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)

Ataxia telangiectasia (AT) cell lines are characterised by their hypersensitivity to ionizing radiation and bleomycin, and their failure to inhibit DNA synthesis after DNA damage. A recent report [Singh et al. (1988) Nucl. Acids Res. 16, 3919-3929] indicated that a reduction in topoisomerase II (topo II) activity was a feature of AT lymphoblast cell lines. We have studied the possible role of DNA topoisomerases in determining the phenotype of an AT fibroblast cell line. AT5BIVA cells are sensitive to the topo II inhibitors etoposide (VP16) and amsacrine (m-AMSA), compared to normal human fibroblasts (MRC5-V1 and VA13). AT5BIVA cells express a 3-fold higher level of topo II protein than MRC5-V1 cells, and 6-fold higher than VA13. This is reflected in elevated topo II activity in AT5BIVA cells. Untransformed AT5BI cells also show elevated topo II activity compared to untransformed normal cells. The extent of overproduction of topo II in AT5BIVA cells is comparable with that seen in a mutant Chinese hamster cell line, ADR-1, which is similarly hypersensitive to both bleomycin and topo II inhibitors. However, ADR-1 cells show neither hypersensitivity to ionizing radiation nor abnormal inhibition of DNA synthesis following DNA damage. Topo II overproduction per se does not appear sufficient to generate an "AT-like" phenotype. AT5BIVA cells express a reduced level of topoisomerase I (topo I) and are hypersensitive to the topo I inhibitor, camptothecin. ADR-1 cells express a normal level of topo I, indicating that a reduction in the level of topo I is not the inevitable consequence of an elevation in topo II.
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PMID:Overproduction of topoisomerase II in an ataxia telangiectasia fibroblast cell line: comparison with a topoisomerase II-overproducing hamster cell mutant. 253 56

The mechanism of augmentation of tumor cell killing by immune effector cells and chemotherapeutic drugs was studied. The effect of treating tumor cells with various antineoplastic drugs on their sensitivity to murine natural cell-mediated cytotoxicity in vitro was investigated. Pretreatment with actinomycin D at nontoxic concentrations rendered L929 and WEHI-164 tumor cells more susceptible to killing by mouse spleen lymphocytes in a dose-dependent manner. Similarly, enhancement of L929 tumor cell killing by natural cell-mediated cytotoxicity was observed following treatment of the target cells with the topoisomerase II inhibitors, Adriamycin, amsacrine, bisantrene, etoposide, and teniposide, as well as with topoisomerase I inhibitor, camptothecin. In contrast, drugs which induce their cytotoxic effects by mechanisms that do not involve topoisomerase inhibition such as bleomycin, vinblastine, vincristine, and mitomycin C failed to exhibit synergism with natural cell-mediated cytotoxicity. However, moderate synergy was consistently observed with cis-platinum. The effector cells responsible for the cytotoxicity in the present system are natural cytotoxic cells since they kill WEHI-164 but not YAC cells, are resistant to treatment with anti-asialo-GM1 antibody, and their activity is abolished by anti-tumor necrosis factor antibodies. Indeed, tumor necrosis factor-mediated cytotoxicity of WEHI-164 or L929 was enhanced by treatment of the target cells with topoisomerase II inhibitors. Moreover, WEHI-164 cells selected for tumor necrosis factor resistance were resistant to natural cell-mediated cytotoxicity, and no synergy could be observed with topoisomerase inhibitors.
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PMID:Synergistic antitumor effects of topoisomerase inhibitors and natural cell-mediated cytotoxicity. 253 25

DNA topoisomerase I has been purified from homogenates of mature Xenopus laevis ovaries. The initial stages in purification of the native enzyme employed a rapid series of three chromatographic steps, followed by gel filtration performed in the presence of sodium dodecyl sulfate. Polypeptides that might represent topoisomerase I were identified by specific labeling of the topoisomerase species with radioactive DNA. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of topoisomerase I radiolabeled with DNA identified three polypeptides with mobilities consistent with sizes of 165, 125, and 88 kDa. All three polypeptides were found to possess topoisomerase activity following elution from the gel and renaturation. Partial proteolytic digestion of the radiolabeled 165-, 125-, and 88-kDa polypeptides with Staphylococcus aureus V8 endoproteinase resulted in identical autoradiographic patterns. This suggests that the 125-kDa and 88-kDa polypeptides may be degradation products of the 165-kDa species. The 165-kDa topoisomerase I exhibited the same sensitivity to camptothecin as the total, native topoisomerase I fraction.
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PMID:A high molecular weight topoisomerase I from Xenopus laevis ovaries. 253 54

When hepatocyte proliferation is stimulated in the liver by partial hepatectomy, messenger RNAs coding for fibrinogen, actin, c-myc and topoisomerase I are rapidly accumulated. We distinguish an early phase of accumulation (0-3 h after partial hepatectomy) which is also observed after a sham operation for the four genes, and during inflammation produced by Freund's adjuvant in the case of fibrinogen and c-myc genes. The hepatic response to inflammation appears therefore to mimic events characteristic of the G0/G1 transition, such as the accumulation of the c-myc mRNA. The late phase of mRNA accumulation (beyond 3 h after partial hepatectomy) is typical of liver regeneration. The level of c-myc mRNA is transiently increased (20-fold over normal) 20 h after partial hepatectomy, that is, at the time of DNA synthesis. Topoisomerase-I mRNA level increases between 3 and 24 h after partial hepatectomy (5-10-fold over normal). These results suggest that accumulation of c-myc and topoisomerase-I mRNAs is associated with DNA replication in regenerating liver.
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PMID:Gene expression in regenerating liver in relation to cell proliferation and stress. 254 2

Circular plasmid DNA was efficiently converted into huge catenated intranuclear networks by incubation with isolated nuclei in the presence of ATP. The network production is abolished by omission of ATP, strongly inhibited by etoposide (VP-16), but only slightly inhibited by antibody to topoisomerase I, indicating that the major enzyme responsible for catenation is DNA topoisomerase II. Under optimal conditions, a single nucleus incorporates about 4.2 x 10(4) DNA rings into its networks. Under the light microscope, networks retrieved from nuclei appear like spheres of various sizes. Sedimentation analysis showed that most of the networks are composed of thousands of catenated rings, which was confirmed by electron microscopy. Data from experiments that caused partial disruption of the networks were submitted to analysis based on probable models of catenane structure. The results suggest that the predominant pattern is a linear alignment of catenated rings. Similar networks are formed when the nuclear scaffold is incubated with circular DNA in the presence of nuclear extract containing topoisomerase II. Titration experiments showed that the scaffold binds a stoichiometric amount of the substrate and that a critical level of DNA is required for network formation. The results are consistent with the idea that DNA-binding sites are fixed on the scaffold and mediate catenation of bound DNA circles by holding them in close proximity to each other. We propose that catenation by the nuclear scaffold also occurs in intact nuclei, suggesting additional roles for the scaffold in vivo.
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PMID:Incorporation of exogenous circular DNA into large catenated networks in isolated nuclei. Evidence for involvement of the nuclear scaffold. 254 Jan 99

Merbarone has previously been shown to have antitumor activity of unknown mechanism in P388 and L1210 tumor models (A. D. Brewer et al., Biochem. Pharmacol., 34:2047-2050, 1985) and is currently undergoing Phase I clinical trials. Here we report that merbarone is an inhibitor of topoisomerase II. Merbarone inhibited purified mammalian topoisomerase II with a 50% inhibitory concentration of 20 microM, as assessed by ATP-dependent unknotting of P4 phage DNA or relaxation of supercoiled pBR322 plasmid. In contrast to the type II enzyme, inhibition of catalytic activity of topoisomerase I required about 10-fold higher concentrations of merbarone, with a 50% inhibitory concentration of approximately 200 microM. Unlike epipodophyllotoxin analogues and certain DNA intercalative agents which stabilize the topoisomerase II-DNA "cleavable complex," merbarone did not cause detectable topoisomerase II-induced DNA cleavage. Furthermore, merbarone inhibited the production by amsacrine or teniposide of topoisomerase II-associated DNA strand breaks; under identical conditions novobiocin did not decrease these breaks, setting merbarone apart from a novobiocin-like class of topoisomerase II inhibitor. In L1210 cells, merbarone produced only small numbers of protein-associated DNA strand breaks, and only at very high concentrations. Merbarone reduced in a concentration-dependent manner the number of amsacrine- or teniposide-stimulated protein-associated DNA strand breaks in L1210 cells or their isolated nuclei. The data suggest that merbarone represents a novel type of topoisomerase II inhibitor.
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PMID:In vitro and intracellular inhibition of topoisomerase II by the antitumor agent merbarone. 254 Sep 3

A hyper-recombination mutation was isolated that causes an increase in recombination between short repeated delta sequences surrounding the SUP4-omicron gene in S. cerevisiae. The wild-type copy of this gene was cloned by complementation of one of its pleiotropic phenotypes, slow growth. DNA sequence of the clone revealed a 656 amino acid open reading frame capable of encoding a protein homologous to the bacterial type I topoisomerase. No homology was detected with previously identified eukaryotic topoisomerases. Construction of double mutants with either of the two known yeast topoisomerase genes revealed synergistic effects on growth suggesting overlapping functions. Expression of bacterial topoisomerase I in yeast can fully complement the slow growth defect of a null mutation. We have named this locus TOP3 and suggest that it defines a novel eukaryotic topoisomerase gene.
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PMID:A hyper-recombination mutation in S. cerevisiae identifies a novel eukaryotic topoisomerase. 254 82

The specificity of splitting of the cloned alpha A-globin gene from chicken erythrocytes induced by three topoisomerases I differing in molecular masses was demonstrated. The localization and relative number of topoisomerase breaks in the alpha A-globin gene vary in different topoisomerase I forms.
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PMID:[Specific splitting of the alpha-A-globin gene by molecular forms of DNA-topoisomerase type I from calf thymus]. 254 55

Incubation of topologically relaxed plasmid DNA with simian virus 40 (SV40) large tumor antigen (T antigen), ATP, and eubacterial DNA topoisomerase I resulted in the formation of highly positively supercoiled DNA. Eukaryotic DNA topoisomerase I could not substitute for eubacterial DNA topoisomerase 1 in this reaction. Furthermore, the addition of eukaryotic topoisomerase I to a preincubated reaction mixture containing both T antigen and eubacterial topoisomerase I caused rapid relaxation of the positively supercoiled DNA. These results suggest that SV40 T antigen can introduce topoisomerase-relaxable supercoils into DNA in a reaction coupled to ATP hydrolysis. We interpret the observed T antigen supercoiling reaction in terms of a recently proposed twin-supercoiled-domain model that describes the mechanics of DNA helix-tracking processes. According to this model positive and negative supercoils are generated ahead of and behind the moving SV40 T antigen, respectively. The preferential relaxation of negative supercoils by eubacterial DNA topoisomerase I explains the accumulation of positive supercoils in the DNA template. The supercoiling assay using DNA conformation-specific eubacterial DNA topoisomerase I may be of general use for the detection of ATP-dependent DNA helix-tracking proteins.
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PMID:Template supercoiling during ATP-dependent DNA helix tracking: studies with simian virus 40 large tumor antigen. 254 99

The relationship between gene expression and the patterns of histone methylation in Drosophila cells has been investigated using inhibitors of transcription acting at various levels. Inhibition of ribosomal RNA synthesis and processing by 5-fluorouridine or of general RNA synthesis by camptothecin, an inhibitor of topoisomerase I, does not affect the methylation pattern of core histones. This suggests that the arrest of transcription per se is not involved in the changes in histone methylation such as those encountered in heat-shocked cells. However, ethidium bromide and novobiocin, which are known to disrupt nucleosome structure, and VM-26 (teniposide), a specific inhibitor of topoisomerase II, induce changes in histone methylation patterns which, though less severe, are similar to those observed under cellular stress. These results suggest that chromatin conformation is probably an important factor in the accessibility of histones to methyltransferases.
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PMID:Transcriptional inhibitors affecting topoisomerase II induce changes in histone methylation patterns similar to those induced by heat shock. 254 90


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