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PubMed1997

Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia.

The ataxia-telangiectasia mutated (ATM) gene, which is mutated in the autosomal recessive disorder ataxia-telangiectasia (AT), was isolated in 1995 by positional cloning. Although in vitro cell fusion studies had suggested that AT was genetically heterogeneous, all AT patients studied to date have been found to harbor mutations in the ATM gene. More that 100 ATM mutations occurring in AT patients have been documented. The mutations are broadly distributed throughout the ATM gene. Except for patients from families with known consanguinity, most AT patients are compound heterozygotes. The majority (> 70%) of mutations are predicted to lead to protein truncation. A significant number of the reported mutations affect mRNA splicing with at least half of the coding exons (32/62) having been observed to undergo exon skipping. The large size of the ATM gene, 66 exons spanning approximately 150 kb of genomic DNA, together with the diversity and broad distribution of mutations in AT patients greatly limits the utility of direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved.

Ataxia Telangiectasia↗
PubMed2003

Site-directed mutagenesis of the ATM promoter: consequences for response to proliferation and ionizing radiation.

Although ATM, the protein defective in ataxia-telangiectasia (A-T), is activated primarily by radiation, there is also evidence that expression of the protein can be regulated by both radiation and growth factors. Computer analysis of the ATM promoter proximal 700-bp sequence reveals a number of potentially important cis-regulatory sequences. Using nucleotide substitutions to delete putative functional elements in the promoter of ATM, we examined the importance of some of these sites for both the basal and the radiation-induced activity of the promoter. In lymphoblastoid cells, most of the mutations in transcription factor consensus sequences [Sp1(1), Sp1(2), Cre, Ets, Xre, gammaIre(2), a modified AP1 site (Fse), and GCF] reduced basal activity to various extents, whereas others [gammaIre(1), NF1, Myb] left basal activity unaffected. In human skin fibroblasts, results were generally the same, but the basal activity varied up to 8-fold in these and other cell lines. Radiation activated the promoter approximately 2.5-fold in serum-starved lymphoblastoid cells, reaching a maximum by 3 hr, and all mutated elements equally blocked this activation. Reduction in Sp1 and AP1 DNA binding activity by serum starvation was rapidly reversed by exposure of cells to radiation. This reduction was not evident in A-T cells, and the response to radiation was less marked. Data provided for interaction between ATM and Sp1 by protein binding and co-immunoprecipitation could explain the altered regulation of Sp1 in A-T cells. The data described here provide additional evidence that basal and radiation-induced regulation of the ATM promoter is under multifactorial control.

Animals↗
PubMed2006

Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling.

Mutations in ATM are responsible for the autosomal recessive disorder ataxia telangiectasia. Heterozygous mutations in ATM have been associated with an elevated risk of breast cancer. We previously reported one breast cancer family in which ATM 7271T>G (V2424G) segregated with disease, and apparently acted in a dominant negative manner. We now report the screening of 782 multiple-case breast cancer families that identified two additional index cases with ATM 7271T>G. Phylogenetic sequence analysis showed that V2424 is a highly conserved residue, and that the 2424G variant is likely to interfere with function. To elucidate the consequences of this mutation, we expression profiled wild-type, heterozygous, and homozygous lymphoblastoid cell lines (LCLs) from Scottish and Australian families using an oligonucleotide microarray. Cluster analysis revealed 77 genes that were differentially expressed in homozygous and heterozygous V2424G cells (compared to wild-type) and 11 genes differentially expressed in the homozygous cells. We also evaluated the profiles of LCLs after exposure to ionizing radiation (IR) and identified 77 genes that were differentially expressed in wild-type cells, but not in homozygous or heterozygous V2424G cells. We validated the expression differences by RT-PCR in additional heterozygous V2424G LCLs from another breast cancer family. We found no consistent cytotoxicity or abrogation of ATM kinase activity after IR in seven heterozygous V2424G LCLs, compared to wild-type LCLs, but did find an increase in the number of chromosomal aberrations. These data suggest that the V2424G missense mutation acts largely as a dominant negative in terms of the associated expression profiles.

Amino Acid Sequence↗
PubMed2003

ATM mutations on distinct SNP and STR haplotypes in ataxia-telangiectasia patients of differing ethnicities reveal ancestral founder effects.

Due to the large size (150 kb) of the ataxia-telangiectasia mutated (ATM) gene and the existence of over 400 mutations, identifying mutations in patients with ataxia-telangiectasia (A-T) is labor intensive. We compared the SNP and STR haplotypes of A-T patients from varying ethnicities who were carrying common ATM mutations. We used SSCP to determine SNP haplotypes. To our surprise, all of the most common ATM mutations in our large multiethnic cohort were associated with specific SNP haplotypes, whereas the STR haplotypes varied, suggesting that ATM mutations predated STR haplotypes but not SNP haplotypes. We conclude that these frequently observed ATM mutations are not hot spots, but have occurred only once and spread with time to different ethnic populations. More generally, a combination of SNP and STR haplotyping could be used as a screening strategy for identifying mutations in other large genes by first determining the ancestral SNP and STR haplotypes in order to identify specific founder mutations. We estimate this approach will identify approximately 30% of mutations in A-T patients across all ethnic groups.

Ataxia Telangiectasia↗
PubMed2005

ATM mutations, haplotype analysis, and immunological status of Russian patients with ataxia telangiectasia.

Mutations in the ATM gene are responsible for the autosomal recessive disorder, ataxia telangiectasia (A-T). Mutations in different ethnic groups are distributed along the entire length of the large, 66 exon ATM gene. In this study, A-T patients from 16 Russian families were assessed for immunological status and ATM haplotype analysis, and screened for ATM mutations. Haplotype analysis was performed to enhance the efficiency of mutation detection. Mutations predicted to cause disease were identified in 19 of 32 alleles (59%), including a truncating mutation (c.5932G>T) that was identified in 8/32 (25%) alleles both by haplotype analysis and mutation screening. This mutation has been found in low abundance in other European A-T cohorts suggesting that this founder-effect mutation may be of Russian origin. The abundance of this mutation may allow for large-scale screening of cancer patients to help clarify the role of ATM in breast and other cancers. Nine of the remaining mutations were previously unreported, and add to the multitude of unique mutations found throughout the gene.

Adolescent↗
PubMed1996

Ataxia-telangiectasia and the ATM gene: linking neurodegeneration, immunodeficiency, and cancer to cell cycle checkpoints.

Defects in regulation of the cellular life cycle may lead to premature cellular death or malignant transformation. Most of the proteins known to be involved in these processes are mediators of mitogenic signals or components of the cell cycle machinery. It has recently become evident, however, that systems responsible for ensuring genome stability and integrity are no less important in maintaining the normal life cycle of the cell. These systems include DNA repair enzymes and a recently emerging group of proteins that alert growth regulating mechanisms to the presence of DNA damage. These signals slow down the cell cycle while DNA repair ensues. Ataxia telangiectasia (A-T) is a genetic disorder whose clinical and cellular phenotype points to a defect in such a signaling system. A-T is characterized by neurodegeneration, immunodeficiency, radiosensitivity, cancer predisposition, and defective cell cycle checkpoints. The responsible gene, ATM, was recently cloned and sequenced. ATM encodes a large protein with a region highly similar to the catalytic domain of PI 3-kinases. The ATM protein is similar to a group of proteins in various organisms which are directly involved in the cell cycle response to DNA damage. It is expected to be part of a protein complex that responds to a specific type of DNA strand break by conveying a regulatory signal to other proteins. Interestingly, the immune and nervous systems, which differ markedly in their proliferation rates, are particularly sensitive to the absence of ATM function. The identification of the ATM gene highlights the growing importance of signal transduction initiated in the nucleus rather than in the external environment, for normal cellular growth.

Animals↗
PubMed2005

ATM polymorphism and hereditary nonpolyposis colorectal cancer (HNPCC) age of onset (United States).

OBJECTIVE: We examined a G-to-A single nucleotide polymorphism of the ATM gene, to determine if it influences hereditary non-polyposis colorectal cancer (HNPCC) age of onset. HNPCC is caused by mutations in mismatch repair genes, especially hMLH1 and hMSH2. ATM germline mutations have been associated with breast and digestive cancers. In a smaller European study, the G-to-A polymorphism was associated with an increased risk of developing an HNPCC-related cancer within HNPCC families. MATERIALS AND METHODS: We genotyped 109 mismatch repair gene (MMR) mutation carriers from 53 HNPCC families for the ATM polymorphism using PCR and single strand conformational polymorphism (SSCP) analysis. We tested the association between the ATM genotypes and HNPCC age of onset by survival analysis. RESULTS: The ATM polymorphism did not significantly modify HNPCC age of onset, nor overall risk, in our population. CONCLUSIONS: Although a modifier effect was not seen in our study, future studies that examine the polymorphism in combination with other genetic and environmental factors may elucidate an association. Revealing such associations in MMR mutation carriers may improve risk estimates and help to identify individuals who are genetically susceptible to developing HNPCC at an earlier age.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Genetic variation in p53 and ATM haplotypes and risk of glioma and meningioma.

BACKGROUND: P53 and ATM are central checkpoint genes involved in the repair of DNA damage after ionising irradiation, which has been associated with risk of brain tumours. Therefore, we tested the hypothesis that polymorphisms and haplotypes in p53 and ATM could be associated with glioma and meningioma risk. MATERIAL AND METHODS: Six hundred and eighty glioma cases (298 glioblastoma (GBM)), 503 meningioma cases, and 1555 controls recruited in the Nordic-UK Interphone study, were analysed in association with three polymorphisms in p53 (rs2287499, rs1042533, rs1625895) and five polymorphisms in ATM ( rs228599, rs3092992, rs664143, rs170548, rs3092993). Haplotypes were constructed using the HAPLOSTAT program. RESULTS: The global statistical test of glioblastoma and p53 haplotypes was p = 0.02. The haplotype analysis on glioblastoma revealed the 1-2-2 haplotype (promotor-codon72-intron 6) had a frequency of 6.1% in cases compared with 9.8% in controls (p = 0.003). The 1-2-1 haplotype was significantly more frequent in GBM cases, 10.2%, than in controls, 7.3% (p = 0.02). The haplotype analysis in ATM revealed an increased frequency of the 1-1-1-2-1 haplotype in meningioma cases (33.8%) compared with controls (30.3%) (p = 0.03). The 2-1-2-1-1 haplotype had a lower frequency in meningioma cases (36.1%) than controls (40.7%) (p = 0.009). CONCLUSIONS: This study found both positive and negative associations of haplotypes in p53 for glioblastoma and ATM for meningioma. This study provides new data that could add to our understanding of brain tumour susceptibility.

Adult↗
PubMed2005

Mice heterozygous for the ATM gene are more sensitive to both X-ray and heavy ion exposure than are wildtypes.

Previous studies have shown that the eyes of ATM heterozygous mice exposed to low-LET radiation (X-rays) are significantly more susceptible to the development of cataracts than are those of wildtype mice. The findings, as well as others, run counter to the assumption underpinning current radiation safety guidelines, that individuals are all equally sensitive to the biological effects of radiation. A question, highly relevant to human space activities is whether or not, in similar fashion there may exist a genetic predisposition to high-LET radiation damage. Mice haplodeficient for the ATM gene and wildtypes were exposed to 325 mGy of 1 GeV/amu 56Fe ions at the AGS facility of Brookhaven National Laboratory. The fluence was equivalent to 1 ion per lens epithelial cell nuclear area. Controls consisted of irradiated wildtype as well as unirradiated wildtype and heterozygous mice. Prevalence analyses for stage 0.5-3.0 cataracts indicated that not only cataract onset but also progression were accelerated in the mice haplo-deficient for the ATM gene. The data show that heterozygosity for the ATM gene predisposes the eye to the cataractogenic influence of heavy ions and suggest that ATM heterozygotes in the human population may also be radiosensitive. This may have to be considered in the selection of individuals who will be exposed to both HZE particles and low-LET radiation as they may be predisposed to increased late normal tissue damage.

Animals↗
PubMed2004

Poly(ADP-ribose) polymerase-1 inhibits ATM kinase activity in DNA damage response.

DNA double-strand breaks (DSB) mobilize DNA-repair machinery and cell cycle checkpoint by activating the ataxia-telangiectasia (A-T) mutated (ATM). Here we show that ATM kinase activity is inhibited by poly(ADP-ribose) polymerase-1 (PARP-1) in vitro. It was shown by biochemical fractionation procedure that PARP-1 as well as ATM increases at chromatin level after induction of DSB with neocarzinostatin (NCS). Phosphorylation of histone H2AX on serine 139 and p53 on serine 15 in Parp-1 knockout (Parp-1(-/-)) mouse embryonic fibroblasts (MEF) was significantly induced by NCS treatment compared with MEF derived from wild-type (Parp-1(+/+)) mouse. NCS-induced phosphorylation of histone H2AX on serine 139 in Parp-1(-/-) embryonic stem cell (ES) clones was also higher than that in Parp-1(+/+) ES clone. Furthermore, in vitro, PARP-1 inhibited phosphorylation of p53 on serine 15 and (32)P-incorporation into p53 by ATM in a DNA-dependent manner. These results suggest that PARP-1 negatively regulates ATM kinase activity in response to DSB.

Animals↗
PubMed2004

Cryptic deletion involving the ATM locus at 11q22.3 approximately q23.1 in B-cell chronic lymphocytic leukemia and related disorders.

B-cell chronic lymphocytic leukemia (B-CLL) follows a heterogeneous clinical course, and several biological parameters have been investigated to try to predict its clinical outcome. New staging systems including cytogenetics and CD38 expression as predictive values have been developed. Deletions of 11q22.3 approximately q23.1 detected at diagnosis in cases of CLL patients have been associated with a relatively aggressive disease. This region, which contains the ataxia telangiectasia mutated (ATM) locus, may be implicated in the pathogenesis of lymphoid malignancies. We developed a set of dual-color specific probes to evaluate the ATM deletion by means of fluorescence in situ hybridization (FISH). We also used flow cytometry to investigate CD38 expression. Forty-one patients with CLL or low-grade B-cell lymphomas were studied at diagnosis or before treatment. FISH showed that only three CLL patients had deletions in the 11q23 locus; all three had progressive disease and were resistant to treatment. These data show that our FISH set of probes efficiently detects ATM deletions in CLL. No correlation was found between ATM deletions and CD38 expression level. These results confirm the prognostic significance of ATM deletions in CLL.

ADP-ribosyl Cyclase↗
PubMed2006

The role of NBS1 in the modulation of PIKK family proteins ATM and ATR in the cellular response to DNA damage.

Ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases have been considered the primary activators of the cellular response to DNA damage. They belong to the protein kinase family, phosphoinositide 3-kinase-related kinase (PIKKs). In human beings, deficiency of these kinases leads to hereditary diseases, namely ataxia telangiectasia (AT) with ATM deficiency and ATR-Seckel with ATR deficiency. NBS1, a component of MRE11/RAD50/NBS1 (MRN) complex, is another important player in DNA damage response (DDR). Mutations of NBS1 are responsible for Nijmegen breakage syndrome (NBS), a human hereditary disease with the characteristics that almost encompassed those of AT and ATR-Seckel. NBS1 has been conventionally thought to be a downstream substrate of ATM and ATR in DDR; however, recent studies suggest that NBS1/MRN functions upstream of both ATM and ATR by recruiting them to the proximity of DNA damage sites and activating their functions. In this mini-review, we would emphasize the requirement of NBS1 as an upstream mediator for the modulation of PIKK family proteins ATM and ATR.

Animals↗
PubMed2005

Harmonising the response to DSBs: a new string in the ATM bow.

Ataxia telangiestasia mutated protein (ATM) is the major kinase that initiates the DNA damage signal transduction response following exposure to ionising radiation (IR) in mammalian cells. DNA non-homologous end-joining (NHEJ) is the most significant double strand break (DSB) repair pathway in mammalian cells. ATM-defective cell lines display cell cycle checkpoint defects and show pronounced radiosensitivity. ATM signalling was previously thought to be dispensable for NHEJ. This review discusses recent findings that ATM activates an end-processing mechanism dependent upon Artemis, a nuclease that also functions to cleave the hairpin intermediate generated during V(D)J recombination. ATM/Artemis-dependent end-processing is required for the repair of a sub-fraction (approximately 10%) of DSBs induced by IR and makes a significant contribution to survival following exposure to ionising radiation. This result represents a new role for ATM and demonstrates a novel cross communication between the DNA repair and signal transduction machinery.

Animals↗
PubMed2005

ATM sequence variants are predictive of adverse radiotherapy response among patients treated for prostate cancer.

PURPOSE: To examine whether the presence of sequence variants in the ATM (mutated in ataxia-telangiectasia) gene is predictive for the development of radiation-induced adverse responses resulting from (125)I prostate brachytherapy for early-stage prostate cancer. MATERIALS AND METHODS: Thirty-seven patients with a minimum of 1-year follow-up who underwent (125)I prostate brachytherapy of early-stage prostate cancer were screened for DNA sequence variations in all 62 coding exons of the ATM gene using denaturing high-performance liquid chromatography. The clinical course and postimplant dosimetry for each genetically characterized patient were obtained from a database of 2,020 patients implanted at Mount Sinai Hospital after 1990. RESULTS: Twenty-one ATM sequence alterations located within exons, or in short intronic regions flanking each exon, were found in 16 of the 37 patients screened. For this group, 10 of 16 (63%) exhibited at least one form of adverse response. In contrast, of the 21 patients who did not harbor an ATM sequence variation, only 3 of 21 (14%) manifested radiation-induced adverse responses (p = 0.005). Nine of the patients with sequence alterations specifically possessed missense mutations, which encode for amino acid substitutions and are therefore more likely to possess functional importance. For this group, 7 of 9 (78%) exhibited at least one form of adverse response. In contrast, of the 28 patients who did not have a missense alteration, only 6 of 28 (21%) manifested any form of adverse response to the radiotherapy (p = 0.004). Of the patients with missense variants, 5 of 9 (56%) exhibited late rectal bleeding vs. 1 of 28 (4%) without such alterations (p = 0.002). Of those patients who were at risk for developing erectile dysfunction, 5 of 8 (63%) patients with missense mutations developed prospectively evaluated erectile dysfunction as opposed to 2 of 20 (10%) without these sequence alterations (p = 0.009). CONCLUSIONS: Possession of sequence variants in the ATM gene, particularly those that encode for an amino acid substitution, is predictive for the development of adverse radiotherapy responses among patients treated with (125)I prostate brachytherapy.

Aged↗
PubMed2004

A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci.

The hereditary disorder ataxia telangiectasia (A-T) is associated with striking cellular radiosensitivity that cannot be attributed to the characterized cell cycle checkpoint defects. By epistasis analysis, we show that ataxia telangiectasia mutated protein (ATM) and Artemis, the protein defective in patients with RS-SCID, function in a common double-strand break (DSB) repair pathway that also requires H2AX, 53BP1, Nbs1, Mre11, and DNA-PK. We show that radiation-induced Artemis hyperphosphorylation is ATM dependent. The DSB repair process requires Artemis nuclease activity and rejoins approximately 10% of radiation-induced DSBs. Our findings are consistent with a model in which ATM is required for Artemis-dependent processing of double-stranded ends with damaged termini. We demonstrate that Artemis is a downstream component of the ATM signaling pathway required uniquely for the DSB repair function but dispensable for ATM-dependent cell cycle checkpoint arrest. The significant radiosensitivity of Artemis-deficient cells demonstrates the importance of this component of DSB repair to survival.

Animals↗
PubMed2004

The ATM-SMC1 pathway is essential for activation of the chromium[VI]-induced S-phase checkpoint.

Hexavalent chromium (Cr[VI]) is a common industrial waste product, an environmental pollutant, and a recognized human carcinogen. Following cellular uptake, Cr[VI] can cause DNA damage, however, the mechanisms by which mammalian cells respond to Cr-induced DNA damage remain to be elucidated. Using single cell gel electrophoresis (e.g., Comet Assay) and immunofluoresence microscopy to detect the presence of gamma-H2AX foci, we find that Cr[VI] induces DNA double-strand breaks similar to ionizing radiation (IR). We also demonstrated that ataxia telangiectasia mutated (ATM) is activated in response to Cr[VI] and exposure to Cr[VI] triggers a dose and ATM-dependent S-phase arrest. Further, we document that ATM is required for phosphorylation of the structural maintenance of chromosome protein 1 (SMC1). Finally, we find that ATM-dependent phosphorylation of SMC1 is required to facilitate S-phase cell-cycle arrest in response to Cr[VI] exposure. Collectively, these results indicate that the ATM-SMC1 pathway plays a critical role in cellular response to Cr[VI].

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

The two edges of the ATM sword: co-operation between repair and checkpoint functions.

ATM is a central component of a signal transduction process that responds to DNA double strand breaks (DSBs) ultimately effecting cell cycle checkpoint arrest and/or apoptosis. Recent studies have shown that ATM also regulates a mechanism of processing a subset of DNA ends that appear to be difficult to ligate, since they are rejoined with slow kinetics in control cells. In the absence of this process, which involves the nuclease, Artemis, the DSBs either remain unrejoined or potentially undergo misrejoining. Thus, ATM's checkpoint function specifically facilitates its repair function. Here, we discuss the contribution of this novel function of ATM to survival after ionising irradiation and to cancer avoidance. We suggest that ATM's strength as a damage response protein lies in the co-ordination of its repair and checkpoint functions making a razor sharp knife out of two blunter edges.

Animals↗
PubMed2000

Protective roles for ATM in cellular response to oxidative stress.

ATM (ataxia telangiectasia mutated), the gene mutated in ataxia telangiectasia, is related to a family of large phosphatidylinositol 3-kinase domain-containing proteins involved in cell cycle control and DNA repair. We found that ATM(-/-) DT40 cells were more susceptible than wild-type cells to apoptosis induced not only by ionizing radiation and bleomycin but also by non-DNA-damaging apoptotic stimuli such as C(2)-ceramide. Furthermore, the apoptosis induced by C(2)-ceramide and H(2)O(2) was blocked by anti-oxidants, indicating that the ATM(-/-) DT40 cells had a heightened susceptibility to apoptosis induced by reactive oxygen intermediates (ROI), presumably due to defective ROI-detoxification activities. In support of this hypothesis, we found that more ROI were generated in ATM(-/-) DT40 cells than in wild-type cells, following treatment with the above apoptotic stimuli. These results indicate that ATM plays important roles in the maintenance of the cell homeostasis in response to oxidative damage.

Animals↗