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

In order to investigate the biochemical events involved in potentially lethal DNA damage repair (PLDR), we have identified a pleiotropic protein expression response that is activated upon X-irradiation of confluence-arrested human malignant melanoma (U1-Mel) cells. Plateau-phase U1-Mel cells were selected because of their extraordinary capacity for PLDR. Eight major X-ray-induced polypeptides (XIPs) of Mr 126,000-275,000 (i.e., XIP126 through XIP275) were detected by resolving L-[35S]methionine-labeled whole cell extracts using two-dimensional gel electrophoresis. XIPs were found in unirradiated, proliferating U1-Mel cells, shut off under plateau-phase conditions and resynthesized in response to X-irradiation. The expression of three classes of proteins was affected by X-irradiation. Class I proteins, XIP145 and XIP269, were induced linearly with increasing X-ray doses. The rate of synthesis of class II proteins, XIP126, XIP135, XIP138, XIP141, XIP147, and XIP275, increased linearly with low X-irradiation doses, but plateaued at doses of 150-250 cGy. In contrast, the expression of class III proteins, 47,000 and 254,000 Mr proteins, decreased with increasing X-ray doses. Tumor, cancer-prone, and normal human cells, which represent a wide range of cells with varied repair capacities, were investigated to better understand the role of XIPs in DNA damage responses. X-irradiated normal and tumor cells induced the synthesis of XIP145 and XIP269. A strong correlation between the induction of XIP269 and PLDR capacity, as measured by delayed plating of plateau-phase cells, was noted. XIP269 was present in six of seven normal and tumor cells types, but was completely absent in cells from patients with Bloom's syndrome and ataxia telangiectasia. X-irradiated Fanconi's anemia and xeroderma pigmentosum cells synthesized low levels of XIP269. The majority of XIPs synthesized by X-irradiated cells from cancer-prone patients were of low molecular weights. A number of XIP expression characteristics suggest their role in either gross chromosomal PLDR and/or in X-ray adaptivity responses: (a) XIP expression was inhibited by 1 microgram/ml cycloheximide, a dose which decreased survival 6-fold during PLDR holding and resulted in greater than 80% inhibition of protein synthesis; (b) XIP expression was specific for ionizing radiation damage, since heat shock, hypoxia, and alkylating agents failed to induce their synthesis; (c) the time course of expression was long, with the first appearance of XIPs at 3 h and maximal expression at 4 h.
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PMID:Identification and characterization of X-ray-induced proteins in human cells. 272 Jun 48

Human hereditary diseases such as xeroderma pigmentosum, Fanconi's anemia, ataxia telangiectasia, and Bloom's syndrome are characterized by a proneness for developing cancer associated with abnormalities in the processing of DNA damage. The molecular defects responsible for predisposing human tissues to cancer are still not well understood, despite the fact that a considerable amount of work has already been done on this problem. In this paper, we show that in human tumor cell lines, in cells transformed by DNA tumor viruses, and in cells derived from certain cancer-prone disorders, the level of activity of a 42-kDa deoxyribonuclease is many times higher than in diploid untransformed control cells. This suggests that this activity is linked to, or may play a role in, malignant transformation.
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PMID:Enhanced deoxyribonuclease activity in human transformed cells and in Bloom's syndrome cells. 280 19

We describe the clinical features and findings of biopsied sural nerves of 4 cases of xeroderma pigmentosum. Nine genetic forms of xeroderma pigmentosum have been reported by complementation studies. These four cases were diagnosed as Group A xeroderma pigmentosum by complementation studies using cultured skin fibroblasts. All cases had delayed mental and motor development in areas such as head control over 4 months of age and walking without support over 18 months of age. Three cases had the gradual onset of a gait disturbance between 6 and 9 years of age. Motor conduction velocity and sensory conduction velocity of the ulnar nerve were slightly delayed. The sural nerve of the slightly impaired patient showed a normal density of myelinated fibers, but a selective reduction of the large myelinated fibers with zebra-body-like structures in Schwann cell cytoplasm. The population density of all nerve fibers was severely diminished in the severely impaired cases. Ultrastructural observation disclosed many denervated Schwann cells and pockets of collagen isolated by loops of denervated Schwann cell cytoplasm. These findings suggest that the degenerative process in peripheral nerves of xeroderma pigmentosum is axonal. Peripheral neuropathy in Group A xeroderma pigmentosum resembles that of patients with ataxia telangiectasia who are known to have a defect in the repair mechanisms of their DNA in cultured skin fibroblasts.
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PMID:Peripheral neuropathy in four cases of group A xeroderma pigmentosum. 283 98

Chromosome alterations, which are directly visible changes in the DNA, have close associations to cancer development, non-specific ageing, and heritable genetic status. Human lymphocyte cultures can be used for cytogenetic monitoring of genetic health because many cancers and genetic effects are caused by long-term unhealthy life-styles. We have investigated the sensitivities of lymphocytes from inherited-cancer-prone diseases to the induction of the chromosome alterations by mutagens and carcinogens, and the correlations between the frequency of sister chromatid exchanges (SCEs) in peripheral lymphocytes and life-styles or daily ways of living. Lymphocytes from patients with Down syndrome, Fanconi anemia, xeroderma pigmentosum, ataxia telangiectasia, and Bloom syndromes showed altered (usually enhanced) susceptibilities to the induction of chromosome aberrations and SCEs by mutagens and carcinogens in our environments. Mean frequencies of baseline SCEs in lymphocytes from normal men with poor life-styles have also been shown to be significantly higher than those in cells from men having good life-styles. The former cells have further been shown to have hyper sensitivities to the induction of SCEs by mitomycin-C' treatment compared to latter cells. Unhealthy life-styles also make the lymphocytes to be more sensitive to ara-C's enhancement of radiation-induced chromosome aberrations.
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PMID:[Sister chromatid exchanges and chromosome aberrations as parameters for human risk of cancer development]. 295 45

Experiments were performed to determine if differences in porphyrin photosensitivity could be observed for cells with varying efficiency in DNA damage repair, as well as for cells which make up components of the vasculature. Photofrin II is undergoing current clinical evaluation for photodynamic therapy of solid tumors, and therefore the retention, dark toxicity, and photosensitizing effects of this drug on human DNA repair-deficient fibroblasts (ataxia telangiectasia and xeroderma pigmentosum) were compared to normal human fibroblasts. In addition, bovine cells of endothelial, smooth muscle, and fibroblast origin were compared for porphyrin retention, toxicity, and photosensitivity. All human fibroblasts exhibited porphyrin-induced dark toxicity, but there were no significant differences in photosensitization or porphyrin retention for any of these cell lines. However, bovine endothelial cells were considerably more photosensitive than smooth muscle or fibroblast cells treated under identical conditions. All bovine cells accumulated similar levels of porphyrin, and therefore the increased sensitivity of the endothelial cells was not due to differences in porphyrin retention. These results provide additional evidence that nuclear damage and/or repair is not a dominant factor in the cytotoxicity induced by porphyrin photosensitization. In addition, these results indicate that endothelial cell photosensitivity may play a role in the vascular damage observed following photodynamic therapy.
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PMID:Differential cell photosensitivity following porphyrin photodynamic therapy. 296 80

A permanent ataxia-telangiectasia (A-T) cell line has been established from the fibroblast strain AT2SF after transfection with the bacterial plasmid pSV ori-, which contains replication origin-defective SV40 sequences. The original transfection frequency, as measured by transformed foci, was markedly reduced in two A-T strains when compared with either normal or xeroderma pigmentosum fibroblasts. As with SV40 virion-transformed fibroblasts, pSV ori--transformed cells entered a crisis phase, from which about one-fourth of the original clones from A-T and normal fibroblasts recovered. Both the pSV ori--transformed TAT2SF cell line and an SV40 virion-transformed AT5BI (GM5489) cell line retained their characteristic sensitivity to the lethal effects of ionizing radiation, as well as their X ray-resistant DNA synthesis. Southern blot analysis of cellular SV40 sequences demonstrated a single major integration site of pSV ori- in the AT2SF cells. In contrast, AT5BI cells transformed with SV40 virions demonstrated a high degree of heterogeneity of integrated viral sequences. Neither the TAT2SF nor the GM5489 transformed cell line contains any detectable freely replicating SV40 viral sequences, which are seen in many other semipermissive SV40-transformed cells.
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PMID:Establishment and characterization of a permanent pSV ori--transformed ataxia-telangiectasia cell line. 298 7

We have developed a host cell reactivation assay of DNA repair utilizing UV-treated plasmid vectors. The assay primarily reflects cellular repair of transcriptional activity of damaged DNA measured indirectly as enzyme activity of the transfected genes. We studied three plasmids (pSV2cat, 5020 base pairs; pSV2catSVgpt, 7268 base pairs; and pRSVcat, 5027 base pairs) with different sizes and promoters carrying the bacterial cat gene (CAT, chloramphenicol acetyltransferase) in a construction that permits cat expression in human cells. All human simian virus 40-transformed cells studied expressed high levels of the transfected cat gene. UV treatment of the plasmids prior to transfection resulted in differential decrease in CAT activity in different cell lines. With pSV2catSVgpt, UV inactivation of CAT expression was greater in the xeroderma pigmentosum group A and D lines (D0 = 56 J X m-2) than in the other human cell lines tested (normal, ataxia-telangiectasia, Lesch-Nyhan, retinoblastoma)(D0 = 680 J X m-2)(D0 is the dose that reduces the percentage of CAT activity by 63% along the exponential portion of the dose-response curve). The D0 of the CAT inactivation curve was 50 J X m-2 for pSV2cat and for pRSVcat in the xeroderma pigmentosum group A cells. The similarity of the D0 data in the xeroderma pigmentosum group A cells for three plasmids of different size and promoters implies they all have similar UV-inactivation target size. UV-induced pyrimidine dimer formation in the plasmids was quantified by assay of the number of UV-induced T4 endonuclease V-sensitive sites. In the most sensitive xeroderma pigmentosum cells, with all three plasmids, one UV-induced pyrimidine dimer inactivates a target of about 2 kilobases, close to the size of the putative CAT mRNA.
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PMID:One pyrimidine dimer inactivates expression of a transfected gene in xeroderma pigmentosum cells. 299 75

It has been previously shown that skin biopsies isolated from various xeroderma pigmentosum (XP) patients present a permanent decline in catalase activity from the onset of the disease to the tumor formation. We report here that cultured XP cell strains are also markedly deficient in the catalase activity with about only 25% of the activity measured in normal human cells. No direct correlation between catalatic activity and excision repair ability has been found, since a XP variant line is as deficient as an XP-C strain. The exact cause of the catalase deficiency is still unknown but could be due to the synthesis of a modified enzyme or to an abnormal regulation leading to a limited enzyme synthesis. Furthermore, simian virus 40 transformation of normal and radiosensitive cells (XP, ataxia telangiectasia) provokes a decrease in catalase activity of about 80% compared to the control derivatives. Mathematical analysis performed on our data shows a clearcut distinction between XP and normal cells while some of the XP heterozygote cells exhibit an intermediate behavior. Although most of the XP syndrome could be explained by the impairment in the excision repair ability, the decrease in catalase activity leading to a probable increase in intracellular H2O2 concentration and/or to a higher sensitivity to any oxygen-activated species could represent an additive effect in inducing the carcinogenic process.
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PMID:Deficiency in the catalase activity of xeroderma pigmentosum cell and simian virus 40-transformed human cell extracts. 300 May 76

Four human fibroblast cell lines, three of which were derived from a patient with ataxia telangiectasia and the other from a patient with xeroderma pigmentosum, were established after transfection with cloned SV40 DNA. These 4 cell lines showed some phenotypes characteristic of neoplastically transformed cells, and had a human karyotype with heteromorphisms identical to those of the parental fibroblasts. Their sensitivity to the cytotoxic effects of gamma-rays or ultraviolet irradiation was as high as those of their parental fibroblasts.
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PMID:Establishment of cell lines derived from ataxia telangiectasia and xeroderma pigmentosum patients with high radiation sensitivity. 302 Apr

We have compared the sites of nucleotide incision on DNA damaged by oxidizing agents when cleavage is mediated by either Escherichia coli endonuclease III or an endonuclease present in bovine and human cells. E. coli endonuclease III, the bovine endonuclease isolated from calf thymus, and the human endonuclease partially purified from HeLa and CEM-C1 lymphoblastoid cells incised DNA damaged with osmium tetroxide, ionizing radiation, or high doses of UV light at sites of pyrimidines. For each damaging agent studied, regardless of whether the E. coli, bovine, or human endonuclease was used, the same sequence specificity of cleavage was observed. We detected this endonuclease activity in a variety of human fibroblasts derived from normal individuals as well as individuals with the DNA repair deficiency diseases ataxia telangiectasia and xeroderma pigmentosum. The highly conserved nature of such a DNA damage-specific endonuclease suggests that a common pathway exists in bacteria, humans, and other mammals for the reversal of certain types of oxidative DNA damage.
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PMID:A highly conserved endonuclease activity present in Escherichia coli, bovine, and human cells recognizes oxidative DNA damage at sites of pyrimidines. 303 65


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