Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the contributions of O6-alkylguanine-DNA alkyl-transferase (AGT) and nucleotide excision repair to the protection of human cells from the toxic and mutagenic effects of ethylnitrosourea. Three human lymphoblastoid cell lines were used: one which possesses both of these DNA repair pathways; one derived from a xeroderma pigmentosum complementation group A patient, which expresses AGT but is deficient in nucleotide excision repair; and a third which does not express AGT but is capable of excision repair. The level of active AGT in the cells was further modulated with the use of the AGT inhibitor, O6-benzylguanine. These cells were exposed to ethylnitrosourea in both the presence and absence of O6-benzylguanine, and population survival, growth, and mutagenesis at the hypoxanthine-guanine phosphoribosyl-transferase locus were measured. The results for all three measurements indicated that the lack of either AGT or nucleotide excision repair significantly impairs the ability of human cells to withstand DNA ethylation damage. Furthermore, the inhibition of AGT in xeroderma pigmentosum group A cells did not increase toxicity or mutagenicity, suggesting that AGT and nucleotide excision repair cooperate in the removal of DNA ethyl adducts. Related studies in our laboratory have shown that AGT and nucleotide excision repair are both necessary for the efficient removal of O6-ethyldeoxyguanosine.
Cancer Res 1992 Jul 15
PMID:Modulation of ethylnitrosourea-induced toxicity and mutagenicity in human cells by O6-benzylguanine. 161 59

Fibroblast cultures of 16 basal cell epithelioma (basalioma, BCE) patients with an unusually young age at onset of disease (29-51 years; 42.5 +/- 7.04), and healthy normal controls (27-55 years; 40.73 +/- 9.52) were studied for chromosome instability induced by ultraviolet rays (UV). We used an UV source that emitted predominantly UV-A and UV-B at an intensity of 375 J/m2 and evaluated the induction of micronuclei (MN) and sister chromatid exchange (SCE). Young basalioma patients and normal controls showed no significant differences in MN and SCE frequencies, neither with respect to spontaneous nor to UV-induced values (MN spontaneous: 10.80 +/- 5.65 vs. 11.32 +/- 8.21; UV-induced increase: 7.36 +/- 4.40 vs. 9.93 +/- 7.55; SCE spontaneous: 10.28 +/- 1.61 vs. 10.72 +/- 1.09; UV-induced increase: 7.30 +/- 2.19 vs. 7.55 +/- 2.14). We conclude from these data that an enhanced UV sensitivity as observed in cells from patients with cutaneous malignant melanoma and xeroderma pigmentosum is not a constitutive risk factor in basalioma patients.
Cancer Genet Cytogenet 1992 Jul 01
PMID:Fibroblast cultures of patients with basal cell epithelioma exhibit a normal sensitivity to the genotoxic effect of ultraviolet irradiation. 163 84

UV exposure has been linked to skin cancer in humans by epidemiology and the rare genetic disease xeroderma pigmentosum. However, UV produces multiple photoproducts in DNA, and their relative contribution is uncertain. An enzyme which specifically repairs cyclobutane pyrimidine dimers in DNA, T4 endonuclease V, was encapsulated in liposomes for topical delivery into mouse and human skin. In both species, liposomes applied after UV exposure localized in the epidermis and stimulated the removal of cyclobutane pyrimidine dimers. UV-irradiated mice treated with these liposomes had a dose-dependent decrease in the incidence of squamous cell carcinoma compared to controls. The results demonstrate that unrepaired cyclobutane pyrimidine dimers in DNA are a direct cause of cancer in mammalian skin.
Cancer Res 1992 Aug 01
PMID:Pyrimidine dimer removal enhanced by DNA repair liposomes reduces the incidence of UV skin cancer in mice. 163 36

Accumulation of gadd153 mRNA is strongly stimulated in mammalian cells by treatments which arrest growth or damage DNA (A. J. Fornace, Jr. et al., Mol. Cell. Biol., 9: 4196-4203, 1989). In previous studies, we demonstrated that the increased expression of gadd153 following treatment with several DNA-damaging agents was mediated transcriptionally (J. D. Luethy et al., J. Biol. Chem., 265: 16521-16526, 1990). To better define the specificity of this response, we have established a sensitive reporter system in which we have stably integrated a chimeric gene containing the gadd153 promoter linked to the coding region of the chloramphenicol acetyltransferase (CAT) gene into the genome of HeLa cells. Transcriptional activation from the gadd153 promoter was monitored by determining levels of CAT activity in cellular lysates prepared from gadd153CAT/HeLa cells treated with a variety of agents. The gadd153 promoter was strongly activated by a broad spectrum of genotoxic agents including UV-mimetic agents, DNA-cross-linking and alkylating agents, DNA intercalators, and topoisomerase inhibitors. Of the DNA-damaging agents tested, only X-irradiation and bleomycin treatments failed to induce gadd153 promoter activity. Agents which inhibit replication and cell division and agents which otherwise result in cytotoxicity or growth arrest also had little influence on gadd153 promoter activity. Expression of the gadd153CAT chimeric gene in xeroderma pigmentosum Group A cells, which are deficient in nucleotide excision DNA repair of pyrimidine dimers, was maximally induced at UV doses at least 6-fold lower than those required for similar induction in repair-proficient HeLa cells. However, the methyl methanesulfonate-induced gadd153 promoter activities were similar in both cell lines. Novobiocin pretreatment inhibited both UV- and methyl methanesulfonate-induced gadd153CAT expression. Collectively, these data indicate that: (a) the gadd153 promoter is activated rapidly and specifically by DNA damage; (b) the altered DNA structure is the inducing signal for the activation of the signal transduction pathway responsible for enhanced gadd153 expression; and (c) regulation of gadd153 by growth arrest is distinct from that of DNA damage. Thus, the gadd153CAT/HeLa cells are a useful model for examining the molecular mechanisms associated with the response to DNA damage and provide a reporter system for the screening of potential genotoxic agents.
Cancer Res 1992 Jan 01
PMID:Activation of the gadd153 promoter by genotoxic agents: a rapid and specific response to DNA damage. 172 86

By using PCR amplification and oligonucleotide mismatch hybridization, base-substitution mutations of the ras genes in 26 skin tumors of Japanese xeroderma pigmentosum (XP) patients were studied. Thin sections of tumor tissues which were fixed and embedded in paraffin blocks were used in this study. After analyzing codons 12, 13 and 61 of the H-, K- and N-ras genes by using 66 oligomer probes, we detected only one mutation of the K-ras gene at codon 61 in one tumor sample. All the other tumors were therefore considered not to have a mutation in the ras genes. These results suggest that mutations of the ras genes are not particularly associated with skin tumors of Japanese XP patients.
Int J Cancer 1992 Feb 01
PMID:Infrequent mutation of the ras genes in skin tumors of xeroderma pigmentosum patients in Japan. 173 6

We showed previously that the persistence of chromatid breaks and gaps after G2 phase irradiation with X-rays or near-UV visible light characterizes skin fibroblasts from individuals with cancer-prone genetic diseases. This abnormal response appears to result from deficient DNA repair during G2 and to be associated with cancer proneness. We have, therefore, compared the responses of cells from two genetic disorders, Cockayne syndrome (CS) and xeroderma pigmentosum complementation group C(XP-C), both of which exhibit cellular hypersensitivity to sunlight, but only one of which, XP, manifests a high rate of sunlight-induced cancer. CS cells, in contrast to XP cells, showed a normal G2 response to irradiation with either X-rays or near-UV visible light. However, CS cells showed a deficiency in repair of DNA damage inflicted by light during S and G1 phases of the cell cycle. The present results support the concept that deficient DNA repair during G2 phase plays a role in carcinogenesis. This deficient repair in the presence of DNA damage and continuous cell cycling from activation of proto-oncogenes or loss of suppressor genes may be necessary and sufficient for cancer development.
Cancer Genet Cytogenet 1991 Nov
PMID:Radiation-induced chromatid aberrations in Cockayne syndrome and xeroderma pigmentosum group C fibroblasts in relation to cancer predisposition. 175 75

The chemical integrity and proper functioning of DNA is threatened by numerous chemical and physical agents that cause a wide spectrum of DNA lesions. When unrepaired, DNA injury interferes with vital, cellular functions such as DNA replication and transcription and give rise to mutations leading to genetic defects, carcinogenesis and cell death. The contribution of DNA repair systems in preventing cancer is apparent from the high rate of tumorigenesis found in many repair syndromes. A classical example is the excision repair disorder xeroderma pigmentosum (XP) in which patients exhibit hypersensitivity to sun (UV) light and predisposition to skin cancer. Genetic analysis of cultured cells from XP patients has revealed the presence of at least 7 complementation groups, all showing a deficiency in the excision of UV-induced lesions in the DNA. To identify the genes and characterize the genetic defects in these complementation groups, cloning of human DNA repair genes has been attempted by a number of investigators. Recently, the first human DNA repair genes have been cloned including at least two genes involved in XP. Comparison of the coding sequences of these genes with sequences of cloned (repair) genes of lower organisms (e.g. E. coli and yeast) provides information on their function. This leads to understanding of the relationship between molecular defect at the level of the gene and the gene product and the clinical manifestation of the disease in different XP patients and complementation groups.
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PMID:The genetic basis of xeroderma pigmentosum. 180 20

The aim of our work was to investigate whether DNA topoisomerase II participates in the repair-specific incision of UV-irradiated genomic DNA. Therefore, the influence upon DNA incision of the topoisomerase II inhibitors (nalidixic and oxolinic acid, novobiocin and coumermycin A1) as well as the intercalating agent quinacrine has been measured in normal human fibroblasts using the alkaline elution technique. In addition, inhibition by novobiocin has been determined in fibroblast strains from 11 normal donors and from 16 xeroderma pigmentosum (XP) patients belonging to the complementation groups A, C, D, E, and XP variant. Nalidixic and oxolonic acid did not inhibit endonucleolytic cleavage, whereas novobiocin was a potent inhibitor of DNA incision. It was observed that in normal and in all XP strains 50% inhibition by novobiocin occurred on average in the dose range 315-590 microM. Since inhibition by novobiocin was not paralleled by that with the other topoisomerase II inhibitors nalidixic and oxolinic acid, it must be concluded that reduction of enzyme-catalysed breaks was not due to the participation of topoisomerase II in the incision step, but to the displacement of ATP at the binding site of the DNA-incising enzyme. This enzyme absolutely requires ATP as a cofactor for endonucleolytic cleavage. Quinacrine, however, inhibited DNA incision in normal fibroblasts at a mean Ki of 318 microM. Inhibition by this intercalating agent seems to be caused by structural perturbations in DNA, which render it a poor substrate for endonucleolytic cleavage.
J Cancer Res Clin Oncol 1991
PMID:The effects of inhibitors of topoisomerase II and quinacrine on ultraviolet-light-induced DNA incision in normal and xeroderma pigmentosum fibroblasts. 184

The time course of DNA repair, using (3H)thymidine uptake as parameter, was measured during 8 h after a single exposure to 2, 8, and 16 UV-C J/m2 in lymphocytes of 8 cancer patients, 1 xeroderma pigmentosum patient and 10 controls. All patients had reduced repair, and all controls normal repair, as calculated 2 h after a single exposure. Six patients reached normal levels with a delay of 2-6 h, whereas 2 patients and the xeroderma pigmentosum patient did not. Although the kinetic curves in controls and patients had a similar form, those for 8 and 16 J/m2 in patients were shifted so that they corresponded to that of 2 J/m2 in controls. Additionally the ability to repair repeated damage (cells irradiated twice or three times at 2-hour intervals with doses of 2 or 8 J/m2) was investigated in 6 patients and in 7 controls. The incorporation values showed significant differences between patients and controls at each dose and time point. Cancer patients tend to repair repeated damage less efficiently than controls. Using these parameters subtle differences between the repair ability of individuals might be identified. Because of the known connection between reduced DNA repair and carcinogenesis, this might help to distinguish cancer-prone individuals.
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PMID:Differences in the kinetics of DNA repair in cancer patients and healthy controls. 189 Nov 74

We showed previously that in repair-proficient human cells the location of the premutagenic lesion induced by (+-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo(a)pyrene (BPDE), namely, the guanine in a G.C base substitution, in mutants derived from cells treated at the beginning of S phase just when the hypoxanthine (guanine) phosphoribosyltransferase gene is replicated, differs significantly from their location in cells treated 12 h prior to the beginning of S phase (early G1 phase) (R-H. Chen et al., Proc. Natl. Acad. Sci. USA, 87:8680-8684, 1990). This suggests that the cells preferentially remove BPDE adducts from the transcribed strand. We have now determined the kinds and location of independent mutations induced by BPDE in the coding region of the hypoxanthine (guanine) phosphoribosyltransferase gene of synchronized repair-deficient xeroderma pigmentosum cells (XP12BE, complementation group A), treated at S or in G1. Nineteen of 25 mutants derived from S-treated cells and 23 of 28 mutants from G1-treated cells contained base substitutions. Eighty-nine percent of these involved a G.C base pair, primarily G.C----T.A transversions. This is similar to the kinds of mutations we saw in the repair-proficient cells. However, in contrast to our earlier results, there was no change in strand distribution of premutagenic BPDE lesions. In both populations, approximately 26% of the base substitutions involving G.C base pairs had the G located in the transcribed strand, 5 of 18 in the S phase mutants, and 5 of 21 in the G1 phase mutants. These results support the hypothesis that the strong strand bias of induced mutations observed in the repair-proficient cells results from preferential repair of BPDE-induced DNA damage from the transcribed strand.
Cancer Res 1991 May 15
PMID:Lack of a cell cycle-dependent strand bias for mutations induced in the HPRT gene by (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene in excision repair-deficient human cells. 190 94


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