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PubMedDate not supplied

DNA damage-induced activation of ATM and ATM-dependent signaling pathways.

Ataxia-telangiectasia mutated (ATM) plays a key role in regulating the cellular response to ionizing radiation. Activation of ATM results in phosphorylation of many downstream targets that modulate numerous damage response pathways, most notably cell cycle checkpoints. In this review, we describe recent developments in our understanding of the mechanism of activation of ATM and its downstream signaling pathways, and explore whether DNA double-strand breaks are the sole activators of ATM and ATM-dependent signaling pathways.

Animals↗
PubMed2004

The telomeric protein TRF2 binds the ATM kinase and can inhibit the ATM-dependent DNA damage response.

The telomeric protein TRF2 is required to prevent mammalian telomeres from activating DNA damage checkpoints. Here we show that overexpression of TRF2 affects the response of the ATM kinase to DNA damage. Overexpression of TRF2 abrogated the cell cycle arrest after ionizing radiation and diminished several other readouts of the DNA damage response, including phosphorylation of Nbs1, induction of p53, and upregulation of p53 targets. TRF2 inhibited autophosphorylation of ATM on S1981, an early step in the activation of this kinase. A region of ATM containing S1981 was found to directly interact with TRF2 in vitro, and ATM immunoprecipitates contained TRF2. We propose that TRF2 has the ability to inhibit ATM activation at telomeres. Because TRF2 is abundant at chromosome ends but not elsewhere in the nucleus, this mechanism of checkpoint control could specifically block a DNA damage response at telomeres without affecting the surveillance of chromosome internal damage.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2004

ATR and ATM-dependent movement of BLM helicase during replication stress ensures optimal ATM activation and 53BP1 focus formation.

The BLM helicase, a deficiency that markedly increases cancer incidence in humans, is required for optimal repair during DNA replication. We show that BLM rapidly moves from PML nuclear bodies to damaged replication forks, returning to PML bodies several hours later, owing to activities of the DNA damage response kinases ATR and ATM, respectively. Immunofluorescence and cellular fractionation demonstrate that BLM partitions to different sub-cellular compartments after replication stress. Unexpectedly, fibroblasts lacking BLM were deficient in phospho-ATM (S-1981) and 53-binding protein-1 (53BP1), and these proteins failed to form foci following replication stress. Expression of a dominant p53 mutant or helicase-deficient BLM restored replication stress-induced 53BP1 foci, but only mutant p53 restored optimal ATM activation. Thus, optimal repair of damaged replication fork lesions likely requires both ATR and ATM. BLM recruits 53BP1 to these lesions independent of its helicase activity, and optimal activation of ATM requires both p53 and BLM helicase activities.

Adenosine Triphosphatases↗
PubMed2000

The RETAIN project: DICOM teleradiology over an ATM-based network. Radiological Examinations Transfer on an ATM Integrated Network.

The RETAIN project (Radiological Examinations Transfer on an ATM Integrated Network) has aimed at testing videoconferencing and DICOM image transfers to get advice about difficult radiological cases over an asynchronous transfer mode (ATM)-based network, which affords a more comfortable interface than narrow-band networks and allows exchange of complete image series using the DICOM format of studies. For this purpose, an experimental ATM network was applied between six university hospitals in four different countries. An assessment of the functionalities of the system was performed by means of log-file analysis, video recording of the sessions and forms filled out by the participants at the end of each session. Questionnaires were answered by the users at the end of the project to bring out perspectives of utilisation and added value. We discussed 43 cases during 20 sessions. For technical or organisational problems, only 20 of the 36 planned sessions took place. The throughput over ATM (10.5 Mbit/s, 20 times faster than six ISDN B-channels) was adequate. Despite the experimental configuration of the network, the system was considered as satisfactory by all the physicians. In 72 % of the sessions, the expected result (answer to the question) was gained. By common consent, videoconferencing was unanimously regarded as a prominent tool in improving the interaction quality. Asynchronous transfer mode is an efficient method for fast transferring of radiologic examinations in DICOM format and for discussing them through high-quality videoconferencing.

Computer Communication Networks↗
PubMed2005

CKIP-1 recruits nuclear ATM partially to the plasma membrane through interaction with ATM.

CKIP-1 (casein kinase-2 interacting protein-1) is implicated in muscle differentiation, regulation of cell morphology and actin cytoskeleton. More recently, we showed that CKIP-1 regulated AP-1 activity and promoted apoptosis via caspase-3-dependent cleavage and translocation. Here, we report that overexpression of CKIP-1 in SK-BR-3 breast cancer cells prevents p53 degradation induced by cycloheximide treatment through increase of p53 N-terminal Ser-15 phosphorylation level. CKIP-1 could interact with ATM, which is an upstream kinase of p53, thereby enhance the stability of p53. Interestingly, CKIP-1 is localized both at the plasma membrane and in the nucleus dependent on the cell types, and only the plasma membrane-localized CKIP-1 could form a complex with ATM. Importantly, CKIP-1 recruits nuclear ATM proteins partially to the plasma membrane. Our data provide the first evidence that ATM, a predominantly nuclear kinase, could be relocalized to the plasma membrane by CKIP-1 and shed new light on the multi-functional CKIP-1.

Animals↗
PubMed2000

ATM heterozygosity and breast cancer: screening of 37 breast cancer patients for ATM mutations using a non-isotopic RNase cleavage-based assay.

Based upon the results of several epidemiologic studies, it has been suggested that women who are carriers for a mutation in the ataxia telangiectasia-mutated (ATM) gene are susceptible for the development of breast cancer. Therefore, 37 consecutive breast cancer patients were screened for the presence of a germline ATM mutation using a non-isotopic RNase cleavage-based assay (NIRCA). This paper reports the first use of NIRCA for detection of ATM mutations in breast cancer patients. Using this assay, no ATM mutations were found in our patient population. This result is similar to the findings of other studies that have employed approaches complementary to NIRCA.

Adult↗
PubMed2001

Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies.

Recent studies have provided evidence that breast cancer susceptibility gene products (Brca1 and Brca2) suppress cancer, at least in part, by participating in DNA damage signaling and DNA repair. Brca1 is hyperphosphorylated in response to DNA damage and co-localizes with Rad51, a protein involved in homologous-recombination, and Nbs1.Mre11.Rad50, a complex required for both homologous-recombination and nonhomologous end joining repair of damaged DNA. Here, we report that there is a qualitative difference in the phosphorylation states of Brca1 between ionizing radiation (IR) and UV radiation. Brca1 is phosphorylated at Ser-1423 and Ser-1524 after IR and UV; however, Ser-1387 is specifically phosphorylated after IR, and Ser-1457 is predominantly phosphorylated after UV. These results suggest that different types of DNA-damaging agents might signal to Brca1 in different ways. We also provide evidence that the rapid phosphorylation of Brca1 at Ser-1423 and Ser-1524 after IR (but not after UV) is largely ataxia telangiectasia mutated (ATM) kinase-dependent. The overexpression of catalytically inactive ATM and Rad3 related (ATR) kinase inhibited the UV-induced phosphorylation of Brca1 at these sites, indicating that ATR controls Brca1 phosphorylation in vivo after the exposure of cells to UV light. Moreover, ATR associates with Brca1; ATR and Brca1 foci co-localize both in cells synchronized in S phase and after exposure of cells to DNA-damaging agents. ATR can itself phosphorylate the region of Brca1 phosphorylated by ATM (Ser-Gln cluster in the C terminus of Brca1, amino acids 1241-1530). However, there are additional uncharacterized ATR phosphorylation site(s) between residues 521 and 757 of Brca1. Taken together, our results support a model in which ATM and ATR act in parallel but somewhat overlapping pathways of DNA damage signaling but respond primarily to different types of DNA lesion.

Ataxia Telangiectasia↗
PubMed2006

Human cytomegalovirus disrupts both ataxia telangiectasia mutated protein (ATM)- and ATM-Rad3-related kinase-mediated DNA damage responses during lytic infection.

Many viruses (herpes simplex virus type 1, polyomavirus, and human immunodeficiency virus type 1) require the activation of ataxia telangiectasia mutated protein (ATM) and/or Mre11 for a fully permissive infection. However, the longer life cycle of human cytomegalovirus (HCMV) may require more specific interactions with the DNA repair machinery to maximize viral replication. A prototypical damage response to the double-stranded ends of the incoming linear viral DNA was not observed in fibroblasts at early times postinfection (p.i.). Apparently, a constant low level of phosphorylated ATM was enough to phosphorylate its downstream targets, p53 and Nbs1. p53 was the only cellular protein observed to relocate at early times, forming foci in infected cell nuclei between 3.5 and 5.5 h p.i. Approximately half of these foci localized with input viral DNA, and all localized with viral UL112/113 prereplication site foci. No other DNA repair proteins localized with the virus or prereplication foci in the first 24 h p.i. When viral replication began in earnest, between 24 and 48 h p.i., there were large increases in steady-state levels and phosphorylation of many proteins involved in the damage response, presumably triggered by ATM-Rad3-related kinase activation. However, a sieving process occurred in which only certain proteins were specifically sequestered into viral replication centers and others were particularly excluded. In contrast to other viruses, activation of a damage response is neither necessary nor detrimental to infection, as neither ATM nor Mre11 was required for full virus replication and production. Thus, by preventing simultaneous relocalization of all the necessary repair components to the replication centers, HCMV subverts full activation and completion of both double-stranded break and S-phase checkpoints that should arrest all replication within the cell and likely lead to apoptosis.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1998

A model for ATM heterozygote identification in a large population: four founder-effect ATM mutations identify most of Costa Rican patients with ataxia telangiectasia.

Ataxia telangiectasia (A-T) is an autosomal recessive disorder with a broad range of clinical manifestations and a frequency of 1:40,000-100,000 live births. Epidemiological studies have suggested that A-T heterozygotes are at an elevated risk of breast cancer. ATM mutations occur worldwide over the entire ATM gene, making it difficult to identify heterozygotes in large populations. However, some founder-effect mutations are specific for certain populations. Here, we present four mutations in Costa Rican A-T patients that accounted for 86-93% of 41 patients studied in two batches. We have developed assays for rapid detection of these four mutations which can be used diagnostically. They will also enable the Costa Rican population to be used as a model for analyzing the role of ATM heterozygosity in cancer development and other disorders.

Ataxia Telangiectasia↗
PubMed2006

DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations.

The gene for ataxia-telangiectasia (A-T:MIM: #208900), ATM, spans about 150 kb of genomic DNA and is composed of 62 coding exons. ATM mutations are found along the entire coding sequence of the gene, without evidence of mutational hot spots. Using DNA as the starting material, we used denaturing high performance liquid chromatography (DHPLC) technique to search for ATM gene mutations. Initially, DHPLC was validated in a retrospective study of 16 positive control samples that included 19 known mutations; 100% of mutations were detected. Subsequently, DHPLC was used to screen for mutations a cohort of 22 patients with the classical form of A-T. A total of 27 different mutations were identified on 38 of the 44 alleles, corresponding to a 86% detection rate. Fourteen of the mutations were novel. In addition, 15 different variants and polymorphisms of unknown functional significance were found. The high incidence of new and individual A-T mutations in our cohort of patients demonstrates marked mutational heterogeneity of A-T in Italy and corroborate the efficiency of DHPLC as a method for the mutation screening of A-T patients.

Ataxia Telangiectasia↗
PubMed2001

X-irradiation induces up-regulation of ATM gene expression in wild-type lymphoblastoid cell lines, but not in their heterozygous or homozygous ataxia-telangiectasia counterparts.

Ataxia-telangiectasia (AT) is an autosomal recessive disease. The relevant gene has been cloned and designated ATM. We studied the expression of both ATM mRNA and the ATM protein in unirradiated and X-irradiated EBV (Epstein-Barr virus)-transformed lymphoblastoid cell lines (LCLs) derived from donors who were normal (ATM + / + ), AT heterozygotes (ATM + / - ), or AT homozygotes (ATM - / - ), respectively. In ATM + / + LCLs, the levels of ATM mRNA were found to have increased by approximately 1.5-fold within 1 h of exposure to 10 Gy of X-rays, while the ATM protein levels had increased by 1.5- to 2.0-fold within 2 to 3 h of irradiation. The wild-type mRNA and protein levels both returned to their basal values fairly quickly after this time. The results obtained with the ATM + / - LCLs were quite different, however: neither the mRNA nor protein levels were found to have increased as a consequence of X-irradiation in any ATM + / - LCL. Twelve of the mutations in the ATM - / - LCLs we used were truncating mutations, and we suspected that the corresponding truncated ATM proteins would be too labile to be detected by western blot analysis. However, five of the ATM - / - LCLs produced mutant ATM proteins that were identical in molecular weight to the wild-type ATM protein. When cells from three of these five clones were exposed to X-rays, transcription of the mutant ATM genes appeared to reduce somewhat, as were the levels of protein being produced. These results suggest that the normal ATM gene responds to ionizing radiation by up-regulating its activity, whereas none of the mutant ATM genes we studied were able to respond in this way.

Ataxia Telangiectasia↗
PubMed2001

Rapid radiation-induction of ATM protein levels in situ.

Ataxia-telangiectasia (A-T) is characterised by hypersensitivity to ionising radiation (IR), immunodeficiency, neurodegeneration and predisposition to malignancy. Mutations in the A-T gene (ATM) often result in reduced levels of ATM protein and/or compromise ATM function. IR induced DNA damage is known to rapidly upregulate ATM kinase activity/phosphorylation events in the control of cell cycle progression and other processes. Variable expression of ATM levels in different tissues and its upregulation during cellular proliferation indicate that the level of ATM is also regulated by mechanisms other than gene mutation. Here, we report on the IR induction of ATM protein levels within a number of different cell types and tissues. Induction had begun within 5 min and peaked within 2 h of exposure to 2 Gy of IR, suggesting a rapid post-translational mechanism. Low basal levels of ATM protein were more responsive to IR induction compared to high ATM levels in the same cell type. Irradiation of fresh skin biopsies led to an average three-fold increase in ATM levels while immunohistochemical analyses indicated "low expressing" cells within the basal layer with ten-fold increases in ATM levels following IR. ATM "high expressing" lymphoblastoid cell lines (LCLs) which were initially resistant to the radiation-induction of ATM levels also became responsive to IR after ATM antisense expression was used to reduce the basal levels of the protein. These results demonstrate that ATM is present in variable amounts in different tissue/cell types and where basal levels are low ATM levels can be rapidly induced by IR to saturable levels specific for different cell types. ATM radiation-induction is a sensitive and rapid radioprotective response that complements the IR mediated activation of ATM.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2004

Loss of ATM sensitizes against O6-methylguanine triggered apoptosis, SCEs and chromosomal aberrations.

A critical pre-cytotoxic and -apoptotic DNA lesion induced by methylating carcinogens and chemotherapeutic drugs is O6-methylguanine (O6MeG). The mechanism by which O6MeG causes cell death via apoptosis is only partially understood. The current model ascribes a role to DNA replication and mismatch repair, which converts O6MeG into a critical distal lesion (presumably a DNA double-strand break) that is finally responsible for genotoxicity and apoptosis. Here we analysed whether the PI3-like kinase ATM is involved in this process. ATM is a major player in recognizing and signaling DNA breaks, but most reports are limited to ionizing radiation. Comparing mouse ATM knockout fibroblasts (ATM-/-) with the corresponding wild-type (ATM+/+) we show that ATM-/- cells are hypersensitive to the cytotoxic and apoptosis-inducing effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Inhibition of O6-methylguanine-DNA methyltransferase (MGMT) activity by O6-benzylguanine enhanced cell killing whereas the increase of MGMT activity by transfection with an expression vector provoked MNNG resistance. This was more pronounced in ATM-/- than in ATM+/+ cells, suggesting that O6MeG is responsible, at least in part, for increased MNNG sensitivity of ATM-/- cells. Cytogenetic studies showed that MNNG-induced sister-chromatid exchange frequencies were the same in ATM-/- and ATM+/+ cells in the first mitoses following treatment, but higher in ATM-/- cells than in the wild-type in the second post-treatment mitoses, when MGMT was depleted. Also, a significant higher frequency of MNNG-induced chromosomal aberrations was observed in ATM-/- than in ATM+/+ cells when analysed at a late recovery time, which is consistent with O6MeG being the inducing lesion. In summary, we conclude that ATM is not only involved in resistance to ionizing radiation but also to methylating agents, playing a role in the repair of secondary DNA damage generated from O6MeG lesions. The data also show that ATM is not required for activating the apoptotic pathway in response to O6MeG since ATM-/- cells are able to undergo apoptosis with high frequency.

Animals↗
PubMed2003

Variations in ATM protein expression during normal lymphoid differentiation and among B-cell-derived neoplasias.

The ataxia telangiectasia mutated (ATM) protein plays a central role in the cellular response to DNA double-strand breaks (DSBs). Developmentally programmed DSBs are restricted to cellular subsets within lymphoid tissues and we asked whether ATM expression is differentially regulated during lymphoid differentiation. We showed that immature B cells in bone marrow and immature T cells of the thymic cortex were negative or weakly ATM-positive. T cells of thymic medulla and peripheral tissues strongly expressed ATM. High levels of ATM were present in the B lymphocytes of the mantle zone and in plasma cells, while the majority of germinal center B cells were negative or weakly labeled. Therefore, ATM expression appears to be down-regulated at those stages of lymphoid development where physiological DNA DSBs occur. In B-chronic lymphocytic leukemia and mantle cell lymphoma we observed two categories: ATM-negative tumors, most likely reflecting the presence of ATM mutation, and tumors with abundant ATM expression. Most follicular center-cell lymphomas and diffuse large B-cell lymphomas, which rarely show inactivation of the ATM gene, were negative or weakly ATM-positive. Tumor cells from most cases of Hodgkin's disease were ATM-negative. Therefore, unless ATM inactivation occurs, ATM expression in lymphoid tumors is likely to reflect their cellular origin. As a result, immunostaining to identify lymphoid neoplasias with ATM inactivation might only be feasible for tumors derived from the stages where ATM is constitutively highly expressed.

Antibodies, Monoclonal↗
PubMed2002

ATM mutations in sporadic lymphoid tumours.

Patients with the autosomal recessive disorder ataxia telangiectasia (A-T) show the biallelic inactivation of the ataxia telangiectasia mutated (ATM) gene. A-T patients exhibit a predisposition to the development of a wide range of lymphoid tumours, suggesting that the ATM protein normally plays an important role in the prevention of both T and B cell malignancies. The ATM protein is a 370 kDa protein kinase implicated in the integration of different cellular responses to particular forms of DNA damage. Several recent studies have reported the possibility that the ATM gene can act as a tumour suppressor gene in non A-T individuals. Frequent ATM inactivation was confirmed in three sporadic lymphoid tumours of mature phenotype: T cell prolymphocytic leukaemia (T-PLL), B-cell chronic lymphocytic leukaemia (B-CLL) and mantle cell lymphoma (MCL). Here, we provide a summary of the published ATM mutations in sporadic lymphoid tumours, including our own study on the role of ATM mutations in the pathogenesis of sporadic B-CLL. The published results suggest possible differences in the origin, the nature and distribution of ATM mutations between sporadic B-CLL, MCL and T-PLL. While ATM mutations in mature B cell tumours (B-CLL and MCL) represent a mixture of missense and truncating errors distributed across the whole of the ATM coding sequence, mutations in sporadic T-PLL appear to be predominantly missense, clustering in the region encoding the PI-3 kinase catalytic domain of the protein. The reason for this difference is unclear, but the difference itself supports the notion that the pathogenesis of B and T cell tumours on an ATM deficient background might be different. In addition, in both B-CLL and MCL ATM mutation carriers have been reported, raising the possibility that ATM mutation carriers may have an increased risk of developing these tumours. The existence as well as magnitude of the risk, however, remains to be established. Furthermore, our own studies indicate that the presence of ATM mutations in sporadic B-CLL causes a distinctive defect in response to DNA damaging agents, offering a possible explanation for the poor response of ATM mutant tumours to standard treatment. Therefore, one of the future challenges will be to devise strategies to bypass the existing defect in response to DNA damage and activate apoptosis in ATM mutant sporadic lymphoid tumours.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2006

gamma-H2AX foci after low-dose-rate irradiation reveal atm haploinsufficiency in mice.

We have investigated the use of the gamma-H2AX assay, reflecting the presence of DNA double-strand breaks (DSBs), as a possible means for identifying individuals who may be intermediate with respect to the extremes of hyper-radiosensitivity phenotypes. In this case, cells were studied from mice that were normal (Atm+/+), heterozygous (Atm+/-), or homozygous recessive (Atm-/-) for a truncating mutation in the Atm gene. After single acute (high-dose-rate) exposures, differences in mean numbers of gamma-H2AX foci per cell between samples from Atm+/+ and Atm-/- mice were clear at nearly all sampling times, but at no sampling time was there a clear distinction for cells from Atm+/+ and Atm+/- mice. In contrast, under conditions of low-dose-rate irradiation at 10 cGy/h, appreciable differences in the levels of gamma-H2AX foci per cell were observed in synchronized G1 cells derived from Atm+/- mice relative to cells from Atm+/+ mice. The levels were intermediate between those for cells from Atm+/+ and Atm-/- mice. After 24 h exposure at this dose rate, measurements in cells from four different mice for each genotype yielded mean frequencies of foci per cell of 1.77 +/- 0.13 (SEM) for Atm+/+ cells, 4.75 +/- 0.20 for the Atm+/- cells, and 11.10 +/- 0.33 for the Atm-/-cells. The distributions of foci per G1 cell were not significantly different from Poisson. To the extent that variations in sensitivity with respect to gamma-H2AX focus formation reflect variations in radiosensitivity for biological effects of concern, such as carcinogenesis, and that similar differences are seen for other genetic DNA DSB processing defects in general, this assay may provide a relatively straightforward means for distinguishing individuals who may be mildly hypersensitive to radiation such as we observed for Atm heterozygous mice.

Animals↗