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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the conversion of intermediates of DNA replication in normal human skin fibroblasts and fibroblasts isolated from patients with genetic diseases caused by putative DNA repair defects. Experiments were performed in non-transformed, unchallenged cells using alkaline sucrose sedimentation analysis to demonstrate precursor low molecular weight (LMW) DNA molecules which converted into high molecular weight (HMW) DNA with time. Analyses of conversion of replicative intermediates were conducted in cells from patients with ataxia telangiectasia (AT), Fanconi anemia (FA), Bloom syndrome (BS), Cockayne syndrome (CS) and xeroderma pigmentosum (XP). Our studies show that conversion of replicative intermediates occurs in all cell strains examined. However, XP cells (complementation groups A and E) show evidence of abnormalities in the conversion of LMW replicative intermediates, with the most dramatic alterations shown by cells from complementation group A.
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PMID:Conversion of replicative intermediates in human DNA-repair defective cells. 395 84

A genetically high risk group for cancer may consist of persons with the following characteristics. Deficient or reduced capacity for repair of DNA damage, mostly occurring in patients with cancer-prone hereditary diseases, and possibly heterozygotes with the autosomal recessive genes of these diseases. The presence of chromosomal diseases with high incidence of cancer (e. g. Down's syndrome). The presence of autosomal dominantly inherited cancer-prone diseases. Efficient capacities for metabolic activation of potential carcinogens or reduced capacities for decomposition of carcinogens. Although the number of persons with a hereditary high risk may be small, heterozygotes of cancer-prone hereditary disease genes may account for a few percent of the general population. Relative risk, however, may be much lower in these heterozygotes than in patients, judging from the epidemiological data for ataxia telangiectasia and xeroderma pigmentosum. Correlation between cancer-proneness in these genetically high-risk groups for cancer and mutability in the cells originating from these persons has not been clearly demonstrated. Family studies and twin studies may provide further aspects for consideration of genetic factors.
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PMID:[Genetic factors in carcinogenesis]. 396 34

Multiple skin cancers and other cancers in patients with xeroderma pigmentosum (XP) were investigated in relation to DNA repair defects in the cells of the patients. Multiple skin cancers of the same or different histopathological types were found in many patients and six patients had cancers, one each, in organs other than the skin. The frequency of basal cell carcinoma was higher than that of squamous cell carcinoma in XP patients, while the two types were reported to be approximately equal in frequency in all skin cancers in Japanese. Defect in the excision-resynthesis type of repair presumably enhances the error-prone type of repair of DNA damage in XP patients and may lead to the development of cancer. Although a similar DNA repair defect of damage caused by ionizing radiation has been suspected in ataxia telangiectasia (AT), induction of mutation by gamma-rays in AT cells was lower than that in normal cells at the same survival levels. The high incidence of malignancy in AT patients could be due to factors not associated with DNA repair.
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PMID:DNA repair and its possible involvement in the origin of multiple cancer. 400 91

Human xeroderma pigmentosum (XP) or Fanconi anemia (FA) fibroblasts displayed shouldered 45 degrees C heat survival curves not significantly different from normal fibroblasts, a result similar to that previously found for ataxia telangiectasia (AT) cells, indicating heat resistance is not linked to either uv or low-LET ionizing radiation resistance. Hyperthermia (45 degrees C) sensitized normal and XP fibroblasts to killing by gamma radiation but failed to sensitize the cells to the lethal effects of 254 nm uv radiation. Thermal inhibition of repair of ionizing radiation lesions but not uv-induced lesions appears to contribute synergistically to cell death. The thermal enhancement ratio (TER) for the synergistic interaction of hyperthermia (45 degrees C, 30 min) and gamma radiation was significantly lower in one FA and two strains (TER = 1.7-1.8) than that reported previously for three normal strains (TER = 2.5-3.0). These XP and FA strains may be more gamma sensitive than normal human fibroblasts. Since hyperthermia treatment only slightly increases the gamma-radiation sensitivity of ataxia telangiectasia (AT) fibroblasts compared to normal strains, it is possible that the degree of thermal enhancement attainable reflects the genetically inherent ionizing radiation repair capacity of the cells. The data indicate that both repair inhibition and particular lesion types are required for lethal synergism between heat and radiation. We therefore postulate that the transient thermal inhibition of repair results in the conversion of gamma-induced lesions to irrepairable lethal damage, while uv-type damage can remain unaltered during this period.
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PMID:Sensitivity of hyperthermia-treated human cells to killing by ultraviolet or gamma radiation. 408 Sep 76

Bleomycin exposure evoked a specific sensitivity in five ataxia telangiectasia (AT) long-term lymphoblastoid cell lines when compared to lines derived from four normal individuals or three patients with xeroderma pigmentosum. At all concentrations tested or after each treatment regimen, statistically significant differences in viability and cytogenetic damage were obvious, with the AT cell lines demonstrating reduced survival and increased chromosomal breakage. However, similar differences were not observed following treatment of all cell lines with mitomycin C. The normal and xeroderma pigmentosum cells appear capable of overcoming the effects of bleomycin during a 48- or 72-hr recovery period while the AT cell lines could not. This specific response to bleomycin constitutes the first demonstration of increased chromosome breakage in vitro in long-term AT lymphoblastoid cell lines.
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PMID:Specificity of bleomycin-induced cytotoxic effects on ataxia telangiectasia lymphoid cell lines. 616 29

The ability of human fibroblasts to repair bleomycin-damaged DNA was examined in vivo. Repair of the specific lesions caused by bleomycin (BLM) was investigated in normal cell strains as well as those isolated from patients with apparent DNA repair defects. The diseases ataxia telangiectasia (AT), Bloom syndrome (BS), Cockayne syndrome (CS), Fanconi anemia (FA), and xeroderma pigmentosum (XP) were those selected for study. The method used for studying the repair of DNA after BLM exposure was alkaline sucrose gradient centrifugation. After exposure to BLM, a fall in the molecular weight of DNA was observed, and after drug removal the DNA reformed rapidly to high molecular weight. The fall in molecular weight upon exposure to BLM was observed in all cells examined with the exception of some XP strains. Prelabeled cells from some XP complementation groups were found to have a higher percentage of low molecular weight DNA on alkaline gradients than did normal cells. This prelabeled low molecular weight DNA disappeared upon exposure to BLM.
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PMID:Repair of Bleomycin-damaged DNA by human fibroblasts. 617 50

Bleomycin, a radiomimetic glycopeptide, inhibits de novo DNA synthesis in ataxia telangiectasia lymphoblastoid B cells to a markedly lesser extent than in normal and xeroderma pigmentosum lymphoid cells. This observation is similar to that following ionizing radiation; however, the effect is slower following the chemical treatment. Recovery of the normal cells occurs 15-18 hours after treatment, whereas the ataxia telangiectasia lines do not attain normal levels of DNA synthesis during the entire 24-hour observation period. Similar differences were not observed following treatment with mitomycin C, a bifunctional alkylating agent, indicating a specific effect of bleomycin on DNA synthesis in ataxia telangiectasia cells. Following bleomycin treatment and preincubation with hydroxyurea, residual DNA synthesis in ataxia telangiectasia cells was similar to that in both normal and xeroderma pigmentosum lymphoid cells, suggesting that the capacity to repair the induced DNA lesion is present.
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PMID:The effect of bleomycin on DNA synthesis in ataxia telangiectasia lymphoid cells. 617 10

Cytogenetic damage was investigated in long term lymphoid cell lines derived from normal individuals, patients with Fanconi's anemia (FA), ataxia telangiectasia (AT), xeroderma pigmentosum (XP), and FA heterozygotes. The cell lines were exposed to various concentrations of four chemical clastogens, including the alkylating agents diepoxybutane, mitomycin C, and nitrogen mustard, as well as the antitumor glycopeptide bleomycin. The FA cells exhibited chromosomal hypersensitivity to all four clastogens and could be distinguished from the other genotypes. AT cells were identified by bleomycin, while FA heterozygotes could not be reliably detected. Discriminant function analysis was used to describe the cytogenetic response to the various clastogens. This method might prove useful for evaluation and classification of multivariate chromosome breakage studies.
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PMID:The cytogenetic response of Fanconi's anemia lymphoblastoid cell lines to various clastogens. 618 57

Cytogenetic damage in cells cultured from normal individuals and patients with ataxia telangiectasia (A-T) and xeroderma pigmentosum (XP) was induced by the chemotherapeutic antibiotics neocarzinostatin (NCS), tallysomycin (TLM) and bleomycin (BLM). Chromosomal breakage was specifically elevated in A-T cells when compared to the other genotypes tested. Similar results were not observed with the clastogens mitomycin C (MMC) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as all cells responded similarly. All 5 chemical agents caused a marked suppression of de novo DNA synthesis in normal and XP long-term lymphoid cell lines while the A-T cells seemed resistant to this effect of NCS, TLM and BLM.
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PMID:Increased clastogenicity and decreased inhibition of DNA synthesis by neocarzinostatin and tallysomycin in ataxia telangiectasia lymphoid cells. 618 42

Neocarzinostatin (NCS) is an acidic, single-chain polypeptide of 109 amino acids that has shown some antitumor activity in clinical trials. NCS is mutagenic in recA+ strains of Escherichia coli, but not in recA strains; on the other hand, a defect in the nucleotide-excision-repair pathway has no effect on the mutagenicity of NCS in E. coli. Similar results are seen in mammalian cells. Excision-repair-deficient xeroderma pigmentosum (XP) cells repair NCS-induced DNA damage at the same rate as repair-proficient XP heterozygotes, and X-ray-sensitive ataxia telangiectasia fibroblasts are also sensitive to NCS. I have investigated the mutagenicity of NCS in the ad-3 forward-mutation test in nucleotide excision-repair-sufficient and -deficient heterokaryons of Neurospora crassa. Resting conidia from a repair-sufficient strain, H-12, and a nucleotide-excision-repair-deficient strain (uvs-2) H-59, were exposed to NCS. These conidia were assayed for survival and ad-3 forward mutation. The results show that H-59 is more sensitive to the killing and mutagenic activities of NCS than is H-12. These data indicate, in contrast to E. coli and mammalian cells, that the nucleotide-excision-repair pathway of N. crassa does repair NCS-induced lesions. In other experiments, ad-3 mutants induced by NCS in H-59 were characterized to determine the spectrum of NCS-induced mutation. The results show that NCS induces both intracistronic mutations and multilocus deletions in H-59.
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PMID:Mutagenicity of neocarzinostatin in Neurospora crassa. 623 65


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