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)

UV-induced thymine dimers (10 J/m2 of UV-C) were assayed in normal human and xeroderma pigmentosum (XP) fibroblasts with a monoclonal antibody against these dimers and quantitative fluorescence microscopy. In repair-proficient cells dimer-specific immunofluorescence gradually decreased with time, reaching about 25% of the initial fluorescence after 27 h. Rapid disappearance of dimers was observed in cells which had been microinjected with yeast photoreactivating enzyme prior to UV irradiation. This photoreactivation (PHR) was light dependent and (virtually) complete within 15 min of PHR illumination. In general, PHR of dimers strongly reduces UV-induced unscheduled DNA synthesis (UDS). However, when PHR was applied immediately after UV irradiation, UDS remained unchanged initially; the decrease set in only after 30 min. When PHR was performed 2 h after UV exposure, UDS dropped without delay. An explanation for this difference is preferential removal of some type(s) of nondimer lesions, e.g., (6-4) photoproducts, which is responsible for the PHR-resistant UDS immediately following UV irradiation. After the rapid removal of these photoproducts, the bulk of UDS is due to dimer repair. From the rapid effect of dimer removal by PHR on UDS it can be deduced that the excision of dimers up to the repair synthesis step takes considerably less than 30 min. Also in XP fibroblasts of various complementation groups the effect of PHR was investigated. The immunochemical dimer assay showed rapid PHR-dependent removal comparable to that in normal cells. However, the decrease of (residual) UDS due to PHR was absent (in XP-D) or much delayed (in XP-A and -E) compared to normal cells. This supports the idea that in these XP cells preferential repair of nondimer lesions does occur, but at a much lower rate.
Cancer Res 1990 Mar 15
PMID:Effects of microinjected photoreactivating enzyme on thymine dimer removal and DNA repair synthesis in normal human and xeroderma pigmentosum fibroblasts. 230 42

Cells from patients with the cancer-prone inherited disease, xeroderma pigmentosum (XP) are known to be defective in the endonuclease-mediated incision step in excision repair of a number of different types of DNA adducts, but the molecular events responsible have not been delineated. We have previously reported isolation of two DNA endonucleases, pI 4.6 and 7.6, from normal human chromatin which recognize adducts produced by psoralen plus long wavelength ultraviolet radiation (UVA). These endonucleases are both present in XP complementation group A (XPA) cells even though these cells are hypersensitive to this type of damage. We now report that introduction by electroporation of either normal endonuclease into XPA cells restored their markedly deficient DNA repair-related unscheduled DNA synthesis (UDS) to higher than normal levels following exposure to psoralen plus UVA. Introduction of XPA endonucleases into similarly treated XPA cells had little or no restorative effect on UDS. However, both normal and XPA endonucleases increased UDS in normal cells to higher than normal levels. These results indicate that XPA cells have endonucleases which can repair these adducts but which cannot function in intact cells unless a factor(s), which they lack is provided by normal cells.
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PMID:Electroporation of normal human DNA endonucleases into xeroderma pigmentosum cells corrects their DNA repair defect. 231 Nov 96

Using a DNA band shift assay, we have identified a DNA-binding protein complex in primate cells which is present constitutively and has a high affinity for UV-irradiated, double-stranded DNA. Cells pretreated with UV light, mitomycin C, or aphidicolin have higher levels of this damage-specific DNA-binding protein complex, suggesting that the signal for induction can either be damage to the DNA or interference with cellular DNA replication. Physiochemical modifications of the DNA and competition analysis with defined substrates suggest that the most probable target site for the damage-specific DNA-binding protein complex is a 6-4'-(pyrimidine-2'-one)-pyrimidine dimer: specific binding could not be detected with probes which contain -TT- cyclobutane dimers, and damage-specific DNA binding did not decrease after photoreactivation of UV-irradiated DNA. This damage-specific DNA-binding protein complex is the first such inducible protein complex identified in primate cells. Cells from patients with the sun-sensitive cancer-prone disease, xeroderma pigmentosum (group E), are lacking both the constitutive and the induced damage-specific DNA-binding activities. These findings suggest a possible role for this DNA-binding protein complex in lesion recognition and DNA repair of UV-light-induced photoproducts.
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PMID:A constitutive damage-specific DNA-binding protein is synthesized at higher levels in UV-irradiated primate cells. 232 44

Cancer treatment with the drug cisplatin is often thwarted by the emergence of drug-resistant cells. To study this phenomenon, we identified two independent cellular factors that recognize cisplatin-damaged DNA. One of the two factors, designated XPE binding factor, is deficient in complementation group E of xeroderma pigmentosum, an inherited disease characterized by defective repair of DNA damaged by ultraviolet radiation, cisplatin, and other agents. Human tumor cell lines selected for resistance to cisplatin showed more efficient DNA repair and increased expression of XPE binding factor. These results suggest that XPE binding factor may be responsible, at least in part, for the development of cisplatin resistance in human tumors and that the mechanism may be increased DNA repair.
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PMID:Cisplatin-resistant cells express increased levels of a factor that recognizes damaged DNA. 233 86

Fibroblasts from patients with ataxia-telangiectasia (A-T) were found to be hypersensitive to killing by the antineoplastic agent etoposide. The A-T fibroblast strains GM5823, GM367, and GM2052 were twofold to threefold more sensitive to killing by etoposide than fibroblasts from normal controls (AG1521, AG1522, and IMR90). A simian virus 40 (SV40)-transformed, immortal human fibroblast line (GM5849) derived from the A-T cell line GM5823 was also studied. GM5849 retained the unusual sensitivity of nontransformed A-T fibroblast lines to x-irradiation, bleomycin, and neocarzinostatin (zinostatin). GM5849 was also more sensitive to etoposide than were SV40-transformed fibroblasts from normal controls. M1, and SV40-transformed fibroblast line derived from a patient with xeroderma pigmentosum, had the same sensitivity to etoposide as SV40-transformed fibroblasts derived from normal controls.
J Natl Cancer Inst 1986 Jun
PMID:Hypersensitivity of cultured ataxia-telangiectasia cells to etoposide. 242 35

The effects of 5-aza-2'-deoxycytidine (aza-dCyd) and 5,6-dihydro-5-azacytidine (H2-aza-Cyd) on the integrity of DNA from several mammalian cell lines were compared using the alkaline elution technique. While both compounds have been shown to inhibit DNA methylation, a direct comparison of their effects on DNA structure has not previously been reported. Exposure of L1210 cells to H2-aza-Cyd (1-100 micrograms/ml) and simultaneous labeling with [14C]thymidine for 24 h resulted in the production of single-strand breaks in DNA, which were significantly repaired when cells were incubated in drug-free medium for an additional 24 h. This differed from our previous findings for aza-dCyd, confirmed here in parallel experiments, which showed that this compound produces alkali-labile lesions that persist for 48 h. The DNA effects of both drugs were significantly reduced when cells were prelabeled with [14C]thymidine, indicating that production of DNA lesions requires incorporation of the anomalous base. Studies utilizing pulse-labeled DNA indicated that aza-dCyd has little effect on the rate of DNA elongation, whereas H2-aza-Cyd produced a complete inhibition for at least 6 h after drug removal. The contrasting pattern of DNA damage induced by these compounds in L1210 was also observed in two human lymphoblastoid cells lines, one of which was derived from a patient with xeroderma pigmentosum. We had previously concluded that alkali-labile sites in DNA from aza-dCyd-treated cells probably arise due to the chemical instability of aza-dCyd. In contrast, incorporated H2-aza-Cyd is chemically stable. The single-strand breaks produced in H2-aza-Cyd treated cells were not of the alkali-labile type, and may represent an accumulation of DNA replication fragments and/or intermediates in an excision repair process. Thus, the DNA lesions produced by the two drugs have markedly different characteristics, and H2-aza-Cyd should not be considered to be merely a stable pharmacological congener of aza-dCyd.
Cancer Res 1986 Nov
PMID:Differences in DNA damage produced by incorporation of 5-aza-2'-deoxycytidine or 5,6-dihydro-5-azacytidine into DNA of mammalian cells. 242 79

Trichothiodystrophy (TTD) is an autosomal recessive disorder characterized by brittle hair with reduced sulfur content, ichthyosis, peculiar face, and mental and physical retardation. Some patients are photosensitive. A previous study by Stefanini et al. (Hum. Genet., 74: 107-112, 1986) showed that cells from four photosensitive patients with TTD had a molecular defect in DNA repair, which was not complemented by cells from xeroderma pigmentosum, complementation group D. In a detailed molecular and cellular study of the effects of UV light on cells cultured from three further TTD patients who did not exhibit photosensitivity we have found an array of different responses. In cells from the first patient, survival, excision repair, and DNA and RNA synthesis following UV irradiation were all normal, whereas in cells from the second patient all these responses were similar to those of excision-defective xeroderma pigmentosum (group D) cells. With the third patient, cell survival measured by colony-forming ability was normal following UV irradiation, even though repair synthesis was only 50% of normal and RNA synthesis was severely reduced. The excision-repair defect in these cells was not complemented by other TTD cell strains. These cellular characteristics of patient 3 have not been described previously for any other cell line. The normal survival may be attributed to the finding that the deficiency in excision-repair is confined to early times after irradiation. Our results pose a number of questions about the relationship between the molecular defect in DNA repair and the clinical symptoms of xeroderma pigmentosum and TTD.
Cancer Res 1988 Nov 01
PMID:Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light. 245 32

Primary epidermal keratinocytes obtained from 25 patients with xeroderma pigmentosum (XP) (nine with XP-A, one with XP-C, two with XP-D, five with XP-E, and eight with XP-variant) exhibited less UV-induced unscheduled DNA synthesis (UDS) than did those from 34 normal subjects. Levels of UDS depended greatly on the type of XP; i.e., 3-17% of the control in XP-A, 14% in XP-C, 33-53% in XP-D, 38-77% in XP-E and 58-98% in XP-variant. The extent of UDS in epidermal keratinocytes was almost the same as that in dermal fibroblasts in XP-C, D, and E, but in three out of eight of the XP-variant the level of UDS in epidermal keratinocytes was significantly lower than that in normal subjects. Clinically, three out of nine XP-A patients developed skin neoplasms before 20 years of age. Both patients with XP-D developed skin neoplasms around 40 years of age. In the five XP-E patients, two developed multiple basal cell epithelioma on sun-exposed areas during the forth decade, and one of them also developed squamous cell carcinoma at the age of 50. Four out of the eight patients with the XP-variant developed various skin neoplasms during their 20s and 30s. These results suggest that a defect in UV-induced UDS in epidermal keratinocytes of XP patients is responsible for skin carcinogenesis and the extent to which this defect occurs tends to relate to the age of onset of skin neoplasms.
Cancer Res 1989 Apr 15
PMID:Reduced levels of UV-induced unscheduled DNA synthesis in epidermal keratinocytes of patients with xeroderma pigmentosum and correlation with development of skin neoplasms. 246 39

Lymphoblastoid cell lines established from three unrelated kindreds with familial melanoma (FM) were cytogenetically analyzed for spontaneous and 4-nitroquinoline-1-oxide (4NQO)-induced chromosome aberrations. There were no significant differences between control, FM, or xeroderma pigmentosum (XP) cell lines for spontaneous aberrations. As a group, FM patients, as well as XP patients, had significantly higher 4NQO-induced aberrations than controls when metaphase cells were analyzed 2.5 hours after treatment during the G2 phase of the cell cycle. When selected cell lines were analyzed 18 hours after 4NQO treatment, the frequency of chromosome aberrations in FM cells returned to spontaneous levels, but XP cells retained significantly elevated aberration frequencies. The wide variability for chromosome aberrations within the control. FM relative, and FM patient groups during G2, however, indicated that analysis of total breakage rates alone would not be predictive of susceptibility to FM. Heterogeneity for carcinogen-induced chromosome breakage between some cancer-prone individuals and the possible significance of site-specific chromosome aberrations are discussed.
Cancer Genet Cytogenet 1989 Jun
PMID:Spontaneous and 4-nitroquinoline 1-oxide-induced G2 chromosome aberrations in lymphoblasts from familial melanoma patients. 250 7

The effect of UV irradiation on the rate of DNA synthesis was compared among normal human, xeroderma pigmentosum (XP, group A and variant) and mouse cells with and without caffeine in the culture medium after UV irradiation. At the same levels of survival, approximately 37%, all cells showed reduction in the rate of synthesis 0-3 h after UV irradiation followed by a recovery to normal or near-normal level 12 h later. In the presence of caffeine, no change in the recovery patterns was observed in normal human and XP A cells. XP variant cells and mouse cells showed little or no recovery in the presence of caffeine even after 12 h, when full recovery was obtained without caffeine. XP variant and mouse cells appear to have a common response in that post-irradiation treatment with caffeine inhibits reinitiation of UV-reduced DNA replication. Enhancement by caffeine of UV-killing in XP variant and mouse cells may be due to the retarded resumption of DNA replication.
Jpn J Cancer Res 1989 Aug
PMID:Similarity in the effect of caffeine on DNA synthesis after UV irradiation between xeroderma pigmentosum variant cells and mouse cells. 251 Nov 83


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