Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral blood lymphocytes from four patients with ataxia telangiectasia (AT), an inherited disorder showing, among other features, radiosensitivity and a high frequency of cancers, were shown to be cytogenetically more sensitive to bleomycin than were lymphocytes from both normal individuals and a single patient with xeroderma pigmentosum. With cell survival techniques, a biphasic dose-response curve was seen for both normal and AT fibroblasts, although the AT cells showed a much lower survival. The increased sensitivity to bleomycin in AT cells might be expected since it is a radiomimetic drug, but more importantly the known action of bleomycin in producing DNA strand scission suggests that AT cells might be defective in rejoining a proportion of DNA strand breaks.
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PMID:Unusual sensitivity of ataxia telangiectasia cells to bleomycin. 8 79

Xeroderma pigmentosum (XP), Fanconi anaemia (FA), ataxia telangiectasia (AT) and Bloom disease (BS) are four rare autosomal recessive disorders in which there is defective DNA repair and/or chromosome instability and proneness to malignancy. Between 80 and 90% of patients with XP have a defect, demonstrable at cell level, of excision of DNA lesions induced by ultraviolet rays, while the remainder have a cellular error of post-replication repair. XP cells are also deficient in repairing DNA damage caused by a variety of chemical mutagens. There are at least five different complementation groups of the first, or classical, type of XP (A to D, etc.) Apparently group C patients, as well as those with defective post-replication repair, do not show the progressive neurological illness found in a proportion of the other patients. AT is heterogeneous clinically and genetically. Clinically it presents with a progressive neurological illness, progressive telangiectases and a developmental disorder of the thymus. AT is characterized by sensitivity to X-rays and AT cells are unable to repair gamma-ray-induced damage to bases in the DNA. It appears that in many cases of the disorder a chromosomally marked cellular clone is found. In BS the main defect, which results in growth retardation, sun-induced lesions of the face and susceptibility to infection, appears to be a slow DNA chain maturation during DNA synthesis. An increase of sister chromatid exchanges is characteristically seen in the chromosomes of cultured BS cells. In FA, in which there is progressive pancytopenia with eventual bone marrow exhaustion and a tendency to haemorrhage and infection, the cellular defect seems to consist of faulty removal of repair of cross-links in the DNA. In this condition, as in BS and AT, various structural chromosome changes are detected in cultured cells. Patients with XP develop skin cancers in early life and often maligant melanomas. In the other three disorders, in which an immune deficiency is often present, leukaemia and related proliferative disorders are a frequent cause of death while other malignancies also occur. There is some evidence that points to an increased risk of malignancy in heterozygotes who carry the FA and AT genes.
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PMID:DNA repair defects and chromosome instability disorders. 25 77

Liquid-holding conditions can be obtained for human diploid skin fibroblasts by keeping confluent cultures stationary over periods of 7 days or longer by means of conditioned medium. Under this condition recovery of radiation damage induced by ultraviolet light or X-rays is observed as an increase in cloning efficiency. The amount of recovery when expressed in a dose-modifying-factor appears higher than in bacteria and yeast. The repair-deficient human cell strains XP25Ro and XP7Be (xeroderma pigmentosum from complementation groups A and D respectively) exhibit less but still discernible recovery after UV-irradiation and the same was observed for AT5Bi (ataxia telangiectasia) after X-irradiation. Experiments on mutation induction indicated that the repair which takes place during liquid holding of UV-irradiated XP7Be cells reduces the mutant frequency considerably while after liquid holding of UV-irradiated wild-type cells the same or lower mutant frequencies were found for the lower exposures and the same or higher mutant frequencies for the higher exposures.
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PMID:Development of a liquid-holding technique for the study of DNA-repair in human diploid fibroblasts. 37 75

Several autosomal recessive diseases are associated with apparent DNA repair defects in cell culture. It seemed likely that a defect in excision repair reported for ataxia telangiectasia cells might reflect a lack of apurinic endonuclease activity. We report here normal levels of apurinic endonuclease activity in extracts of cell lines derived from patients with ataxia telangiectasia, xeroderma pigmentosum (complementation group D), Cockayne dwarfism, Fanconi anemia and Bloom syndrome.
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PMID:Apurinic DNA endonuclease activities in repair-deficient human cell lines. 63 94

Uracil DNA N-glycosidase, an enzyme which participates in the excision of uracil from DNA, was measured in extracts from fibroblasts lines cultured from normal subjects, from several subjects with the genetic disease xeroderma pigmentosum, and from a subject with ataxia telangiectasia. The cell lines representative of complementation groups A and D of xeroderma pigmentosum and of ataxia telangiectasia had roughly the same level of activity as did the normal cells. On the other hand, cells from two xeroderma pigmentosum variants (XP4BE and XP13BE) had roughly half the normal level of activity, and cells from the heterozygous mother of XP4BE had an intermediate level of activity. In spite of these quantitative differences, no systematic alterations in reaction characteristics, apparent Km for substrate, or purification characteristics were noted for enzyme from any of the lines. Thus a causal relationship, if any, between levels of activity and the disease symptoms is equivocal.
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PMID:Human uracil DNA N-glycosidase: studies in normal and repair defective cultured fibroblasts. 64 2

An assay has been developed to measure the ability of human lymphocytes to repair damage to DNA. In this assay, purified human lymphocytes are exposed to graded doses of radiation and then stimulated with phytohemagglutinin to undergo DNA replication. The rate of incorporation of thymidine in irradiated lymphocytes during the second and subsequent rounds of DNA replication is taken to be indicative of the ability of the cells to repair damage to DNA. In lymphocytes from normal individuals, X-irradiation with doses of 100 to 800 rads was found to inhibit phytohemagglutinin-stimulated thymidine incorporation proportionally to the dose of radiation without curtailing the induction of DNA polymerase. The response to phytohemagglutinin of lymphocytes from a patient with xeroderma pigmentosum after exposure to graded doses of X-irradiation was found to be similar to that of the normal controls, whereas the response after ultraviolet irradiation was markedly impaired. In contrast, lymphocytes from patients with ataxia telangiectasia were hypersensitive to X-irradiation. The data on these clinical syndromes support the idea that this assay measures DNA repair and indicates the feasibility of using this method for screening individuals for genetic deficits in DNA repair.
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PMID:Screening for deficits in DNA repair by the response of irradiated human lymphocytes to phytohemagglutinin. 90 9

The frequency of BrdU-induced sister chromatid exchanges (SCE) in cultured lymphocytes from patients with ataxia telangiectasia, Werner syndrome, and xeroderma pigmentosum was normal. The rate was increased in xeroderma pigmentosum following exposure to ultraviolet light and spontaneously raised in the Bloom syndrome. Quadriradial exchanges between homologous chromosomes in Bloom syndrome not only involve sister chromatids but also homologous (non-sister) chromatids. This could result in the formation of recombinant chromosomes and is viewed as a genetically determined form of increased somatic recombination in man. Endoreduplicated metaphases showed 'twin' and 'single' exchanges in a 1:2 ratio. This suggests a comparable frequency of exchanges at both divisions and provides evidence for the polarity of the chromatid subunits and the presence of a single chain of DNA.
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PMID:Chromatid exchanges in ataxia telangiectasia, Bloom syndrome, Werner syndrome, and xeroderma pigmentosum. 96 24

The co-recessive inheritance hypothesis proposes that certain recessively inherited diseases require homozygosity and/or hemizygosity for defective alleles at more than one locus simultaneously for the trait to be expressed. Although this hypothesis was originally proposed in the context of defective alleles for genes coding for DNA-repair functions, it need not be limited to this context, and genetic selection pressure may favor this model for genes involved in surveillance of any type. The co-recessive inheritance hypothesis also predicts extremely high carrier frequencies, likely affecting much of the general population, for defective alleles associated with these rare recessive diseases. The model predicts much lower rates of consanguinity between the parents of affected individuals than autosomal recessive inheritance, allowing it to be tested epidemiologically, and recent data suggest that the hypothesis may be valid for some cases of ataxia telangiectasia and xeroderma pigmentosum. The model provides possible explanations for a number of otherwise puzzling findings in several diseases associated with defective DNA repair.
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PMID:Co-recessive inheritance: a model for DNA repair and other surveillance genes in higher eukaryotes. 137 1

In order to assess spontaneous mutability and accuracy of DNA joining in ataxia telangiectasia, a disorder with spontaneous chromosome breakage, the replicating shuttle vector plasmid, pZ189, was transfected into SV40 virus-transformed fibroblasts from ataxia telangiectasia patients. The ataxia telangiectasia fibroblasts showed elevated frequency of micronuclei, a measure of chromosome breakage. The spontaneous mutation frequency was normal with circular plasmids passed through the ataxia telangiectasia line. These results were compared to those with transformed fibroblasts from a patient with xeroderma pigmentosum, and from a normal donor. Mutation analysis revealed spontaneous point mutations and deletions in the plasmids with all 3 cell lines, however, insertions or complex mutations were only detectable with the ataxia telangiectasia line. To assess DNA-joining ability, linear plasmids which require joining of the DNA ends by host cell enzymes for survival, were transfected into the cells. We found a 2.4-fold less efficient DNA joining in ataxia telangiectasia fibroblasts (p = 0.04) and a 2.0-fold higher mutation frequency (p less than 0.01) in the recircularized plasmids than with the normal line. Plasmid DNA joining and mutation frequency were normal with the xeroderma pigmentosum fibroblasts. These findings with the ataxia telangiectasia fibroblasts of abnormal types of spontaneous mutations in the transfected plasmid and inefficient, error-prone DNA joining may be related to the increased chromosome breakage in these cells. In contrast, an EB virus-transformed ataxia telangiectasia lymphoblast line with normal frequency of micronuclei showed normal types of spontaneous mutations in the transfected plasmid and normal frequency of DNA joining which was error-prone. These data indicate that mechanisms that produce chromosome breakage in ataxia telangiectasia cells can be reflected in processing of plasmid vectors.
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PMID:Abnormal processing of transfected plasmid DNA in cells from patients with ataxia telangiectasia. 138 10

The familial occurrence of head and neck cancers supports the role of heredity in this disease group. The roles of environmental and genetic factors are difficult to separate. There are several well-characterized entities, however, that are associated with risk and prognosis of head and neck cancer, including Lynch-II syndrome, Bloom syndrome, Fanconi's anemia, xeroderma pigmentosum, ataxia telangiectasia, and Li-Fraumeni syndrome. Mutagen-induced chromosomal damage is associated with an increased risk of multiple primary neoplasms and upper aerodigestive tract cancers. A possible reduction of genotoxicity, mediated by micronutrients, was demonstrated in vitro. Sister chromatid exchanges and micronuclei are useful exposure and disease markers. Metabolic changes (acetylation, DBQ phenotype, and the AH locus polymorphism) have been found to be associated with cancer of the upper aerodigestive tract. Most associations between histocompatibility antigens and solid tumors are relatively weak, probably because of the masking effects of environmental factors. Infections by HPV, EBV, and HSV have a causative or predisposing role in several types of head and neck cancer. Amplification and rearrangement of oncogenes may also play a role in carcinogenesis, and oncogene amplification may be associated with aggressive tumor behavior and unfavorable clinical prognosis. Ploidy of tumors seems to be an important determinant of survival and response to therapy.
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PMID:Hereditary and environmental factors associated with risk and progression of head and neck cancer. 140 93


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