Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rearrangements of chromatin structure during excision repair were examined in xeroderma pigmentosum (XP; complementation group A) human fibroblasts treated with the small-molecule alkylating agent methyl methanesulfonate (MMS). In agreement with past reports, we observed normal levels of repair synthesis in these cells during the first 12 h after exposure to 1.5 mM MMS, in contrast to the near zero incorporation of repair patches following exposure to 12 J/m2 u.v. light. Our results indicate that the relative nuclease sensitivity of newly repaired regions in MMS-treated nuclease sensitivity of newly repaired regions in MMS-treated XP (group A) cells is quantitatively similar to that of newly repaired regions in MMS-treated normal human fibroblasts. This enhanced sensitivity is accompanied by a marked under-representation of repair-incorporated nucleotides in isolated nucleosome core DNA. Pulse-chase experiments demonstrated that these regions rapidly undergo rearrangements in chromatin structure, and both the rate and extent of these rearrangements are similar (but not identical) to those observed in normal cells. This was also the case for the rate and extent of ligation of repair patches, as measured by the sensitivity of these regions to exonuclease III digestion. If the changes in nuclease sensitivity of newly repaired regions in DNA reflect an unfolding of nucleosome structure during excision repair, then these results indicate that the activity associated with this unfolding is present in XP (group A) cells.
Carcinogenesis 1987 May
PMID:Rearrangement of nucleosome structure during excision repair in xeroderma pigmentosum (group A) human fibroblasts. 358 32

The repair of u.v.-induced damage in human and rodent cells was investigated at the level of DNA loops attached to the nuclear matrix. After 2 h post-u.v. incubation, DNase I digestion studies revealed a 3- to 4-fold enrichment of repair-labeled DNA at the nuclear matrix in four xeroderma pigmentosum cell strains belonging to complementation group C. This non-random distribution was not affected by treatment with sodium butyrate. In other cells with limited excision repair, i.e. two xeroderma pigmentosum cell strains of complementation group D and Syrian hamster embryonic cells, as well as in HeLa cells and normal human fibroblasts, no enrichment of repair-labeled DNA at the nuclear matrix was observed. Visualization of repair events in DNA loops by autoradiography of DNA halo-matrix structures confirmed the biochemical observations. The presence or absence of preferential repair of nuclear matrix-associated DNA paralleled the presence or absence of inhomogeneity in the distribution of T4 endonuclease-V-sensitive sites. A detailed analysis of repair events in xeroderma pigmentosum cells of complementation group C showed that after 2 h post-u.v. incubation, repair events were found at both attachment sites in a limited number of loops and that large domains of loops were not subjected to repair.
Carcinogenesis 1986 Jun
PMID:Distribution of u.v.-induced repair events in higher-order chromatin loops in human and hamster fibroblasts. 370 60

The aromatic N-heterocyclic 7H-dibenzo(c,g)carbazole (DBC), like polynuclear aromatic hydrocarbons, is a potent inducer of local sarcomas, papillomas, and respiratory tumors, but unlike such compounds it also induces hepatomas. The N-methyl derivative of DBC, N-methyl-dibenzo(c,g)carbazole (MeDBC), also induces sarcomas, papillomas, and respiratory tumors but at a lower frequency than DBC. However, MeDBC lacks hepatocarcinogenic potential, suggesting that DBC undergoes metabolic activation at its carbon atoms and also at the nitrogen position and that the N-7 position plays a role in liver carcinogenesis by DBC. We compared the cytotoxic and mutagenic potential of DBC and MeDBC using a human epithelial cell-mediated activation assay. Repair-deficient, diploid human fibroblasts derived from a xeroderma pigmentosum (XP) patient were used as target cells, and a human hepatoma cell line, Hs703T, was used as a source of exogenous metabolism. Resistance to 6-thioguanine served as the genetic marker for mutations. The Hs703T cells, but not the target XP cells, activated DBC and MeDBC into forms capable of interacting with DNA. In the cell-mediated assay, both DBC and MeDBC induced cytotoxicity and mutations in the target XP cells in a dose-dependent manner. However, DBC was effective at 2-fold lower concentrations than MeDBC. DNA adduct analysis using a 32P-postlabeling assay showed that at biologically significant low doses DBC was 2.5 times more effective than MeDBC in covalent binding to DNA. At higher doses, the difference in ability to bind to DNA was 1.3-fold. In both XP and Hs703T cells, DBC produced three major adducts, while MeDBC produced two major adducts, one of which was the same as one detected in the DBC adduct pattern. The number of DBC- and MeDBC-induced DNA adducts corresponding to a particular level of cytotoxicity and mutagenicity in the XP cells was 10 times lower than that for (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene.
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PMID:Human cell-mediated cytotoxicity, mutagenicity, and DNA adduct formation of 7H-dibenzo(c,g)carbazole and its N-methyl derivative in diploid human fibroblasts. 373 Nov 21

Hybrids formed between HeLa cells and fibroblasts from xeroderma pigmentosum group D show either HeLa sensitivity or XPD-like hypersensitivity to u.v. radiation and corresponding high or low excision repair capability. Hybrids with low repair are presumed to have lost, via chromosome segregation, the HeLa wild type D alleles. In this paper we analyse the u.v. sensitivity and excision repair capability of another hybrid, HD1A, derived spontaneously from the normally sensitive hybrid HD1. While HD1A closely resembles the XPD phenotype in terms of u.v. sensitivity and excision repair it differs from XPD because of its ability to reactivate u.v.-irradiated adenovirus 2 to an extent similar to that of its HeLa parent. This capacity functionally dissociates excision repair of chromatin-based damage from damage in a viral environment. Moreover, on the basis of complementation studies the excision repair of genomic damage by HD1A is subtly different from that of a true XPD-like hybrid, HD2. The data are discussed in terms of a second change in the defective D allele of the HD1A cell.
Carcinogenesis 1986 Oct
PMID:Analysis of DNA repair in XP-HeLa hybrids; lack of correlation between excision repair of u.v. damage and adenovirus reactivation in an XP(D)-like cell line. 375 74

The persistence of O6-n-butyldeoxyguanosine (O6-nBudG) in DNA, the presence of O6-alkylguanine DNA alkyltransferase (AT) activity in cell extracts, and cell survival following exposure to N-n-butyl-N-nitrosourea (BNU), have been measured in normal and xeroderma pigmentosum cell strains, both transformed and untransformed. The rates of removal of O6-nBudG did not correlate with AT activity but did correlate with the ability of strains to excise bulky DNA lesions. BNU and N-methyl-N-nitrosourea dose-response curves for cell killing suggests that both AT and excision may be involved in the repair of cytotoxic lesions.
Carcinogenesis 1986 Dec
PMID:Evidence for the excision repair of O6-n-butyldeoxyguanosine in human cells. 377 95

Survival and mutation after u.v. light irradiation were examined in four human lymphoblastoid cell lines; one cell line with normal excision-repair capacity (HH4), two excision-repair-deficient xeroderma pigmentosum (XP) cell lines from patient XP3BE (complementation group C) and XP7NI (group A), and one cell line from an XP heterozygote (XPF7NI, father of XP7NI). Relative to HH4 and XPF7NI, both XP3BE and XP7NI were more sensitive to the cytotoxic effect of u.v. by virtue of a diminished shoulder and a steeper slope in the survival curve determined by growth curve extrapolations. The mutagenesis for 6-thioguanine resistance (TGr) was measured by the limiting dilution technique using 96 well microtiter plates. Even at non-cytotoxic fluences, u.v. light induced TGr mutations in HH4 and XPF7NI with no apparent threshold, and the mutagenic response of XPF7NI was no different than that of HH4. Both XP cell lines were more sensitive than normal cells to u.v.-induced mutation. However, XP7NI cells were extremely hypermutable by u.v.; i.e. 3.3 J/m2 induced an approximately 500-fold increase of mutant fraction with the background of 2 X 10(-6). XP7NI cells remained much more mutable by u.v. even when plotted against survival, whereas the mutant fractions for XP3BE and HH4 followed the same line. These results imply that the mechanism of u.v.-induced mutation in XP7NI cells may intrinsically be different from that in XP3BE, XP heterozygote or normal cells, or that potentially mutagenic lesions are repaired much less efficiently in XP7NI cells than are potentially lethal lesions, as compared with XP3BE, XPF7NI and HH4 cells.
Carcinogenesis 1987 Jan
PMID:Differential hypersensitivity of xeroderma pigmentosum lymphoblastoid cell lines to ultraviolet light mutagenesis. 380 95

Normal human or xeroderma pigmentosum complementation group A (XP-A) fibroblasts were exposed to various concentrations of either 4-nitroquinoline 1-oxide (4NQO) or its 3-methyl derivative, and the rates of repair of the alkali-labile lesions induced in DNA by each agent were monitored over a period of 24 h post-treatment incubation. The data indicate that 4NQO induces at least two major classes of alkali-labile lesions into human DNA; one class disappears rapidly from the DNA of both normal and XP-A fibroblasts, while the other class undergoes repair at a relatively slow rate in normal cells, but is not removed at all in the excision-deficient cells. Methylation of 4NQO at the 3-position appears to abolish the induction of the latter class of alkali-labile lesions, whereas the rapidly removed lesions are still being induced.
Carcinogenesis 1985 Apr
PMID:Defective repair of a class of 4NQO-induced alkali-labile DNA lesions in xeroderma pigmentosum complementation group A fibroblasts. 392 Dec 71

The cytotoxic and mutagenic effects of 1-nitropyrene (1-NP) and its reduced metabolite 1-nitrosopyrene (1-NOP) were determined in diploid human fibroblasts. Conditions for the metabolic activation of the parent compound (1-NP) by human cells in culture were developed. The cytotoxic effect of 1-NP in normal cells was compared with that for repair-deficient xeroderma pigmentosum (XP) cells, and cells from a patient with hereditary cutaneous malignant melanoma (HCMM), which we have shown earlier are abnormally sensitive to 4-nitroquinoline-1-oxide. The slope of the survival curve for XP cells was 2.5 times steeper than that of normal cells; that of HCMM cells was intermediate. When these cells were exposed to 1-NOP, the slope of the survival curve for the XP cells was also 2.5 times steeper than normal but the HCMM cells showed a normal response, suggesting that their defect is not in repair of DNA adducts, but in activation. 1-NP and 1-NOP also proved to be mutagenic in the human cell assay. When compared on the basis of concentration, 1-NOP was much more mutagenic than 1-NP. But when the compounds were compared on the basis of equal cell killing or equal number of DNA adducts initially bound to DNA, they were very similar. An equal number of residues covalently bound to DNA caused approximately the same amount of cell killing for either compound. XP cells were killed by a 7-fold lower number of bound adducts, suggesting that the increased survival and decreased mutation induction in the normal cells reflects their ability to remove potentially cytotoxic and mutagenic lesions.
Carcinogenesis 1986 Jan
PMID:Cytotoxic and mutagenic effects of 1-nitropyrene and 1-nitrosopyrene in diploid human fibroblasts. 394 46

Since the discovery of a DNA repair defect in xeroderma pigmentosum, which had been known as a hereditary cancer-prone disease, the presence of a genetically high risk group for cancer has been clearly recognized. Clinical and cellular investigations on xeroderma pigmentosum patients in Japan in comparison with those carried out in the United States and Europe have revealed that the characteristics of Japanese patients are considerably different from those in other countries. Similar differences have been noted in other related diseases like Bloom's syndrome. These results suggested that each ethnic group might have unique features with regard to the genetic background of carcinogenesis. Our research over the last 10 years has always been in good collaboration with colleagues in the USA, Europe and Korea thanks to support from the Japan Society for the Promotion of Sciences and the US-Japan Cooperative Medical Science Program, which has enabled us to perform comparative experimental work in foreign countries and to standardize methods and evaluation criteria.
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PMID:[Genetically high risk group for cancer associated with DNA repair deficiency]. 398 34

Homozygous xeroderma pigmentosum fibroblasts cannot repair damage to DNA bases, but can repair damage that involves chain breaks. In xeroderma pigmentosum, therefore, there is a defect in an early step in repair at which base damage is recognized and the polynucleotide chain broken enzymatically (by an endonuclease). Heterozygous fibroblasts repair base damage to normal extents. Carcinogenesis in xeroderma pigmentosum, and perhaps in some normal individuals, may be the result of somatic mutations caused by unrepaired damage.
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PMID:Xeroderma pigmentosum: a human disease in which an initial stage of DNA repair is defective. 525 33


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