Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00249 (Mutagen)
 5,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The substrate specificity of the uvr endonuclease, the product of the uvrA, uvrB, and uvrC genes is reviewed. It is suggested that the relatively well-defined substrate specificity of this repair enzyme is useful as a guide in determining the nature of the DNA-lesion caused by a given mutagen.
Environ Mutagen 1979
PMID:Substrate-specificity of uvr excision repair. 23 62

Enzymatic activity, hydrolyzing DNA treated with beta-isopropyl-bis-beta-chloroethylamine (HN2-DNA), HN2-DNA exposed at 50 degrees for 1 h, and DNA treated with acid, to acid-soluble fragments was found in extracts from cells of M. lysodeikticus. The endonucleolytic component ofthe indicated activity manifests chromatographic properties on DEAE- and CM-cellulose, close to those for UV-endonuclease. Activity is manifested by UV-irradiated DNA, proflavin, and cyanide. Two electrophoretically homogeneous fractions of UV-endonuclease (after chromatography on DEAE- and CM-cellulose), with molecular weights about 13,000 and 15,000 daltons, exhibit endonucleolytic activity with respect to HN2-DNA, exposed at 50 degrees for 1 h, and with respect to "acid" DNA, treated for 6 min at 70 degrees in citrate buffer, pH 3.5. The activity with respect to the latter substrate is competitively suppressed by UV-irradiated DNA. The most probable substrate of UV-endonuclease, in addition to cyclobutane dimers, is the depurinized region of DNA.
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PMID:The presence of an endonuclease acting on UV-irradiated and depurinized DNA in cells of Micrococcus lysodeikticus. 112 5

Previous DNA sequence analysis of bleomycin-induced forward mutations in repackaged lambda phage has suggested SOS-dependent replicative bypass of oxidized apyrimidinic sites as a possible mechanism of mutagenesis. In order to evaluate this hypothesis further, frequencies of mutation to a clear-plaque phenotype were compared for bleomycin-damaged phage grown in various repair-deficient strains of Escherichia coli. Survival of bleomycin-damaged phage was virtually identical in all host strains. Studies in SOS-deficient strains indicated specific requirements for functional recA+ and umuC+ alleles in the generation of the majority of bleomycin-induced mutations, as well as a less stringent requirement for induction of the SOS response by ultraviolet irradiation of the host cells. These results are expected for mutagenesis resulting from apyrimidinic sites. However, the mutation frequency for bleomycin-damaged phage was the same whether the phage were grown in a wild-type strain or in strains deficient in apurinic/apyrimidinic repair endonucleases; this was true even for an nth-nfo-xth- strain lacking all three major apurinic/apyrimidinic endonucleases (endonuclease III, endonuclease IV, and exonuclease III). Likewise, phage grown in an endonuclease IV-overproducing strain showed the same mutation frequency as those grown in wild-type cells. These data suggest that either i) bleomycin-induced mutagenesis results from SOS-dependent bypass of lesions other than apyrimidinic sites or ii) the number of apyrimidinic sites available for SOS processing is virtually independent of the level of apurinic/apyrimidinic endonuclease activity in the cell. It is possible that a fraction of the apyrimidinic sites induced by bleomycin either are intrinsically resistant to repair or undergo secondary reactions that render them resistant.
Environ Mol Mutagen 1988
PMID:Mutagenesis of bleomycin-damaged lambda phage in SOS-deficient and repair endonuclease-deficient Escherichia coli. 245 58

Chromatid breaks and exchanges are induced by radiation in G2 mammalian cells. Breaks are at a maximum number at about 30 min after irradiation and decrease apparently exponentially with time between irradiation and sampling. Few breaks are observed immediately following exposure, probably as a result of selection of mitotic cells where chromosomes are condensed and there is consequently a lack of time for expression of damage. The change in frequency of breaks with time, from 30 min after radiation exposure and onwards, can be interpreted in two possible ways: either in terms of a repair process or in terms of a change in radiosensitivity through G2. However, our results with an inhibitor of repair of DNA double-strand breaks (ara A) and with "transient hypothermia" which extends the G2 phase, argue for an interpretation based on rejoining of chromatid breaks, possibly reflecting the repair of a subclass of dsb. Data from experiments with irradiated and restriction endonuclease treated radiosensitive mutant rodent lines indicate that enhanced levels of conversion of dsb into chromosomal aberrations may be largely independent of repair rates of bulk dsb. In CHO cells and in human lymphocytes exchanges initially increase rapidly with time and then remain at a constant frequency, supporting the notion of a uniform chromosomal radiosensitivity throughout most of G2 and providing further evidence that the mechanism for mis-joining broken chromatids (leading to exchanges) is different from that for rejoining of chromatoid breaks. Ratios of breaks to exchanges were found to vary in different cell lines and at different times during treatment with inhibitors or at altered temperatures, possibly (in different cell lines) indicating different levels of enzymes involved in misjoining, but suggesting that the mechanisms of chromosomal rejoining and misjoining are independent, at least to some degree.
Environ Mol Mutagen 1993
PMID:G2 chromatid aberrations: kinetics and possible mechanisms. 822 6

1-beta-D-arabinofuranosylcytosine (ara C) enhances the formation of chromosome rearrangements such as translocations or dicentric chromosomes in G1 cells containing DNA lesions. The formation of rearrangements is hypothesized to be the result of inhibition of excision repair. Ara C has also been known to lead to the formation of chromosome rearrangements in G1 cells in the absence of induced DNA lesions. It is not known whether a common mechanism is involved in these two processes. In the present study, we used excision repair-deficient XP cells to investigate whether excision repair is involved in the formation of chromosome rearrangements in G1 cells which do not contain induced DNA lesions. G0 Lymphocytes from an XP patient were either treated with 4-nitroquinoline-1-oxide (4NQO) or left untreated. Cells were then cultured in the presence of ara C for about 18 h. Aphidicolin (APC), which induces chromosome rearrangements in cells containing 4NQO-induced DNA lesions, was used for comparison. The resulting frequency of dicentrics and rings (dic & ring) was determined at the first mitoses after culture initiation. In 4NQO-pretreated XP cells, the frequency of dic & ring was not increased by post-treatment with ara C or with APC. This result is thought to reflect the absence of excision repair in XP cells. However, normal induction of dic & ring was observed in XP cells not pretreated with 4NQO but treated with ara C. Thus, there seems to be two different processes involved in the induction of G1 rearrangements: excision repair-dependent and excision repair-independent. UV-endonuclease is not involved in excision repair-independent rearrangements.
Environ Mol Mutagen 1993
PMID:Evidence for excision repair-dependent and -independent processes in ara C-induced chromosome rearrangements in G1 human lymphocytes. 822 9

The effect of various wavelengths of UVB radiation on the induction of cyclobutane pyrimidine dimers in fish cells and human fibroblasts and the repair of these lesions were studied using an UV-endonuclease to measure dimers (endonuclease sensitive sites) by sedimentation of radioactive DNA, by gel electrophoresis of unlabeled DNA, and by cell survival. The data show that fish cells have an efficient photoreactivation system at wavelength > 304 nm that reverses cytotoxicity and dimer formation after exposure to filtered sunlamp irradiation of a shorter wavelength (lambda > 290 nm). Shorter wavelengths in UVB (> 304 nm) are more effective in photoreversal than longer ones (> 320 nm). As a consequence, 50-85% of dimers induced by these wavelengths in fish are photoreactivated while they are being formed. A major cytotoxicological lesion is the cyclobutane pyrimidine dimers. Cultured human fibroblasts do not possess such a repair system. These results indicate that sunlamp irradiation has wavelengths that both damage and repair DNA.
Environ Mol Mutagen 1993
PMID:DNA damage, photorepair, and survival in fish and human cells exposed to UV radiation. 839 2

The comet assay (single-cell gel electrophoresis), which measures DNA strand breaks at the level of single cells, is very easily applied to human lymphocytes, and therefore lends itself to human biomonitoring studies. For the examination of DNA base oxidation (a specific marker of oxidative damage), the assay is modified by including a stage at which the DNA is incubated with a suitable lesion-specific endonuclease. Here we report on the reliability and reproducibility of this approach, from the level of comparing results from duplicate gels prepared from the same sample of cells, up to an assessment of the natural intra- and interindividual variability in lymphocyte DNA damage measured in groups of normal, healthy human volunteers. We applied the assay in investigations of human disease and occupational exposure of factory workers.
Environ Mol Mutagen 1997
PMID:Comet assay in human biomonitoring studies: reliability, validation, and applications. 932 38

The human AP endonuclease (APE) activity counteracts the mutagenic and cytotoxic effects of the frequent genomic lesions abasic (AP) sites. In order to investigate the interindividual variability of APE levels, a simple and quantitative assay was developed. Crude lymphocyte extracts were incubated with a depurinated or a control supercoiled plasmid substrate, and the accumulation of nicked circular plasmid forms was monitored by agarose gel electrophoresis. The detected incision activity was AP sites-dependent and EDTA-sensitive. The unit of enzymatic activity was defined as that amount able to incise 1 ng of plasmid DNA carrying 1 AP site/plasmid at 30 degrees C in 10 min. The assay was used to measure the APE activity in 10 healthy individuals ages 25-48 years. Values ranged from 0.38 to 0.94 units/ng protein, with a mean value of 0.62. The use of the assay for screening of people with DNA base excision repair (BER) defects is proposed.
Teratog Carcinog Mutagen 1998
PMID:AP endonuclease activity in humans: development of a simple assay and analysis of ten normal individuals. 958 67

The restriction site mutation (RSM) assay was developed in this laboratory for the detection of point mutations that occur within restriction endonuclease recognition sequences in the genomic DNA of the rat. Mutations were detected and identified in a number of tissues from N-methyl-N-nitrosourea (MNU)-treated rats. Resistant restriction enzyme products were detected in 5 of the 13 restriction endonuclease recognition sequences tested (NcoI, BslI, CfoI, DdeI, and HindIII). These mutations were detected in the p53 tumor suppressor gene and the H-ras protooncogene. No resistant RSM products were detected in any of the samples taken from untreated animals. The MNU-induced mutations were identified as G to A and A to G transitions. Our results describe the first successful application of the RSM assay in detecting induced mutations in the rat and highlight the usefulness of the RSM assay in the analysis of mutagen-induced base changes without the requirement for selection of a mutant phenotype. Given the increasing use of the rat as an animal model in genotoxicity studies, the development of such tests is essential for future genotoxicity investigations.
Teratog Carcinog Mutagen 1998
PMID:Application of the restriction site mutation technique to N-methyl-N-nitrosourea-induced mutations in the rat. 980 73

DNA double-strand breaks (DSB) may arise either spontaneously during cellular processes or as a result of exposure to DNA-damaging agents such as ionizing radiation, or radiomimetic agents such as restriction endonucleases or bleomycin. It is widely accepted that nonrepaired or misrepaired DSB are the main lesions leading to the production of chromosomal aberrations, mutagenesis, oncogenic transformation, and cell killing. Studies focusing on this relationship, as well as the possible modulation of DNA repair mechanisms, are currently of major interest. A wide variety of test systems are available to study DNA damage. In the last few years, single-cell gel electrophoresis, commonly known as "comet assay," has been considered a rapid, sensitive, and visual method for quantifying DNA strand breaks and alkali-labile damage in individual cells. In this study, making use of the comet assay, we tried to find out if under conditions that maintain chromatin structure the DNA ligase from T4 phage is able to facilitate the rejoining of strand breaks with different end structures, induced by the restriction endonuclease MspI or bleomycin in living human lymphocytes in a nonproliferating state. T4 DNA ligase, as well as the restriction endonuclease or bleomycin, were introduced together by electroporation into human lymphocytes. Our results support the idea that it is possible to modulate the DSB-rejoining of different DNA strand-breaking agents by exogenous T4 DNA ligase.
Environ Mol Mutagen 1998
PMID:Protection provided by exogenous DNA ligase in G0 human lymphocytes treated with restriction enzyme MspI or bleomycin as shown by the comet assay. 988 8


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