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At least 595 records · Page 33Linked to original sources
PubMed2003

Clinical radiosensitivity in breast cancer patients carrying pathogenic ATM gene mutations: no observation of increased radiation-induced acute or late effects.

BACKGROUND AND PURPOSE: Reports on increased late subcutaneous toxicity after radiation therapy (RT) in breast cancer patients carrying ATM gene mutations has raised concerns about RT as part of the management in these patients. The impact of ataxia-telangiectasia (A-T) heterozygosity on clinical radiosensitivity remains a matter of debate while clinical data are scarce. PATIENTS AND METHODS: Between September 1995 and December 2002 genomic DNA samples were collected from 1100 unselected breast cancer patients receiving adjuvant radiotherapy at our department. Using mutation-specific assays, we screened for frequent ATM gene mutations. Analysis of acute and late radiation-related toxicity for skin and subcutaneous normal tissue was performed in patients identified as A-T heterozygotes applying common toxicity criteria (CTC) and LENT/SOMA (late effects on normal tissue/subjective objective management analytic) scoring criteria, respectively. RESULTS: Eleven patients were identified to be heterozygous for a pathogenic ATM gene mutation. Ten patients had received at least one course of RT. Median follow-up after completion of radiotherapy was 5.1 years (range 1.7-7.2). There was no evidence of increased radiation-induced acute or late skin or subcutaneous reactions in patients treated with linac-based RT. One patient failed distantly and was subsequently irradiated at four different sites for bone and brain metastases. Local relapse occurred in the single patient who had declined adjuvant RT following breast conservative therapy. CONCLUSIONS: Our results do not provide evidence for a relative contraindication to adjuvant RT in A-T heterozygous breast cancer patients. Due to their increased cellular radiosensitivity, these patients may differentially benefit from RT and qualify for dose and volume reduction trials.

Adult↗
PubMed1996

Atm-deficient mice: a paradigm of ataxia telangiectasia.

A murine model of ataxia telangiectasia was created by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. The majority of animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulate the ataxia telangiectasia phenotype in humans, providing a mammalian model in which to study the pathophysiology of this pleiotropic disorder.

Animals↗
PubMed2002

Elevated frequency of ATM gene missense mutations in breast cancer relative to ethnically matched controls.

Studies of families of patients with ataxia telangiectasia (A-T) show an increased risk of breast cancer in heterozygous A-T carriers. However, expected increased levels of mutations in the ATM gene among unselected breast cancer patients have not been found to date. Previous methods of mutation detection were biased toward the detection of truncating mutations, and single nucleotide substitutions were likely to have been underreported. In this study, genomic DNA from 43 breast cancer patients and 43 control individuals were scanned for mutations in the entire ATM coding region (exons 4-65) and adjacent intronic splice regions (three megabases total) using detection of virtually all mutation-single-strand conformation polymorphism (SSCP), a modification of SSCP with sufficient redundancy to detect virtually all mutations. Excluding a polymorphism found commonly in cases and controls, there were missense changes in 12 breast cancer patients, one of whom also had a protein truncating mutation, versus six controls (P=0.09). When all structural changes common to the cases and controls were excluded, missense or truncating changes were found in 10 cases compared to two in controls (P=0.013). The background of missense changes in controls is high. There is a trend towards elevation of all structural changes in cases, but the results are not statistically significant. Cohort-specific structural changes are significantly more prevalent in the breast cancer patients. The data are compatible with certain missense mutations in ATM predisposing to breast cancer.

Adult↗
PubMed1997

Responses to DNA damage and regulation of cell cycle checkpoints by the ATM protein kinase family.

In mammalian cells, four protein kinases form the PI3-kinase-related protein kinase (PIK) superfamily. These four enzymes-FRAP, DNA-PK, ATM, and ATR-are distinguished by their large size (all are >2500 amino acids), their common primary sequence relatedness through the carboxy-terminal protein kinase domain, and their sequence similarity to the p110 lipid kinase subunit of PI3-kinase. FRAP (FKBP12 and rapamycin-binding protein kinase) participates in mitogenic and growth factor responses in G1 and may regulate specific mRNA translation signals. DNA-PK (DNA-dependent protein kinase), ATM (ataxia telangiectasia mutated), and ATR (ataxia telangiectasia and Rad 3 related) are thought to participate in responses to nuclear cues that activate DNA rearrangements or cell cycle arrests. Recent studies in this protein kinase family indicate an important role for ATM and ATR in a meiotic surveillance mechanism that may regulate proper chromosome transmission.

Adenosine Triphosphatases↗
PubMed1998

The 400 kDa subunit of the PCAF histone acetylase complex belongs to the ATM superfamily.

PCAF histone acetylase is found in a complex with more than 20 associated polypeptides. Here we report cloning and characterization of the 400 kDa PCAF-associated factor referred to as PAF400. PAF400 is almost identical to TRRAP, which binds to c-Myc and E2F, and has significant sequence similarities to the ATM superfamily including FRAP, ATM, ATR, and the catalytic subunit of DNA-PK. Remarkably, PAF400 and FRAP share sequence similarity in broad regions that cover 80% of the entire PAF400 sequence. However, unlike the other members of the ATM superfamily, PAF400 is not a protein kinase as judged from the lack of kinase motif and autophosphorylation activity. We discuss the possibility that PAF400 may play a role in signaling of DNA damage to p53 by stimulation of p53 acetylation.

Acetyltransferases↗
PubMed2004

Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a).

Cellular senescence can be triggered by telomere shortening as well as a variety of stresses and signaling imbalances. We used multiparameter single-cell detection methods to investigate upstream signaling pathways and ensuing cell cycle checkpoint responses in human fibroblasts. Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 and causing G1 phase arrest. Inhibition of ATM expression or activity resulted in cell cycle reentry, indicating that stable arrest requires continuous signaling. ATR kinase appears to play a minor role in normal cells but in the absence of ATM elicited a delayed G2 phase arrest. These pathways do not affect expression of p16, which was upregulated in a telomere- and DNA damage-independent manner in a subset of cells. Distinct senescence programs can thus progress in parallel, resulting in mosaic cultures as well as individual cells responding to multiple signals.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2001

Ataxia telangiectasia: new neurons and ATM.

Despite the rarity of the human autosomal recessive disease ataxia telangiectasia (A-T) (affecting approximately 1/40000-1/100000), interest in the function of the mutated gene product (ATM) in this syndrome is intense. Mutation of this single gene can lead to a diverse array of features, including cancer, immune defects, infertility and radiosensitivity. However, it is the pronounced and debilitating neurodegeneration that is the hallmark of this disease. Thus, from a clinical perspective, it is ATM function in the nervous system that, arguably, is the most important to understand. Although the case for DNA damage as a causative factor for neurodegeneration in A-T is compelling, new data point to a possible link to defects in neurogenesis. Thus, whereas ATM is important for nervous system development, it could also be important for adult neurogenesis.

Animals↗
PubMed2002

ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage.

ATM is one of the sentries at the gate of genome stability. This multifunctional protein kinase orchestrates the intricate array of cellular responses to DNA double-strand breaks. Absence or inactivation of ATM leads to the pleiotropic genetic disorder ataxia-telangiectasia (A-T), whose hallmarks are neuronal degeneration, immunodeficiency, genomic instability, premature aging and cancer predisposition. Several features of the complex clinical and cellular phenotype of A-T are reminiscent of other syndromes involving neurodegeneration, premature aging or genomic instability. A common denominator of many of these conditions is the perturbation of the cellular balance of reactive oxygen species, which leads to constant oxidative stress. Of these disorders, ATM deficiency is one of the most extensively studied with regard to the genome instability-oxidative stress connection. This connection may provide new insights into the phenotypes associated with genetic deficiencies of DNA damage responses, and point to new strategies to alleviate some of their clinical symptoms.

Animals↗
PubMed1997

Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy.

The effectiveness of cancer radiotherapy is compromised by the small proportion (approximately 5%) of patients who sustain severe normal tissue damage after standard radiotherapy treatments. Predictive tests are required to identify these highly radiosensitive cases. Patients with the rare, recessively inherited, cancer-prone syndrome ataxia-telangiectasia (A-T) sustain extremely severe normal tissue necrosis after radiotherapy and their cultured cells are also highly radiosensitive. Clinically normal carriers (heterozygotes) of the A-T gene have an increased risk of breast cancer, account for approximately 4% of all breast cancer cases and show a modest increase in cellular radiosensitivity in vitro. It has been suggested that a substantial proportion of highly radiosensitive (HR) breast cancer patients may be A-T heterozygotes, and that screening for mutations in the A-T gene could be used as a predictive test. We have tested this hypothesis in a group of cancer patients who showed adverse reactions to radiotherapy. Sixteen HR breast cancer patients showing mainly acute reactions (and seven HR patients with other cancers) were tested for ATM mutations using the restriction endonuclease fingerprinting assay. No mutations typical of those found in obligate A-T heterozygotes were detected. If the estimate that 4% of breast cancer cases are A-T gene carriers is correct, then ATM mutations do not confer clinical radiosensitivity. These early results suggest that screening for ATM mutations in cancer patients may not be of value in predicting adverse reactions.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2005

Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase.

Chemotherapy that is used to treat human immunodeficiency virus type-1 (HIV-1) infection focuses primarily on targeting virally encoded proteins. However, the combination of a short retroviral life cycle and high mutation rate leads to the selection of drug-resistant HIV-1 variants. One way to address this problem is to inhibit non-essential host cell proteins that are required for viral replication. Here we show that the activity of HIV-1 integrase stimulates an ataxia-telangiectasia-mutated (ATM)-dependent DNA damage response, and that a deficiency of this ATM kinase sensitizes cells to retrovirus-induced cell death. Consistent with these observations, we demonstrate that a novel and specific small molecule inhibitor of ATM kinase activity, KU-55933, is capable of suppressing the replication of both wild-type and drug-resistant HIV-1.

Animals↗
PubMed2005

Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models.

Nijmegen breakage syndrome (NBS) is a chromosomal fragility disorder that shares clinical and cellular features with ataxia telangiectasia. Here we demonstrate that Nbs1-null B cells are defective in the activation of ataxia-telangiectasia-mutated (Atm) in response to ionizing radiation, whereas ataxia-telangiectasia- and Rad3-related (Atr)-dependent signalling and Atm activation in response to ultraviolet light, inhibitors of DNA replication, or hypotonic stress are intact. Expression of the main human NBS allele rescues the lethality of Nbs1-/- mice, but leads to immunodeficiency, cancer predisposition, a defect in meiotic progression in females and cell-cycle checkpoint defects that are associated with a partial reduction in Atm activity. The Mre11 interaction domain of Nbs1 is essential for viability, whereas the Forkhead-associated (FHA) domain is required for T-cell and oocyte development and efficient DNA damage signalling. Reconstitution of Nbs1 knockout mice with various mutant isoforms demonstrates the biological impact of impaired Nbs1 function at the cellular and organismal level.

ATP-Binding Cassette Transporters↗
PubMed2005

DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion.

Telomere attrition and other forms of telomere damage can activate the ATM kinase pathway. What generates the DNA damage signal at mammalian chromosome ends or at other double-strand breaks is not known. Telomere dysfunction is often accompanied by disappearance of the 3' telomeric overhang, raising the possibility that DNA degradation could generate the structure that signals. Here we address these issues by studying telomere structure after conditional deletion of mouse TRF2, the protective factor at telomeres. Upon removal of TRF2 from TRF2(F/-) p53-/- mouse embryo fibroblasts, a telomere damage response is observed at most chromosome ends. As expected, the telomeres lose the 3' overhang and are processed by the non-homologous end-joining pathway. Non-homologous end joining of telomeres was abrogated in DNA ligase IV-deficient (Lig4-/-) cells. Unexpectedly, the telomeres of TRF2-/- Lig4-/- p53-/- cells persisted in a free state without undergoing detectable DNA degradation. Notably, the telomeres retained their 3' overhangs, but they were recognized as sites of DNA damage, accumulating the DNA damage response factors 53BP1 and gamma-H2AX, and activating the ATM kinase. Thus, activation of the ATM kinase pathway at chromosome ends does not require overhang degradation or other overt DNA processing.

Animals↗
PubMed2002

53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer.

53BP1 is a conserved nuclear protein that is implicated in the DNA damage response. After irradiation, 53BP1 localizes rapidly to nuclear foci, which represent sites of DNA double strand breaks, but its precise function is unclear. Using small interference RNA (siRNA), we demonstrate that 53BP1 functions as a DNA damage checkpoint protein. 53BP1 is required for at least a subset of ataxia telangiectasia-mutated (ATM)-dependent phosphorylation events at sites of DNA breaks and for cell cycle arrest at the G2-M interphase after exposure to irradiation. Interestingly, in cancer cell lines expressing mutant p53, 53BP1 was localized to distinct nuclear foci and ATM-dependent phosphorylation of Chk2 at Thr 68 was detected, even in the absence of irradiation. In addition, Chk2 was phosphorylated at Thr 68 in more than 50% of surgically resected lung and breast tumour specimens from otherwise untreated patients [corrected]. We conclude that the constitutive activation of the DNA damage checkpoint pathway may be linked to the high frequency of p53 mutations in human cancer, as p53 is a downstream target of Chk2 and ATM.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2006

ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.

We screened individuals from 443 familial breast cancer pedigrees and 521 controls for ATM sequence variants and identified 12 mutations in affected individuals and two in controls (P = 0.0047). The results demonstrate that ATM mutations that cause ataxia-telangiectasia in biallelic carriers are breast cancer susceptibility alleles in monoallelic carriers, with an estimated relative risk of 2.37 (95% confidence interval (c.i.) = 1.51-3.78, P = 0.0003). There was no evidence that other classes of ATM variant confer a risk of breast cancer.

Alleles↗
PubMed2003

ATM and related protein kinases: safeguarding genome integrity.

Maintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response--a cornerstone of genome stability--occurs by a swift transduction of the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA double-strand breaks, which activate the ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.

Animals↗
PubMed2025

Crosstalk between chromatin state and ATM signalling in DNA damage-induced transcription stress.

The DNA Damage Response (DDR) is a highly regulated process that safeguards genomic integrity against DNA lesions. Increasing evidence supports a reciprocal relationship between damaged chromatin architecture and the signalling pathways that coordinate the DDR. However, the mechanisms underlying this interplay in response to transcription-blocking DNA lesions remain largely unexplored. Here, we show that stalling of RNA polymerase II (RNAPII) at such lesions induces local chromatin acetylation, mediated primarily by the histone acetyltransferase p300. The resulting chromatin relaxation stimulates the dissociation of mature co-transcriptional spliceosomes from nascent RNA and promotes RNA:DNA hybrid (R-loop) formation, leading to ATM activation. In turn, activated ATM modulates chromatin conformation by phosphorylating histone H2A.X and triggering p38MAPK/MSK1-dependent histone H3S10 phosphorylation. Our findings highlight the cross-regulation between chromatin state and ATM signalling as a key component of the cellular response to transcription stress.

Ataxia Telangiectasia Mutated Proteins↗
PubMedDate not supplied

Identical mutation in 55% of the ATM alleles in 11 Norwegian AT families: evidence for a founder effect.

The ATM gene is responsible for the autosomal recessive disorder Ataxia-Telangiectasia (AT). Many different mutations, located all across the gene, have been reported with a predominance of truncating mutations. By using PTT (protein truncation test) a mutation was found in one Norwegian AT family. Sequencing revealed that the mutation affected nucleotides 3245-3247, codon 1082, and changed the sequence from ATC to TGAT, inducing a stop codon downstream at codon 1095 and leading to early truncation of the ATM protein. Perpendicular DGGE (denaturing gradient gel electrophoresis) was used to screen 10 additional families for this mutation. The 3245 delATC insTGAT mutation was found in 12 of 22 proband alleles: five patients were homozygotes and two heterozygotes. Haplotype analyses were performed using eight microsatellite markers, within and flanking the ATM gene. All carriers of the mutation described were found to have a common haplotype of the five closest CA-repeat microsatellite markers. Genealogical investigations of the families identified a common ancestor for three of the families. The common ancestor was a woman born in 1684 in the area from which these families originate. The prevalence of this mutation in Norwegian patients now allows a major subset of AT heterozygotes to be identified, both in the general population and in breast cancer patients, so that their cancer risk can be evaluated.

Ataxia Telangiectasia↗
PubMed2005

ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage.

The p53 tumor suppressor is activated after DNA damage to maintain genomic stability and prevent transformation. Rapid activation of p53 by ionizing radiation is dependent on signaling by the ATM kinase. MDM2 and MDMX are important p53 regulators and logical targets for stress signals. We found that DNA damage induces ATM-dependent phosphorylation and degradation of MDMX. Phosphorylated MDMX is selectively bound and degraded by MDM2 preceding p53 accumulation and activation. Reduction of MDMX level by RNAi enhances p53 response to DNA damage. Loss of ATM prevents MDMX degradation and p53 stabilization after DNA damage. Phosphorylation of MDMX on S342, S367, and S403 were detected by mass spectrometric analysis, with the first two sites confirmed by phosphopeptide-specific antibodies. Mutation of MDMX on S342, S367, and S403 each confers partial resistance to MDM2-mediated ubiquitination and degradation. Phosphorylation of S342 and S367 in vivo require the Chk2 kinase. Chk2 also stimulates MDMX ubiquitination and degradation by MDM2. Therefore, the E3 ligase activity of MDM2 is redirected to MDMX after DNA damage and contributes to p53 activation.

Ataxia Telangiectasia Mutated Proteins↗