Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.99.3 (PRE)
 1,923 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The PRE repairs DNA by the specific and exclusive monomerization of pyrimidine dimers. Photoreactivation thus provides an analytical test for determining the role of pyrimidine dimers in UV damage to biologic systems. We have shown the first UV transformation of cultured human cells (judged by ability to grow in soft agar). Preliminary results indicate that 1) lesions leading to cell transformation are subject to photoreactivation and 2) pyrimidine dimers may well be important in solar carcinogenesis.
Natl Cancer Inst Monogr 1978 Dec
PMID:Photoreactivation: evaluation of pyrimidine dimers in ultraviolet radiation-induced cell transformation. 75 70

The ultraviolet-light induction of DNA damage has been measured in the epidermis of hairless mice with the use of damage-specific endonucleases from Micrococcus luteus. The rates of induction of endonuclease-sensitive sites in HRS/J/Anl and Skh:hairless-1 mice were 6.1 +/- 0.5 X 10(-11) and 6.5 +/- 0.8 X 10(-11)/dalton/J/sq m from a FS40 fluorescent sun lamp (280 to 400 nm), respectively. Enzymatic photoreactivation with yeast photoreactivating enzyme showed that approximately 80% of the endonuclease-sensitive sites were cycloburyl pyrimidine dimers. In both strains of mice the pyrimidine dimers remained in high-molecular-weight DNA for 24 hr after irradiation. These data show that mouse epithelial cells in vivo have little or no capacity for the excision repair of pyrimidine dimers.
Cancer Res 1977 Sep
PMID:Induction and persistence of pyrimidine dimers in the epidermal DNA of two strains of hairless mice. 88 73

beta-Sitosterol (SI-0), beta-sitosterol glucoside (SI-1), dioscin (SI-2), methyl protoprosapogenin A of dioscin (SI-3), methyl protodioscin (SI-4) and protodioscin (SI-5) were isolated and characterized from the whole plant of Solanum indicum L. (Solanaceae). Except for beta-sitosterol, these compounds have not been previously isolated from Solanum indicum L. Both CHCl3 soluble (SI-IV) and insoluble (SI-V) fractions of the ethanolic extract (SI-I) showed cytotoxicity on seven cancer cell lines: Colo-205 (colon), KB (nasopharynx), HeLa (uterine cervix), HA22T (hepatoma), Hep-2 (laryngeal epidermoid), GBM8401/TSGH (glioma) and H1477 (melanoma). The purified constituents, SI-2 and SI-4 showed more potent effects by DEA and MTT assay. SI-2,3,4 and 5 also demonstrated cytotoxicity on cultured C6 glioma cells by PRE assay, ans SI-3,4 and 5 showed a tumor inhibitory effect in vivo in C6 glioma cells. In addition, SI-2 had an inhibitory effect on the DNA synthesis of C6 glioma cells at 10 micrograms/ml.
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PMID:Experimental antitumor agents from Solanum indicum L. 176 63

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

To understand the heterogeneity in genetic predisposition to skin cancer in different nucleotide excision repair-deficient human syndromes, we studied repair of cyclobutane pyrimidine dimers (CPDs) and of pyrimidine(6-4)pyrimidone (6-4PP) photoproducts in cells from trichothiodystrophy (TTD) patients. TTD is not associated with increased incidence of skin cancer, although 50% of the patients are photosensitive and carry a defect in the nucleotide excision repair pathway, similar to Xeroderma pigmentosum patients. However, in striking contrast to TTD, Xeroderma pigmentosum is highly prone to cancer. To address this apparent paradox, two types of studies were conducted: (a) reactivation of UV-irradiated plasmids harboring actively transcribed reporter genes, with or without photolyase treatment before transfection of SV40-transformed fibroblasts; and (b) the kinetics of removal of UV-induced CPDs and 6-4PPs in genomic DNA by immunoblot analysis using lesion-specific mAbs in SV40-transformed and untransformed fibroblasts representative of all genetic TTD complementation groups. Results showed that all cell lines from photosensitive TTD patients efficiently express Cat or luciferase genes in transfected plasmids carrying non-CPD lesions, including 6-4PP, and display wild-type or near-wild-type (50-70% in 3 cell lines) 6-4PP repair in the overall genome after immunoblot analysis. However, CPD lesions (the repair of which is defective in the overall genome) also block the expression of the reporter gene in transfected plasmids. Two cell lines from nonphotosensitive TTD patients showed wild-type levels of repair for both photoproducts in overall genome. A model on the lesion-specific repair in the context of the molecular defect in TTD is proposed. The implication of the defective CPD repair and efficient 6-4PP repair subpathways in cancer prevention in TTD patients is discussed.
Cancer Res 1995 Oct 01
PMID:Different removal of ultraviolet photoproducts in genetically related xeroderma pigmentosum and trichothiodystrophy diseases. 767 Dec 43

We have used the replicating shuttle vector pR2 to determine the role of ultraviolet C (UVC)-induced cyclobutane pyrimidine dimers (CPDs) and nondimer photoproducts in mutagenesis in human trichothiodystrophy (TTD) cells and in their repair-proficient counterparts obtained after complementation with the wild-type XPD/ERCC2 repair gene (TTD + ERCC2 cells). Before transfection in human cells, the UVC-irradiated vector DNA was treated with Anacystis nidulans photolyase [photoreactivation (PR) procedure] that selectively removed CPDs, leaving nondimer photoproducts intact. The mutant frequency of the UV-irradiated pR2 plasmid treated by PR was similar after replication in TTD or in TTD + ERCC2 cells. This result indicates that TTD cells were able to repair nondimer photoproducts as efficiently as TTD cells complemented with the wild-type repair gene and that in TTD cells, CPDs were the major photoproducts generating an increased mutant frequency after UVC irradiation. Sequence analysis of > 300 mutant plasmids indicated that PR of the DNA increased the relative level of tandem mutations and decreased the relative level of multiple mutations in TTD cells. In both cell lines, we observed that CPDs mostly led to GC-AT transitions; whereas only nondimer photoproducts were responsible for the induction of GC-TA transversions in TTD and TTD + ERCC2 cells.
Cancer Res 1998 Jan 01
PMID:Cyclobutane pyrimidine dimers are the main mutagenic DNA photoproducts in DNA repair-deficient trichothiodystrophy cells. 942 65

Ninety chemotherapy-naive cancer patients receiving cisplatin-based (> or = 50 mg/m2) chemotherapy participated in a randomized, double-blind, cross-over study comparing the safety and efficacy of granisetron (GRA) versus granisetron plus prednisolone (GRA + PRE). All patients received i.v. granisetron 3 mg and were randomly allocated to oral prednisolone 50 mg or placebo prior to chemotherapy. At the subsequent cycle of chemotherapy, patients were crossed over to the other antiemetic treatment. A complete response, defined as no emetic episodes and no worse than mild nausea, was obtained in 63% in the GRA group and in 79% of the patients in the GRA + PRE group day 1 (P = 0.013). Complete response rates on days 1-3 were 16% vs 27% (P = 0.251). Significantly less nausea and vomiting was seen with the combination in the first 24 h after cisplatin (P = 0.001 and P = 0.0003) and during days 1-3 (P = 0.005 and 0.044). Patient preference was 51.5% for the combination and 26.5% for granisetron alone, whereas 22% had no preference (P = 0.0270). Adverse reactions were mild and comparable; headache and constipation were the ones most frequently reported. Prednisolone significantly improves the antiemetic effect of granisetron in patients receiving cisplatin-based chemotherapy, but the study also emphasizes the poor complete protection rate in patients receiving multiple-day cisplatin-based chemotherapy.
Support Care Cancer 1998 Jan
PMID:Randomized, double-blind comparison of granisetron versus granisetron plus prednisolone as antiemetic prophylaxis during multiple-day cisplatin-based chemotherapy. 945 39

Strong epidemiological evidence confirms the role of sunlight in human melanoma induction. Furthermore, the frequency of melanocytic nevi is a good indicator of future development of melanoma and a short-term marker of adverse reactions to melanoma-inducing sun exposure in humans. Thus, the aim of this study was to develop and define an animal model for sunlight-induced nevi that can be used as a surrogate model for sunlight-induced melanoma. Five treatment groups of 30-40 Hartley albino guinea pigs/group were treated with topical 7,12-dimethylbenzanthracene at a dose range of 6-240 mg on the dorsum of the skin. At week 20, half of the animals in each group were given a 12-month regimen of minimal erythemal solar-simulated light, 3 times/week, increased weekly to maintain erythema. These regimes induced epidermally derived pigmented melanocytic nevi clinically and histologically similar to human nevi (junctional, compound, and dermal). S100 and HMB45 staining was also consistent with the patterns seen in human nevi. In contrast to the high-dose 7,12-dimethylbenzanthracene-treated animals (60 and 240 mg), where solar-simulated light had no effect on nevi multiplicity, those groups treated with low doses (24, 12, and 6 mg) had a significant increase in nevi multiplicity after 12 months of solar-simulated light treatment (24 mg, 0.5 nevi/animal unirradiated versus 1.4 nevi/animal irradiated, P = 0.03; 12 mg, 0.2 unirradiated versus 1.2 irradiated, P = 0.02; 6 mg, 0 unirradiated versus 1.9 irradiated, P = 0.008). UVB-induced minimal erythemal dose was unaltered after exposure to photoreactivating light, consistent with the observation of others that placental mammals lack the DNA photolyase responsible for strong photoreactivation seen in nonplacental mammals and lower metazoans. Thus, our guinea pig model has some of the essential elements required to be a robust animal model for human nevi and a surrogate model for melanoma. These nevi are augmented by solar-simulated light, are histologically similar, occupy the same level within the skin, have the same natural history as human nevi, and are produced in an animal lacking strong photoreactivation. These features are not found in any previously described small laboratory animal model.
Cancer Res 1998 Dec 01
PMID:The augmentation of melanocytic nevi in guinea pigs by solar-simulated light: an animal model for human melanocytic nevi. 985 66

The role of UV light-induced photoproducts in initiating base substitution mutation in human cells was examined by determining the frequency and spectrum of mutation in a supF tRNA gene in a shuttle vector plasmid transfected into DNA repair deficient cells (xeroderma pigmentosum complementation group A). To compare the role of two major UV-induced photoproducts, cis-syn cyclobutane-type pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), each photoproduct was removed from UV-irradiated plasmid by photoreactivation before transfection. Removal of either CPDs or 6-4PPs by in vitro photoreactivation reduced the mutation frequency while keeping the mutation distribution and the predominance of G:C-A:T transitions as UV-irradiated plasmid without photoreactivation, indicating that both cytosine-containing CPDs and 6-4PPs were premutagenic lesions for G:C-A:T transitions. On the other hand, A:T-G:C transitions were not recovered from plasmids after the removal of 6-4PPs, whereas this type of mutation occurred at a significant level (11%) after the removal of CPDs. Thus, the premutagenic lesions for the A:T-G:C transition are 6-4PPs. Removal of both CPDs and 6-4PPs resulted in the disappearance of mutational hot spots and random distribution of mutation as observed in unirradiated control plasmids. However, the mutational spectrum of photoreactivated plasmids differed significantly from that of unirradiated plasmids. A characteristic feature is a high portion of A:T-T:A transversions (11%) in the photoreactivated plasmid. This mutation is due to nondipyrimidinic "minor" photoproducts, and the mutation spectrum suggests that TA*, the major photoproduct of thymidylyl-(3'-5')-deoxyadenosine, is the premutagenic lesion for this mutation. This is the first report revealing the distinct mutagenic roles of the major UV photoproducts and "minor" photoproducts by the use of (6-4)photolyase.
Cancer Res 2000 Mar 15
PMID:Respective roles of cyclobutane pyrimidine dimers, (6-4)photoproducts, and minor photoproducts in ultraviolet mutagenesis of repair-deficient xeroderma pigmentosum A cells. 1074 46

Photolyase absorbs blue light and employs the energy to remove UV-induced DNA damage, cyclobutane pyrimidine dimers, or pyrimidine pyrimidone (6-4) lesions. These enzymes have been found in many living organisms ranging from bacteria to aplacental mammals, but their photoreactivation effect, such as survival increase of UV-irradiated cells by light-illumination, has not been identified in placental mammals, including humans. Therefore, we introduced a photolyase gene derived from the marsupial rat kangaroo, Potorous tridactylus, into HeLa cells and established the first human cell line capable of photorepairing UV-induced pyrimidine dimers. Several clones were found to increase cell survival after UV irradiation when illuminated by fluorescent light. The induction of apoptosis by UV irradiation was investigated in these photoreactivation-proficient cells. Several typical features of the programmed cell death, such as internucleosomal DNA degradation, presence of subdiploid cells, loss of membrane integrity, and chromosomal condensation, were found to be induced by UV in the HeLa cells, but they can be reduced by photorepair. This implicates that cyclobutane pyrimidine dimers cause UV-induced apoptosis in human cells.
Cancer Res 2000 May 01
PMID:Photorepair prevents ultraviolet-induced apoptosis in human cells expressing the marsupial photolyase gene. 1081 Nov 24


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