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At least 721 records · Page 40Linked to original sources
PubMed1996

High levels of allele loss at the FHIT and ATM genes in non-comedo ductal carcinoma in situ and grade I tubular invasive breast cancers.

Fifty-four grade 1 tubular breast cancers and nine non-comedo ductal carcinoma in situ samples have been analyzed for loss of heterozygosity using a series of microsatellite markers. Markers mapping to regions of the genome for which loss of heterozygosity has been documented previously in higher-grade breast cancers were selected for this analysis. Even within this group of good prognostic early breast cancers, genetic events are very common. The highest levels of loss were observed for D3S1300, which maps within an intron of the recently identified FHIT gene. High levels of loss were also observed within the ATM gene. These findings indicate that allele loss at FHIT and ATM may be an important early event in the development of sporadic breast cancer.

Acid Anhydride Hydrolases↗
PubMed2026

An IRAK1-snRNA axis activates ATM to promote accurate repair within transcriptionally active chromatin.

Genomic integrity in transcriptionally active regions is pivotal for suppressing oncogenic mutations, yet the mechanisms that govern precise homologous recombination (HR) repair within these regions remain elusive. Here, we report that the IRAK1-spliceosome axis operates with small nuclear RNA (snRNA) as a central hub, potently promoting accurate repair at DNA double-strand break (DSB) sites within active chromatin in human cancer cells. Mechanistically, IRAK1 phosphorylates spliceosomal serine/arginine (SR)-rich proteins to recruit snRNA to DSBs, inducing robust condensation of the MRE11-RAD50-NBS1 (MRN) complex near transcriptionally active regions to create an ATM activation platform. Collectively, our findings define a prevalent mechanism governing region-specific precise repair in transcriptionally active domains, where snRNA acts as a "transcription repair bridge" to link transcriptional processes to HR repair and ultimately preserves genomic stability. Inhibiting IRAK1 axis impairs HR repair in transcriptionally active regions, causing a marked increase in mutation rates specific to these regions and cancer-cell chemosensitivity.

Humans↗
PubMed2003

Genotyping African haplotypes in ATM using a co-spotted single-base extension assay.

Human genetic analysis, including population genetic studies, increasingly calls for cost-effective, high-throughput methods for the rapid screening of single nucleotide polymorphisms (SNPs) across many individuals. The modified single-base extension assay described here (arrayed SBE) is a highly accurate and robust method for SNP genotyping that can deliver genotypes at 3.5 cents each, following PCR. Specifically, amino-modified probe/target pairs were prehybridized, then co-spotted in a microarray format prior to enzymatic addition of allele-specific nucleotides. Probe/target identity was determined solely by its physical location on the array rather than by hybridization to a complementary target, resulting in a call rate of 99-100%. These innovations result in an inexpensive, accurate assay with exceptional signal-to-noise ratios, depending on the glass surface employed. Comparison of glass slides from three different manufacturers indicated that aldehyde-based Zyomyx slides provided superior performance for this assay. Arrayed SBE was applied to study the geographic distribution of three African-specific haplotypes in the human ATM gene. Four selectively neutral markers, which define the haplotypes H5, H6, and H7, were screened in a total of 415 individuals. Region-specific haplotype frequencies were consistent with patterns of human migration across and outside of Africa, suggesting a possible haplotype origin in East Africa. Arrayed SBE was a robust tool for this analysis that could be applied to any situation requiring the genotyping of a few SNPs in many individuals.

Africa, Eastern↗
PubMed2004

Nonclassical splicing mutations in the coding and noncoding regions of the ATM Gene: maximum entropy estimates of splice junction strengths.

Ataxia-telangiectasia (A-T) is an autosomal recessive neurological disorder caused by mutations in the ATM gene. Classical splicing mutations (type I) delete entire exons during pre-mRNA splicing. In this report, we describe nine examples of nonclassical splicing mutations in 12 A-T patients and compare cDNA changes to estimates of splice junction strengths based on maximum entropy modeling. These mutations fall into three categories: pseudoexon insertions (type II), single nucleotide changes within the exon (type III), and intronic changes that disrupt the conserved 3' splice sequence and lead to partial exon deletion (type IV). Four patients with a previously reported type II (pseudoexon) mutation all shared a common founder haplotype. Three patients with apparent missense or silent mutations actually had type III aberrant splicing and partial deletion of an exon. Five patients had type IV mutations that could have been misinterpreted as classical splicing mutations. Instead, their mutations disrupt a splice site and use another AG splice site located nearby within the exon; they lead to partial deletions at the beginning of exons. These nonclassical splicing mutations create frameshifts that result in premature termination codons. Without screening cDNA or using accurate models of splice site strength, the consequences of these genomic mutations cannot be reliably predicted. This may lead to further misinterpretation of genotype-phenotype correlations and may subsequently impact upon gene-based therapeutic approaches.

Ataxia Telangiectasia↗
PubMed1999

PCR-mediated detection of a polymorphism in the ATM gene.

In this report, the frequency of the G-->A transition polymorphism at nucleotide 5557 in exon 39 of the coding sequence of the gene mutated in ataxia-telangiectasia (ATM) was analysed. The frequency of the A and G alleles was estimated in the general population at 0. 15 and 0.85, respectively. This polymorphism can be identified by single-strand conformation polymorphism (SSCP) and by a simple and rapid Dde I digestion after polymerase chain reaction (PCR)-mediated site directed mutagenesis (PSDM).

Alleles↗
PubMed2000

[Audiovisual telecommunication by multimedia technology in HNO medicine. ISDN--internet--ATM].

Telemedicine includes all medical activities in diagnosis, therapeutics, or social medicine undertaken by means of an electronic transfer medium, enabling the transmission of visual and acoustic information over long distances to doctors not personally present at the place of the requested consultation. Most experience with telemedicine applications has been gained in the field of diagnosis (teleconsultation, teleradiology, telepathology) and is expanding to quality control and quality assurance. Decisive for each form of application is its availability, practicability, cost, safety, and especially quality of audiovisual transmission. For telesurgical applications, particularly the use of minimally invasive techniques in otorhinolaryngology, head, and neck surgery, the high quality transmission of audiovisual data in real time is necessary. Rapid expansion and further developments in transmission technologies and networks in the last decade have created several technologies with increased quality and costs. In this paper, we tested different transmission media for audiovisual telecommunication--integrated services digital network (ISDN), Internet, and asynchronous transfer mode (ATM)--using real time video transmission of typical operations in otorhinolaryngology. Their applications, costs, and future perspectives are discussed.

Germany↗
PubMedDate not supplied

PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development.

Poly(ADP-ribosyl)ation is an immediate DNA damage-dependent posttranslational modification of histones and nuclear proteins that contributes to the survival of injured proliferating cells. Poly(ADP-ribose) polymerases (PARPs) now constitute a superfamily of 18 proteins, encoded by different genes and displaying a common conserved catalytic domain. PARP-1 (113kDa), the founding member, and PARP-2 (62kDa) are both involved in DNA-break sensing and signaling when single strand break repair (SSBR) or base excision repair (BER) pathways are engaged. The generation by homologous recombination of deficient mouse models have confirmed the caretaker function of PARP-1 and PARP-2 in mammalian cells under genotoxic stress. This review summarizes our present knowledge on their physiological role in the cellular response to DNA damage and on the genetic interactions between PARP-1, PARP-2, Atm that play an essential role during early embryogenesis.

Animals↗
PubMed2004

The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4.

Ataxia-oculomotor apraxia 1 (AOA1) is an autosomal recessive neurodegenerative disease that is reminiscent of ataxia-telangiectasia (A-T). AOA1 is caused by mutations in the gene encoding aprataxin, a protein whose physiological function is currently unknown. We report here that, in contrast to A-T, AOA1 cell lines exhibit neither radioresistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of A-T. In addition, AOA1 primary fibroblasts exhibit only mild sensitivity to ionising radiation, hydrogen peroxide, and methyl methanesulphonate (MMS). Strikingly, however, aprataxin physically interacts in vitro and in vivo with the DNA strand break repair proteins XRCC1 and XRCC4. Aprataxin possesses a divergent forkhead associated (FHA) domain that closely resembles the FHA domain present in polynucleotide kinase, and appears to mediate the interactions with CK2-phosphorylated XRCC1 and XRCC4 through this domain. Aprataxin is therefore physically associated with both the DNA single-strand and double-strand break repair machinery, raising the possibility that AOA1 is a novel DNA damage response-defective disease.

Apraxias↗
PubMed2006

Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and the proteasome.

In response to DNA breaks, human cells delay their progression through the G1, S, and G2 phases of the cell cycle. This response requires the coordinated effort of the ATM-CHK2-p53 and ATR-CHK1 DNA damage-sensing pathways and DNA repair (eg, DNA-PK and RAD51 complexes). The turnover of many of these DNA damage-associated proteins is controlled by the 26S proteasome. In this article, we review molecular strategies that target each of these pathways using silencing RNA (siRNA), antisense, or small-molecule inhibition. Although these agents can radiosensitize tumor cells, little data are available regarding potential effects on normal tissues to determine the potential therapeutic ratio of these strategies after fractionated radiotherapy. Clinical trials using such agents will require novel correlative science endpoints to track DNA repair and cell-cycle arrest and will need careful assessment of normal tissue toxicity and stability.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2006

p53-Dependent but ATM-independent inhibition of DNA synthesis and G2 arrest in cadmium-treated human fibroblasts.

This study focused on the activation of cell cycle checkpoint responses in diploid human fibroblasts that were treated with cadmium chloride and the potential roles of ATM and p53 signaling pathways in cadmium-induced responses. The alkaline comet assay indicated that cadmium caused a dose-dependent increase in DNA damage. Cells that were rendered p53-defective by expression of a dominant-negative p53 allele or knockdown of p53 mRNA were more resistant to cadmium-induced inactivation of colony formation than normal and ataxia telangiectasia (AT) cells. Synchronized fibroblasts in S were more sensitive to cadmium toxicity than cells in G1, suggesting that cadmium may target some element of DNA replication. Cadmium produced a dose- and time-dependent inhibition of DNA synthesis. An immediate inhibition was associated with severe delay in progression through S phase and a delayed inhibition seen 24 h after treatment was associated with accumulation of cells in G2. AT and normal cells displayed similar patterns of inhibition of DNA synthesis and G2 delay after treatment with cadmium, while p53-defective cells displayed significantly less of the delayed inhibition of DNA synthesis and accumulation in G2 post-treatment. Total p53 protein and ser15-phosphorylated p53 were induced by cadmium in normal and AT cells. The p53 transactivation target Gadd45alpha was induced in both p53-effective and p53-defective cells after 4 h cadmium treatment, and this was associated with an acute inhibition of mitosis. Cadmium produced a very unusual pattern of toxicity in human fibroblasts, inhibiting DNA replication and inducing p53-dependent growth arrest but without induction of p21(Cip1/Waf1) or activation of Chk1.

Ataxia Telangiectasia↗
PubMed2003

Ionizing radiation-induced Rad51 nuclear focus formation is cell cycle-regulated and defective in both ATM(-/-) and c-Abl(-/-) cells.

In eukaryotes, DNA double-strand breaks (DSBs) can be repaired by either non-homologous end-joining (NHEJ) or homologous recombination (HR) pathways. Rad50 protein is a component of the Rad50/NBS1/Mre11 nuclease complex that functions in both the NHEJ and recombinational repair of DNA DSBs. On the other hand, Rad51 protein, a homolog of bacterial RecA and a member of the Rad52 epistasis group, plays a crucial role exclusively in the recombinational repair pathway. We analyzed the effects of cell cycle progression and genetic background on the ionizing radiation (IR)-induced Rad51 and Rad50 repair focus formation. Herein, we demonstrated that IR-induced Rad51, but not Rad50, nuclear focus formation was cell cycle-dependent. Furthermore, IR-induced Rad51 focus formation was defective in AT and c-Abl(-/-) cells, but not wild type or NBS cells. A decreased and delayed formation of Rad51 foci-containing nuclei was observed in AT cells upon IR, whereas in c-Abl(-/-) cells a decreased but not delayed formation of Rad51 foci-containing nuclei was observed. In conclusion, effective and prompt IR-induced Rad51 focus formation is cell cycle-regulated and requires both ATM and c-Abl.

Acid Anhydride Hydrolases↗
PubMed1998

Splitting the ATM: distinct repair and checkpoint defects in ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is an autosomal recessive human disorder that, because of its multisystem nature, is of interest to scientists and clinicians from many disciplines. A-T patients have defects in the neurological and immune systems, telangiectasia in the eyes and face, and are, in addition, cancer-prone and radiation-sensitive. A-T cell lines have a range of diverse phenotypes including sensitivity to ionizing radiation and defects in cell-cycle checkpoint control. The ATM protein is a member of the PI 3-kinase-like superfamily, and it has been widely accepted that A-T cells represent mammalian cell-cycle checkpoint mutants and that the radiation sensitivity is a consequence of this defect. However, several lines of evidence suggest that A-T cells have distinct repair and checkpoint defects. A-T cells therefore appear to harbour dual checkpoint/repair defects. Here, we review the evidence supporting this contention and consider its implications for an analysis of the A-T phenotype.

Animals↗
PubMed2002

Neocarzinostatin induces Mre11 phosphorylation and focus formation through an ATM- and NBS1-dependent mechanism.

DNA double-strand breaks, if unrepaired, may lead to the accumulation of chromosomal aberrations and eventually cancer cell formation. Components of the Rad50/NBS/Mre11 nuclease complex are essential for the effective repair of DNA double-stranded breaks. Here, we show that neocarzinostatin, a radiomimetic enediyne antibiotic, induces phosphorylation and nuclear focus formation of Mre11 and NBS1 through a cell cycle-independent mechanism. Furthermore, neocarzinostatin-induced Mre11 phosphorylation and nuclear focus formation are defective in AT and NBS cells, but not wild type cells. Our results suggest that ATM and NBS1 are required for the effective repair of neocarzinostatin-induced DNA double-strand breaks by both non-homologous end joining and homologous recombinational repair pathways.

Antibiotics, Antineoplastic↗
PubMed1998

Absence of ATM truncations in patients with severe acute radiation reactions.

PURPOSE: Severe acute toxicity limits the effective use of radiotherapy in patients who are radiosensitive, and it is not usually possible to identify these radiohypersensitive (R-H) individuals before treatment commences. Five such R-H patients were detected over a 3-year period. We undertook this study to determine whether the severe acute radiohypersensitivity of these five individuals showed any correlation with cellular and molecular parameters known to be abnormal in radiosensitivity-related syndromes such as ataxia-telangiectasia (A-T). METHODS AND MATERIALS: Lymphoblastoid cells were isolated from fresh blood from the 5 R-H individuals who had previously demonstrated clinical R-H at least 9 months prior to sampling. Lymphoblastoid cell lines (LCLs) were established to determine the extent of postradiation chromosomal aberrations, cell cycle delay, cell proliferation, and tumor suppressor p53 protein stabilization. The polymerase chain reaction (PCR) and protein truncation (PTT) assays were used to test for the possibility of mutations in the gene mutated in A-T, termed ATM. RESULTS: LCLs derived from R-H subjects retained a significantly higher degree of radiation-induced chromosomal aberrations when compared to normal control LCLs. p53 stabilization by ionizing radiation appeared normal in all but one R-H subject. There was no evidence of A-T gene truncation mutations in any of the R-H subjects tested. CONCLUSIONS: All R-H subjects in this study had their cellular radiosensitivity confirmed by the chromosomal aberration assay. Delayed p53 stabilization at 4 hours postirradiation in one R-H subject suggested that different etiologies may apply in the radiohypersensitivity investigated in this study.

Adult↗
PubMed2001

DNA-PK, ATM and ATR as sensors of DNA damage: variations on a theme?

The DNA damage signalling pathway is a core element of the cellular response to genotoxic insult, and its components play key roles in defending against neoplastic transformation. Recent work has indicated that the human ATM and ATR proteins, and their yeast homologues, are intimately involved in sensing DNA damage, suggesting parallels with the DNA double-strand break repair enzyme DNA-PK.

Animals↗
PubMed2001

ATM and ATR: networking cellular responses to DNA damage.

Maintenance of genome stability depends on the appropriate response to DNA damage. This response is based on complex networks of signaling pathways that activate numerous processes and lead ultimately to damage repair and cellular survival - or apoptosis. The protein kinases ATM and ATR are master controllers of some of these networks, acting either in concert or separately to orchestrate the responses to specific types of DNA damage or stalled replication. Understanding their mode of action is essential to our understanding of how cells cope with genotoxic stress.

Apoptosis↗
PubMed1997

Cell-cycle signaling: Atm displays its many talents.

The discovery of multiple signaling cascades downstream of Atm may lead to a clearer understanding of the diverse defects seen in ataxia-telangiectasia. These pathways - which include evolutionarily conserved Chk1 and Atr, and non-conserved p21, p53 and AbI - guard genomic integrity after DNA damage.

Animals↗
PubMed1999

The Drosophila ATM homologue Mei-41 has an essential checkpoint function at the midblastula transition.

BACKGROUND: Drosophila embryogenesis is initiated by 13 rapid syncytial mitotic divisions that do not require zygotic gene activity. This maternally directed cleavage phase of development terminates at the midblastula transition (MBT), at which point the cell cycle slows dramatically, membranes surround the cortical nuclei to form a cellular blastoderm, and zygotic gene expression is first required. RESULTS: We show that embryos lacking Mei-41, a Drosophila homologue of the ATM tumor suppressor, proceed through unusually short syncytial mitoses, fail to terminate syncytial division following mitosis 13, and degenerate without forming cells. A similar cleavage-stage arrest is produced by mutations in grapes, which encodes a homologue of the Checkpoint-1 kinase. We present biochemical, cytological and genetic data indicating that Mei-41 and Grapes are components of a conserved DNA-replication/damage checkpoint pathway that triggers inhibitory phosphorylation of the Cdc2 kinase and mediates resistance to replication inhibitors and DNA-damaging agents. This pathway is nonessential during postembryonic development, but it is required to terminate the cleavage stage at the MBT. Cyclins are required for Cdc2 kinase activity, and mutations in cyclin A and cyclin B bypass the requirement for mei-41 at the MBT. These mutations do not restore wild-type syncytial cell-cycle timing or the embryonic replication checkpoint, however, suggesting that Mei-41-mediated inhibition of Cdc2 has an additional essential function at the MBT. CONCLUSIONS: The Drosophila DNA-replication/damage checkpoint pathway can be activated by externally triggered DNA damage or replication defects throughout the life cycle, and under laboratory conditions this inducible function is nonessential. During early embryogenesis, however, this pathway is activated by developmental cues and is required for the transition from maternal to zygotic control of development at the MBT.

Animals↗