molecular defect in ataxia telangiectasia will be of considerable assistance in delineating additional pathways that determine cellular radiosensitivity/radioresistance. Furthermore, since patients with this syndrome are also predisposed to developing a number of leukaemias and lymphomas, the possible connection between radiosensitivity and cancer predisposition is of interest. Now that the gene (ATM) responsible for this genetic disease has been cloned and identified, progress is being made in determining the role of the ATM protein in mediating the effects of cellular exposure to ionizing radiation and other forms of redox stress. Proteins such as the product of the tumour suppressor gene p53 and the proto-oncogene c-Abl (a protein tyrosine kinase) have been shown to interact with ATM. Since several intermediate steps in both the p53 and c-Abl pathways, activated by ionizing radiation, are known it will be possible to map the position of ATM in these pathways and describe its mechanism of action. What are the clinical implications of understanding the molecular basis of the defect in ataxia telangiectasia (A-T)? As outlined above, since radiosensitivity is a universal characteristic of A-T, understanding the mechanism of action of ATM will provide additional information on radiation signalling in human cells. With this information it may be possible to sensitize tumour cells to radiation and thus increase the therapeutic benefit of radiotherapy. This might involve the use of small molecules that would interfere with the normal ATM-controlled pathways and thus sensitize cells to radiation or alternatively it might involve the efficient introduction of ATM anti-sense cDNA constructs into tumours to achieve the same end-point.

Animals↗
PubMed2002

Benefits of a mobile, point-of-care anticoagulation therapy management program.

BACKGROUND: Current guidelines recommend anticoagulation therapy for a number of medical conditions, but this therapy also has the potential for serious complications, particularly bleeding complications. Maintenance of anticoagulation within a narrow therapeutic window usually entails frequent monitoring with a blood test called the international normalized ratio (INR). Anticoagulation therapy management (ATM) clinics lead to improvements in quality of care, in terms of improved INR control and reduced complications. This study examined the impact of a mobile multisite, office-based ATM program that operated in seven cardiology offices in all three counties in Delaware. ATM PROGRAM: The ATM program was managed by a trained nurse who rotated among all seven offices. Patients made office visits to the nurse and received patient education, point-of-care INR testing, and medication adjustment based on a physician-approved algorithm. METHODS: This retrospective cohort study compared INR levels in the year before (May 1998-Apr 1999) and the year after (Aug 1999-Jul 2000) the start of the ATM program. RESULTS: From the year before to the year after implementation of the ATM program, the percentage of in-range INRs increased from 40.7% to 58.5% (p < 0.001). The percentage in the modified target range also increased (50.0% to 62.9%, p < 0.001). DISCUSSION: This study demonstrates the positive impact of a statewide office-based ATM program. If similar programs could be implemented in other networks of specialty offices or primary care offices, they could have a significant benefit to quality of care for patients who require anticoagulation therapy.

Adolescent↗
PubMed1997

Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation.

Ataxia telangiectasia (AT) is a rare human autosomal recessive disorder with pleiotropic phenotypes, including neuronal degeneration, immune dysfunction, premature ageing and increased cancer risk. The gene mutated in AT, ATM, encodes a putative lipid or protein kinase. Most of the human AT patient phenotypes are recapitulated in Atm-deficient mice. Cells derived from Atm-/- mice, like those from AT patients, exhibit abnormal response to ionizing radiation. One of the known responses to ionizing radiation is the activation of a nuclear tyrosine kinase encoded by the c-abl proto-oncogene. Ionizing radiation does not activate c-Abl in cells from AT patients or in thymocytes or fibroblasts from the Atm-deficient mice. Ectopic expression of a functional ATM kinase domain corrects this defect, as it phosphorylates the c-Abl tyrosine kinase in vitro at Ser 465, leading to the activation of c-Abl. A mutant c-Abl with Ser 465 changed to Ala 465 is not activated by ionizing radiation or ATM kinase in vivo. These findings identify the c-Abl tyrosine kinase as a downstream target of phosphorylation and activation by the ATM kinase in the cellular response to ionizing radiation.

3T3 Cells↗
PubMed1997

Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.

Amino Acid Sequence↗
PubMed2000

Caffeine abolishes the mammalian G(2)/M DNA damage checkpoint by inhibiting ataxia-telangiectasia-mutated kinase activity.

Recent evidence indicates that arrest of mammalian cells at the G(2)/M checkpoint involves inactivation and translocation of Cdc25C, which is mediated by phosphorylation of Cdc25C on serine 216. Data obtained with a phospho-specific antibody against serine 216 suggest that activation of the DNA damage checkpoint is accompanied by an increase in serine 216 phosphorylated Cdc25C in the nucleus after exposure of cells to gamma-radiation. Prior treatment of cells with 2 mM caffeine inhibits such a change and markedly reduces radiation-induced ataxia-telangiectasia-mutated (ATM)-dependent Chk2/Cds1 activation and phosphorylation. Chk2/Cds1 is known to localize in the nucleus and to phosphorylate Cdc25C at serine 216 in vitro. Caffeine does not inhibit Chk2/Cds1 activity directly, but rather, blocks the activation of Chk2/Cds1 by inhibiting ATM kinase activity. In vitro, ATM phosphorylates Chk2/Cds1 at threonine 68 close to the N terminus, and caffeine inhibits this phosphorylation with an IC(50) of approximately 200 microM. Using a phospho-specific antibody against threonine 68, we demonstrate that radiation-induced, ATM-dependent phosphorylation of Chk2/Cds1 at this site is caffeine-sensitive. From these results, we propose a model wherein caffeine abrogates the G(2)/M checkpoint by targeting the ATM-Chk2/Cds1 pathway; by inhibiting ATM, it prevents the serine 216 phosphorylation of Cdc25C in the nucleus. Inhibition of ATM provides a molecular explanation for the increased radiosensitivity of caffeine-treated cells.

Ataxia Telangiectasia↗
PubMed1981

Chromosomal and teratogenic effects of oxygen in the mouse.

The effect of oxygen on chromosomes in bone marrow cells and on the early stages of gestation in the mouse were studied. Three groups of male mice were exposed to hyperbaric oxygen at 2, 3 and 4 atm abs. for 1 h, and four other groups breathed pure oxygen at 1 atm abs, for 6, 12, 24 and 48 h respectively. Chromosome were studied after 24 h. In the pure oxygen groups, no significant increase in chromosome aberration was noted, but in the hyperbaric oxygen groups, significant increases in abnormalities (breakage and gap) were noted at 3 and 4 atm abs. (8.0 and 6.7% respectively, P less than 0.05). In another study, four groups of pregnant mice were exposed once to hyperbaric oxygen at either 2 atm abs. for 1 h on the 7th or 8th day of gestation, or 2.5 atm abs. for 2 h on the 5th or 8th day. Six other groups were exposed to 2, 3 and 3.5 atm abs. with either oxygen or air for 1 h daily during first 8 days of gestation. Malformations (umbilical hernia and abnormalities of the coccyx) in the newborn were noted in the groups exposed to hyperbaric oxygen at 2.5 atm abs. for 2 h on the 5th and 8th days of gestation (1/26, 7/42), and all the groups exposed daily to hyperbaric oxygen (1/58, 3/33, 2/24). These findings would seem to indicate a genetic effect of increased oxygen tension in vitro.

Abnormalities, Drug-Induced↗
PubMed2000

Halothane and desflurane requirements in alcohol-tolerant and -nontolerant rats.

On the basis of data implicating GABAA receptors in the effects of volatile general anaesthetics, we hypothesized that alcohol-, barbiturate-, and benzodiazepine-sensitive alcohol-nontolerant (ANT) rats would also be more sensitive than alcohol-tolerant (AT) rats to two clinical general anaesthetics with differing potencies, halothane and desflurane. The obtunding effect of halothane and desflurane on mature ANT (n = 17) and AT (n = 16) rats was assessed by the loss-of-righting reflex endpoint. ANT rats were significantly (P < 0.0001) more sensitive to the obtunding effects of both halothane and desflurane (ED50 = 0.45 +/- 0.03% atm for ANT vs 0.95 +/- 0.04% atm for AT and 2.16 +/- 0.17 vs 3.69 +/- 0.13% atm, respectively). The immobilization effect of halothane and desflurane was assessed with the tail clamp/withdrawal endpoint. ANT rats were more sensitive to the effects of halothane (ED50 = 1.10 +/- 0.08% atm for ANT vs 1.72 +/- 0.09% atm for AT; P < 0.0001) but not desflurane (ED50 = 6.25 +/- 0.25% atm for ANT vs 5.85 +/- 0.21% atm for AT). The data presented support the hypothesis that volatile anaesthetics interact with specific neuronal proteins (possibly GABAA receptors) and agree with recent hypotheses that different elements of the anaesthetic state are produced by separate sites or mechanisms.

Anesthetics, Inhalation↗
PubMed2001

The ataxia-telangiectasia gene product may modulate DNA turnover and control cell fate by regulating cellular redox in lymphocytes.

The ATM kinase, when activated postnatally, exerts multiple functions to prevent the onset of ataxia-telangiectasia (AT). Using freshly isolated thymocytes from Atm-/- mice that were under stress during postnatal differentiation, we noted that thiol redox activity, as indicated by reduction of the tetrazolium MTS, and DNA turnover activity, as indicated by incorporation of [(3)H]thymidine into DNA, were both greatly increased compared with activities in thymocytes from Atm+/+ mice. This increased thymidine incorporation could be suppressed by the thiol N-acetylcysteine. In primary noncycling splenocytes, mitogens proportionally increased both the rate of [(3)H]thymidine incorporation and the rate of reduction of MTS. The mitogen-induced activities in splenocytes were not affected by ATM but were suppressed by the calcineurin-dependent inhibitor FK-506, which has no effect on these activities in thymocytes. These findings suggest that increased [(3)H]thymidine incorporation and reducing power indicate increased cell cycling in mitogenically stimulated splenocytes, whereas these two indicators represent increased FK-506-independent DNA turnover activities in thymocytes. Thus, a primary function of ATM is to activate the redox-sensitive checkpoint required for down-regulation of DNA turnover activities in developing lymphocytes. Cell-cycling checkpoints in undamaged quiescent lymphocytes are not activated by ATM with mitogenic stimulation. ATM may suppress abnormal DNA turnover and the resultant oncogenesis by regulating cellular thiol redox pathways.

Acetylcysteine↗
PubMed1979

Rapidly developing tolerance to acute exposures to anesthetic agents.

Following the observation that mice manifest a characteristic withdrawal syndrome after an hour of exposure to nitrous oxide, the authors reasoned that there might be a very rapidly developing tolerance to nitrous oxide. Thus, they determined the inspired concentrations that cause loss of the righting reflex in mice (i.e, the ED50), in the presence of 1 atm of oxygen, of: 1) nitrous oxide alone; 2) cyclopropane alone; 3) nitrous oxide plus 13.6 atm helium; 4) ethylene plus 13.6 atm helium. In each instance the ED50 was determined after averages of 6,34 and 64 min of exposure to the anesthetic agents. For nitrous oxide alone the ED50 at 6 min was 1.18 +/- 0.049 atm, increasing to 1.39 +/- 0.061 atm at 64 min. For ethylene plus helium the ED50 increased from 1.21 +/- 0.033 atm at 6 min to 1.31 +/- 0.039 atm at 64 min, indicating the development of acute tolerance. Neither cyclopropane alone nor nitrous oxide plus helium caused acute tolerance. This absence of tolerance may have resulted from a slower development of an alveolar anesthetic concentration.

Anesthetics↗
PubMed2002

Effects of xenon on in vitro and in vivo models of neuronal injury.

BACKGROUND: Xenon, the "inert" gaseous anesthetic, is an antagonist at the N-methyl-D-aspartate (NMDA)-type glutamate receptor. Because of the pivotal role that NMDA receptors play in neuronal injury, the authors investigated the efficacy of xenon as a neuroprotectant in both in vitro and in vivo paradigms. METHODS: In a mouse neuronal-glial cell coculture, injury was provoked either by NMDA, glutamate, or oxygen deprivation and assessed by the release of lactate dehydrogenase into the culture medium. Increasing concentrations of either xenon or nitrogen (10-75% of an atmosphere) were coadministered and maintained until injury was assessed. In separate in vivo experiments, rats were administered N-methyl-dl-aspartate and killed 3 h later. Injury was quantified by histologic assessment of neuronal degeneration in the arcuate nucleus of the hypothalamus. RESULTS: Xenon exerted a concentration-dependent protection against neuronal injury provoked by NMDA (IC(50) = 19 +/- 6% atm), glutamate (IC(50) = 28 +/- 8% atm), and oxygen deprivation (IC(50) = 10 +/- 4% atm). Xenon (60% atm) reduced lactate dehydrogenase release to baseline concentrations with oxygen deprivation, whereas xenon (75% atm) reduced lactate dehydrogenase release by 80% with either NMDA- or glutamate-induced injury. In an in vivo brain injury model in rats, xenon exerted a concentration-dependent protective effect (IC(50) = 78 +/- 8% atm) and reduced the injury by 45% at the highest xenon concentration tested (75% atm). CONCLUSIONS: Xenon, when coadministered with the injurious agent, exerts a concentration-dependent neuroprotective effect at concentrations below which anesthesia is produced in rodents. Unlike either nitrous oxide or ketamine (other anesthetics with NMDA antagonist properties), xenon is devoid of both neurotoxicity and clinically significant adverse hemodynamic properties. Studies are proposed to determine whether xenon can be used as a neuroprotectant in certain clinical settings.

Anesthetics, Inhalation↗
PubMed2004

Drosophila atm/telomere fusion is required for telomeric localization of HP1 and telomere position effect.

Terminal deletions of Drosophila chromosomes can be stably protected from end-to-end fusion despite the absence of all telomere-associated sequences. The sequence-independent protection of these telomeres suggests that recognition of chromosome ends might contribute to the epigenetic protection of telomeres. In mammals, Ataxia Telangiectasia Mutated (ATM) is activated by DNA damage and acts through an unknown, telomerase-independent mechanism to regulate telomere length and protection. We demonstrate that the Drosophila homolog of ATM is encoded by the telomere fusion (tefu) gene. In the absence of ATM, telomere fusions occur even though telomere-specific Het-A sequences are still present. High levels of spontaneous apoptosis are observed in ATM-deficient tissues, indicating that telomere dysfunction induces apoptosis in Drosophila. Suppression of this apoptosis by p53 mutations suggests that loss of ATM activates apoptosis through a DNA damage-response mechanism. Loss of ATM reduces the levels of heterochromatin protein 1 (HP1) at telomeres and suppresses telomere position effect. We propose that recognition of chromosome ends by ATM prevents telomere fusion and apoptosis by recruiting chromatin-modifying complexes to telomeres.

Animals↗