Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have characterized the topoisomerase I and II activities in nuclear extracts from immature embryos of Zea mays and the effect of the treatment with 2,4-dichlorophenoxyacetic acid (2,4-D) and abscisic acid (ABA). These extracts were shown to be essentially devoid of protease and nuclease activities and they were tested for their ability to relax supercoiled DNA, unknotting P4 DNA and catenate circular duplex DNA under catalytic conditions. Unknotting and catenation reactions are strictly magnesium- and ATP-dependent, but not the relaxation of circular supercoiled DNA allowing the detection of both topoisomerase I and II activities. Two cytotoxic drugs, camptothecin, a plant alkaloid that inhibits eukaryotic topoisomerase I, and epipodophyllotoxin VM-26 (teniposide) that inhibits topoisomerase II, have been assayed in our extracts showing similar inhibitory effects on topoisomerase enzymes. Alkaline phosphatase treatment of nuclear extracts abolishes both topoisomerase activities. Nuclear extracts from embryos treated with 2,4-D showed 200% increase on topoisomerase II activity as compared with untreated ones, but only residual activity was detected in ABA-treated embryos. Nuclear extracts from hormone-treated and untreated embryos showed similar topoisomerase I activity with deviations of less than 25%. These differences are discussed in terms of possible post-translational modifications of the enzymes associated with the increase in proliferation activity of calli.
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PMID:Characterization of topoisomerase I and II activities in nuclear extracts during callogenesis in immature embryos of Zea mays. 165 30

Several recently developed derivatives of bis(2,6-dioxopiperazine) have been shown to be new antitumor agents and are currently under clinical trials. We found that the mother compound of the bis(2,6-dioxopiperazine)s, ICRF-154, and its derivatives, ICRF-159, ICRF-193, and MST-16, are all inhibitors of mammalian type II DNA topoisomerase. By decatenation assay using kinetoplast DNA from Crithidia fasciculata, inhibition of purified calf thymus topoisomerase II by these compounds was investigated. Potency of inhibition was in the following order: ICRF-193 greater than ICRF-154 = ICRF-159 greater than MST-16. The doses giving 50% inhibition were 2, 13, 30 and 300 microM, respectively, for these compounds. ICRF-193, the most potent inhibitor, however, did not inhibit topoisomerase I at concentrations up to 300 microM. Addition of excess enzyme, but not of the substrate DNA, overcame the inhibition by ICRF-193. The drug did not stimulate the formation of cleavable complex between DNA and the enzyme. Furthermore, ICRF-193 even inhibited the formation of enzyme-mediated DNA cleavage induced by etoposide or 4'-[9-acridinylamino)methanesulfon-m-anisidide. These observations, together with the finding that ICRF-193 did not intercalate into DNA, suggest that ICRF-154 and related compounds are specific inhibitors of topoisomerase II with different modes of action: i.e., they interfere with some step(s) before the formation of the intermediate cleavable complex in the catalytic cycle. This is a property quite distinct from previously known cleavable complex-forming type topoisomerase II-targeting antitumor agents such as acridines, anthracyclines, and epipodophyllotoxins, but rather, mechanistically similar to the recently reported group of inhibitors that includes merbarone, aclarubicin, and fostriecin.
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PMID:Inhibition of topoisomerase II by antitumor agents bis(2,6-dioxopiperazine) derivatives. 165 4

DNA topoisomerases are essential nuclear enzymes that are involved in DNA replication. Clinically useful antitumor drugs such as doxorubicin, daunorubicin (anthracyclines), etoposide, teniposide (epipodophyllotoxins), and amsacrine (an aminoacridine) interfere with the function of topoisomerase II and camptothecin and its analogs inhibit topoisomerase I. Some mammalian tumor cells that express resistance to drugs that interfere with topoisomerase I or topoisomerase II have alterations in their respective topoisomerases. In this paper, we review the functions of the topoisomerases, discuss aspects of their cellular regulation, ask how interference with topoisomerase function can lead to tumor cell death, discuss the biochemical features of tumor cells that are resistant to these anti-topoisomerase drugs, and, in the context of drug resistance, we raise questions about how these drugs exert their cytotoxicity.
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PMID:Mechanisms of resistance to drugs that inhibit DNA topoisomerases. 165 18

We have studied the effect of some specific enzyme inhibitors on DNA repair and replication after UV damage in Chinese hamster ovary cells. The DNA repair was studied at the level of the average, overall genome and also in the active dihydrofolate reductase gene. Replication was measured in the overall genome. We tested inhibitors of DNA polymerase alpha and delta (aphidicolin), of poly(ADPr) polymerase (3-aminobenzamide), of ribonucleotide reductase (hydroxyurea), of topoisomerase I (camptothecin), and of topoisomerase II (merbarone, VP-16). In addition, we tested the effect of the potential topoisomerase I activator, beta-lapachone. All of these compounds inhibited genome replication and all topoisomerase inhibitors affected the overall genome repair; beta-lapachone stimulated it. None of these compounds had any effect on the gene-specific repair.
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PMID:Effect of specific enzyme inhibitors on replication, total genome DNA repair and on gene-specific DNA repair after UV irradiation in CHO cells. 165 49

DNA topoisomerase II (EC 5.99.1.3) is necessary for chromosome condensation and disjunction in yeast but not for other functions. In mammalian cells, it has been reported to be necessary for progression toward mitosis but not for transit through mitosis. We have found, on the contrary, that specific inhibition of topoisomerase II (but not of topoisomerase I) interferes with mammalian mitotic progression. Metaphase is prolonged, and anaphase separation of chromatids is completely inhibited, in cells given high concentrations of topoisomerase II inhibitors; nevertheless these cells attempt cleavage, sometimes generating nucleate and anucleate daughters. Lower concentrations of inhibitors interfere with anaphase and produce abnormalities of segregation. DNA topoisomerase II activity is therefore necessary for mammalian chromatid separation, but it is not tightly coupled to the control of other mitotic events.
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PMID:Inhibitors of DNA topoisomerase II prevent chromatid separation in mammalian cells but do not prevent exit from mitosis. 165 58

Topotecan (SK&F 104864), a water-soluble analogue of the topoisomerase I inhibitor camptothecin, is currently in Phase II clinical trial for solid tumors. We have characterized topotecan in terms of its effect upon gamma-radiation-induced cell killing. In colony formation experiments, subtoxic concentrations of topotecan (2 microM) potentiated radiation-induced killing of exponentially growing Chinese hamster ovary or P388 murine leukemia cultured cells. Survival curve shoulders were reduced; the slopes of the exponential portions of the curves were decreased to a small extent. D37 and D10 (radiation dose resulting in 37 and 10% survival of colony-forming ability) values were reduced by approximately 60 and 50%, respectively, in the case of Chinese hamster ovary cells. In P388 cells, topotecan reduced D37 by 35 to 40% and D10 by 20 to 25%. Potentiation of radiation-induced cell killing by topotecan was absolutely dependent upon the presence of the topoisomerase I inhibitor during the first few (less than 30) min after irradiation. Association of topoisomerase I with this effect was confirmed in studies of Chinese hamster ovary cells previously made resistant to camptothecin (and cross-resistant to topotecan), resulting in decreased cellular content of topoisomerase I. These cells were found to be 2- to 3-fold hypersensitive to gamma-radiation-induced killing. P388 camptothecin-resistant cells were further sensitized to the lethal effects of ionizing radiation by nontoxic treatment with the topoisomerase II inhibitor novobiocin, consistent with increased dependence of topoisomerase I-deficient cells upon topoisomerase II.
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PMID:Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864). 165 71

In order to investigate the mechanism of topoisomerase I inhibition by camptothecin, we studied the induction of DNA cleavage by purified mammalian DNA topoisomerase I in a series of oligonucleotides and analyzed the DNA sequence locations of preferred cleavage sites in the SV40 genome. The oligonucleotides were derived from the sequence of the major camptothecin-induced cleavage site in SV40 DNA (Jaxel, C., Kohn, K. W., and Pommier, Y. (1988) Nucleic Acids Res. 16, 11157 to 11170) with the cleaved bond in their center. DNA length was critical since cleavage was detectable only in 30 and 20 base pair-(bp) oligonucleotides, but not in a 12-bp oligonucleotide. Cleavage was at the same position in the oligonucleotides as in SV40 DNA. Its intensity was greater in the 30- than in the 20-bp oligonucleotide, indicating that sequences more than 10 bp away from the cleavage site may influence intensity. Camptothecin-induced DNA cleavage required duplex DNA since none of the single-stranded oligonucleotides were cleaved. Analysis of base preferences around topoisomerase I cleavage sites in SV40 DNA indicated that camptothecin stabilized topoisomerase I preferentially at sites having a G immediately 3' to the cleaved bond. Experiments with 30-bp oligonucleotides showed that camptothecin produced most intense cleavage in a complementary duplex having a G immediately 3' to the cleavage site. Weaker cleavage was observed in a complementary duplex in which the 3'G was replaced with a T. The identity of the 3' base, however, did not affect topoisomerase I-induced DNA cleavage in the absence of drug. These results indicate that camptothecin traps preferentially a subset of the enzyme cleavage sites, those having a G immediately 3' to the cleaved bond. This strong preference suggests that camptothecin binds reversibly to the DNA at topoisomerase I cleavage sites, in analogy to a model previously proposed for inhibitors of topoisomerase II (Capranico, G., Kohn, K.W., and Pommier, Y. (1990) Nucleic Acids Res. 18, 6611-6619).
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PMID:Effect of local DNA sequence on topoisomerase I cleavage in the presence or absence of camptothecin. 165 24

The principal existence of natural catalytic antibodies in the autoimmune sera is discussed. In the course of the autoimmune process, the induction of antiidiotypic antibodies against topoisomerase I has been shown in the sera of patients with scleroderma, systemic lupus erythematosus, and rheumatoid arthritis. The above antibodies were obtained in preparative amounts. Proceeding from the concept of the idiotypic network, the antibodies were suggested to be natural enzymes and their properties were studied. They appeared to be anti-DNA antibodies, competing with the native topoisomerase I for binding to anti-topoisomerase monoclonal antibodies and possessing highly specific DNA-binding activity (Kd is about 0.1 nM). The antiidiotypic antibodies specifically inhibit the topoisomerase-catalysed relaxation reaction and affect the formation of covalent DNA-protein complex. Possible involvement of antiidiotypic antibodies against topoisomerase in the catalysis of reactions of DNA transformation is analysed. Catalytic antibodies that are natural enzymes possessing DNA-nicking activity have been isolated from the blood sera of patients with different autoimmune pathologies.
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PMID:[Anti-idiotypic and natural catalytically active antibodies]. 165 16

Specialized type I topoisomerases catalyze DNA strand transfer during site-specific recombination in prokaryotes and fungi. As a rule, the site specificity of these systems is determined by the DNA binding and cleavage preference of the topoisomerase per se. The Mr 32,000 topoisomerase I encoded by vaccinia virus (a member of the eukaryotic family of "general" type I enzymes) is also selective in its interaction with DNA; binding and cleavage occur in vitro at a pentameric motif 5'-(C or T)CCTT in duplex DNA. Expression of vaccinia virus DNA topoisomerase I in a lambda lysogen of Escherichia coli promotes int-independent excisive recombination of the prophage. To address whether the topoisomerase directly catalyzes DNA strand transfer in vivo, the recombination junctions of plaque-purified progeny phage were cloned and sequenced. In five of six distinct excision events examined, a topoisomerase cleavage sequence is present in one strand of the DNA duplex of both recombining partners. Recombination entails no duplication, insertion, or deletion of nucleotides at the crossover points, consistent with excision via conservative strand exchange at sites of topoisomerase cleavage. Three of these five recombination events are distinguished by the presence of direct repeats at the parental half-sites that extend beyond the pentameric cleavage motif, suggesting that sequence homology may facilitate excision. The data are consistent with a model in which vaccinia topoisomerase catalyzes reciprocal strand transfer, leading to the formation of a nonmigrating Holliday junction, the resolution of which can lead to excisive recombination.
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PMID:Recombination mediated by vaccinia virus DNA topoisomerase I in Escherichia coli is sequence specific. 165 96

This paper shows that in the yeast Saccharomyces cerevisiae the levels of most mRNAs decrease, in a temporally orchestrated manner, as cells approach and enter the stationary phase. The decreased level of mRNAs is primarily due to transcriptional repression because the overall rate of in vivo transcription by RNA polymerase II is similarly reduced in the stationary phase. The reduction in mRNA levels and the general transcriptional repression are both dependent on topoisomerase I (encoded by TOP1). Specifically, these two processes are much slower in top1 mutants, as their mRNA levels and transcriptional rate remain unchanged for a longer period of time in the stationary phase before they start to decrease. In contrast, the mRNA levels in the stationary phase are not affected by perturbation of topoisomerase II activity. TOP1-dependent repression operates even on HSP26 and SSA3, which have been shown previously to be transcriptionally induced in early stationary phase. Thus, their mRNA levels are high upon the entry of the cells into the stationary phase but gradually decrease, by a TOP1-dependent mechanism, later in the stationary phase. A minor population of mRNAs is not subjected to the TOP1-dependent regulation, as their levels do not change in stationary phase. The possible role of topoisomerase I in the general transcriptional repression is discussed.
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PMID:A general topoisomerase I-dependent transcriptional repression in the stationary phase in yeast. 166 Aug 29


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