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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the effects of topoisomerase inhibitors on human immunodeficiency virus type 1 (HIV-1) infection of H9 cells in cell culture. Infection is blocked or substantially reduced by the topoisomerase I inhibitor camptothecin (CPT), but not by two topoisomerase II inhibitors. Significant reduction (greater than or equal to 90%) in the amount of virus released, as measured by reverse transcriptase, is obtained if the cells are treated for 1 h with 0.01-0.02 microM CPT at the time of virus infection, and expression of viral proteins is also blocked. CPT is also shown to reduce the level of infection when chronically infected cells are cocultivated with uninfected cells. These results with CPT suggest that this compound may represent a new class of drugs with antiretroviral potential.
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PMID:Inhibition of human immunodeficiency virus (HIV-1) replication in vitro by noncytotoxic doses of camptothecin, a topoisomerase I inhibitor. 170 42

Previous work from our laboratory has suggested that topoisomerase II is required for replication of human cytomegalovirus (HCMV). In assays of confluent human embryonic lung cells infected with HCMV, topoisomerase II inhibitors exhibited an irreversible inhibition of viral DNA replication. However, Northern (RNA blot) and Western (immunoblot) analyses of confluent uninfected human embryonic lung cells detected very low levels of cellular topoisomerase II RNA and protein. Quantitation of human topoisomerase II RNA and protein levels at various times after HCMV infection revealed that HCMV induces increased intracellular levels of both topoisomerase II RNA and protein. Such accumulation began at early times of infection, continued through late in infection, and was not reduced by inhibition of viral DNA synthesis. This is the first report of such induction by a viral infection. Topoisomerase II was also detected in isolated HCMV virions.
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PMID:Human cytomegalovirus induces expression of cellular topoisomerase II. 215 37

The time course of appearance of type I topoisomerase activity after the infection of mouse L cytoplasts by vaccinia virus was determined. When the enucleation procedure was carried out with unsynchronized cell cultures, a high level of host-cell-specific type I topoisomerase activity was found associated with the resulting cytoplasts. If cells were first synchronized by the two-cycle thymidine block method and then enucleated after release, the level of host type I topoisomerase activity was also high for S-phase-enucleated cells but was very low for cytoplasts prepared from cells previously synchronized and enucleated during either the G1 or the G2 phase. After the infection of G1-phase-enucleated cytoplasts with vaccinia virus, newly synthesized type I topoisomerase activity first appeared at about 3 h postinfection. Virosomes were isolated from the infected, synchronized cytoplasts and assayed for the presence of type I topoisomerase activity. The activity remained at the top of a sucrose gradient, well resolved from the virosome fraction, at the low salt levels (0.01 M KCl, 0.01 M Tris hydrochloride, pH 8.0) normally used in the course of virosome purification. If the sedimentation was at the higher salt concentration (0.15 M KCl) at which the enzyme shows optimal activity, type I topoisomerase cosedimented with the virosome fraction onto the sucrose gradient cushion. These results show that the type I topoisomerase activity dependent upon vaccinia virus infection may be detected with high sensitivity in G1-phase-enucleated cytoplasts. The association with virosomes is consistent with an involvement of topoisomerase activity either in DNA replication or in late transcription.
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PMID:Type I topoisomerase activity after infection of enucleated, synchronized mouse L cells by vaccinia virus. 300 75

The possible intervention of nuclear proteins as cofactors of integrase-catalyzed integration of retroviral DNA into the host cell genome is not fully understood. Among various nuclear proteins, DNA topoisomerase II appears to be a plausible candidate. This hypothesis is supported by a series of evidence, including the fact that integration is markedly affected by the topology of the target DNA and mainly occurs in transcribed regions in which topoisomerase II is preferentially located. In an attempt to confirm the validity of this hypothesis, we have comparatively investigated the early stages of a recombinant Moloney murine leukemia virus (psi neo) in two related Chinese hamster cell lines (DC3F and R/DC3F) expressing different levels of both isoforms of topoisomerase II. R/DC3F is derived from the parental cell line DC3F and displays a resistant phenotype towards the usual anticancer topoisomerase II inhibitors (actinomycin D, doxorubicin, and taxol). Results show that the early stages of the retroviral cycle are markedly impaired in cells underexpressing topoisomerase II (R/DC3F). This alteration mimics Fv-1 restriction and is characterized by about a 6-fold decrease in viral DNA synthesis and total inhibition of viral genome integration. The specific impairment of integration in R/DC3F cells compared to DC3F cells is assessed by the absence of G418-resistant colonies upon viral infection and a lack of the viral genome in cellular nuclear DNA as detected by the PCR procedure. These features are observed in relevant infecting conditions leading, in both cell lines, to the same amount of linear viral DNA and to the occurrence of two long terminal repeats containing circular DNA in the nuclear fractions.
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PMID:Impairment of Moloney murine leukemia virus integration in a cell line underexpressing DNA topoisomerase II. 760 43

The ts16 mutation of vaccinia virus WR (R. C. Condit, A. Motyczka, and G. Spizz, Virology 128:429-443, 1983) has been mapped by marker rescue to the I7L open reading frame located within the genomic HindIII I DNA fragment. The I7 gene encodes a 423-amino-acid polypeptide. Thermolabile growth was attributed to an amino acid substitution, Pro-344-->Leu, in the predicted I7 protein. A normal temporal pattern of viral protein synthesis was elicited in cells infected with ts16 at the nonpermissive temperature (40 degrees C). Electron microscopy revealed a defect in virion assembly at 40 degrees C. Morphogenesis was arrested at a stage subsequent to formation of spherical immature particles. Western immunoblot analysis with antiserum directed against the I7 polypeptide demonstrated an immunoreactive 47-kDa polypeptide accumulating during the late phase of synchronous vaccinia virus infection. Immunoblotting of extracts of wild-type virions showed that the I7 protein is encapsidated within the virus core. The I7 polypeptide displays amino acid sequence similarity to the type II DNA topoisomerase of Saccharomyces cerevisiae.
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PMID:Vaccinia virus morphogenesis is blocked by a temperature-sensitive mutation in the I7 gene that encodes a virion component. 838 72

The 32-kDa topoisomerase I encoded by vaccinia virus relaxes supercoiled DNA in a manner which is mechanistically equivalent to that utilized by eucaryotic enzymes. Its amino acid sequence contains significant homology to the enzymes encoded by Saccharomyces cerevisiae, Saccharomyces pombe, human cells, and other poxviruses. The small size of the viral enzyme, and its essentiality in the viral life cycle, make it ideally suited for structural and functional analysis. In this report we present the construction and analysis of 15 mutant alleles of the topoisomerase containing amino acid substitutions in a highly conserved region. The enzymes encoded by these alleles were expressed in Escherichia coli and various parameters of their activity were examined. All of the alleles which show diminished (seven alleles) or abrogated (three alleles) DNA relaxation activity are deficient in DNA cleavage and the concomitant formation of the covalent enzyme/DNA intermediate. None are deficient in the prior step of noncovalent interaction with substrate DNA. Five of the mutant enzymes show significant temperature sensitivity in vitro. The extent of in vitro activity of the enzymes shows a good but incomplete correlation with the enzymes' abilities to lethally induce the resident lambda prophage within E. coli BL21(DE3) (via illegitimate recombination). Mutations in 1 amino acid, in particular, impair prophage induction in vivo more significantly than DNA relaxation in vitro. In sum, these studies suggest that this region of the topoisomerase (amino acids 216-225) plays a proximal role in mediating DNA cleavage and the covalent interaction between the 3'-phosphoryl of the nicked DNA and tyrosine 274 of the vaccinia topoisomerase I. The studies also provide useful reagents for the molecular genetic analysis of the role of the topoisomerase within the context of vaccinia virus infection.
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PMID:Biochemical analysis of mutant alleles of the vaccinia virus topoisomerase I carrying targeted substitutions in a highly conserved domain. 839 54

A patient with chronic hepatitis associated with hepatitis C virus infection was observed to convert from antinuclear antibody-negative to antinuclear antibody-positive status at the time when liver cancer was detected. The newly recognized antibodies reacted with a nuclear protein doublet of 170 and 180 kDa in immunoblotting, and in fluorescence-activated flow cytometry the antigens were shown to vary in expression level in a cell cycle-related manner: minimum in G1, increasing in S, and maximum in G2 and M. In synchronized HeLa and HEp-2 cells, immunofluorescence microscopy showed uniformly distributed staining of the nucleoplasm in S-phase, with increased intensity of nucleoplasmic staining in G2, at which time nucleolar staining was also present. In M, condensed chromosomes were uniformly stained. Using previously characterized polyclonal antibodies to DNA topoisomerase II (topo II) as reference markers, the antigens recognized by the patient's serum were shown in Western blotting to have the same mobilities as DNA topo IIalpha (170 kDa) and beta (180 kDa) isoforms. The patient's serum was also highly efficient in inhibiting DNA topo II in an in vitro functional assay. Antibody to DNA topo II appeared de novo in close association with transformation to cancer, and since dysregulation of DNA topo II is considered to be involved in some forms of tumorigenesis, the observed antibody response in this patient could conceivably be an immune reaction to the abnormally regulated protein.
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PMID:Autoantibody to DNA topoisomerase II in primary liver cancer 981 99

Daily journals in France recently published a declaration of eight AIDS-assistance associations stating, because of already established resistance of most of types of HIV1 to the so called "tritherapies" 8,000 subjects in France will soon be "in condition of treatment failure". This tritherapeutic "flat note" is a double flat, for relative and absolute reasons: a) relative indeed was the case of well-known results: the tritherapies initially performed better than bitherapies, which had done better than monotherapies; b) absolute is their failure, which induce, as the other types, toxicity, resistance and relapses. Toxicity and resistance are due to the fact that, as the T1/2 of the virus is very short, virostatics must be applied continuously. But in AIDS groups tritherapies are applied not only in a continuous fashion, but in an identical form and for an undefined time, the process which is used in experimental cancer chemotherapy to induce resistant cell lines. Applying them in sequences of 3 weeks (a duration chosen with the knowledge that resistance may occur in about 12 weeks), we have shown in AIDS not only an absence of toxicity, but also an absence of resistance in patients treated with four drugs affecting four different targets. There is indeed another point to underline: AIDS group tritherapies are comprised of three drugs, but whatever the choices of these drugs they affect only two targets: retrotranscriptase and HIV1-protease. We had obtained in the best murine model of HIV1-infection (Friend's virus infection) eradication with a combination of three drugs, AZT, acriflavine (ACF) and the ellipticine analogue methyl-hydroxy-ellipticine (MHE); (the two last were discovered to be rather more efficient that AZT in our virostatic screening). This combination affects three virus targets (AZT, retrotranscriptase; MHE, topoisomerase 2; and ACF, integrated and proviral DNA). The next article will show that sequential drug combinations of three virostatics chosen from ten drugs available, affecting four targets, are more efficient in HIV1-AIDS than three drug combinations affecting three targets because they were chosen from a pool of only five drugs. It will, however, be shown that the same type of sequential combinations with four drug rotations chosen among the ten available ones affecting four targets rapidly reduced, and for years maintained, the viral load at undetectable levels. This level has been < 200 RNA copies/mL during the trial and is, at the end of the study, < 20 RNA copies/mL.
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PMID:Hypothetical reasons of the HIV1-AIDS "tritherapy" failure. A challenging model. 986 99

Chlorella virus PBCV-1 topoisomerase II is the only functional type II enzyme known to be encoded by a virus that infects eukaryotic cells. However, it has not been established whether the protein is expressed following viral infection or whether the enzyme has any catalytic features that distinguish it from cellular type II topoisomerases. Therefore, the present study characterized the physiological expression of PBCV-1 topoisomerase II and individual reaction steps catalyzed by the enzyme. Results indicate that the topoisomerase II gene is widely distributed among Chlorella viruses and that the protein is expressed 60-90 min after viral infection of algal cells. Furthermore, the enzyme has an extremely high DNA cleavage activity that sets it apart from all known eukaryotic type II topoisomerases. Levels of DNA scission generated by the viral enzyme are approximately 30 times greater than those observed with human topoisomerase IIalpha. The high levels of cleavage are not due to inordinately tight enzyme-DNA binding or to impaired DNA religation. Thus, they most likely reflect an elevated forward rate of scission. The robust DNA cleavage activity of PBCV-1 topoisomerase II provides a unique tool for studying the catalytic functions of type II topoisomerases.
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PMID:Topoisomerase II from Chlorella virus PBCV-1 has an exceptionally high DNA cleavage activity. 1132 25

HTLV-1 is the etiological agent of adult T-cell leukemia (ATL), the neurological syndrome TSP/HAM and certain other clinical disorders. The viral Tax protein is considered to play a central role in the process leading to ATL. Tax modulates the expression of many viral and cellular genes through the CREB/ATF-, SRF- and NF-kappaB-associated pathways. In addition, Tax employs the CBP/p300 and p/CAF co-activators for implementing the full transcriptional activation competence of each of these pathways. Tax also affects the function of various other regulatory proteins by direct protein-protein interaction. Through these activities Tax sets the infected T-cells into continuous uncontrolled replication and destabilizes their genome by interfering with the function of telomerase and topoisomerase-I and by inhibiting DNA repair. Furthermore, Tax prevents cell cycle arrest and apoptosis that would otherwise be induced by the unrepaired DNA damage and enables, thereby, accumulation of mutations that can contribute to the leukemogenic process. Together, these capacities render Tax highly oncogenic as reflected by its ability to transform rodent fibroblasts and primary human T-cells and to induce tumors in transgenic mice. In this article we discuss these effects of Tax and their apparent contribution to the HTLV-1 associated leukemogenic process. Notably, however, shortly after infection the virus enters into a latent state, in which viral gene expression is low in most of the HTLV-1 carriers' infected T-cells and so is the level of Tax protein, although rare infected cells may still display high viral RNA. This low Tax level is evidently insufficient for exerting its multiple oncogenic effects. Therefore, we propose that the latent virus must be activated, at least temporarily, in order to elevate Tax to its effective level and that during this transient activation state the infected cells may acquire some oncogenic mutations which can enable them to further progress towards ATL even if the activated virus is re-suppressed after a while. We conclude this review by outlining an hypothetical flow of events from the initial virus infection up to the ultimate ATL development and comment on the risk factors leading to ATL development in some people and to TSP/HAM in others.
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PMID:Role of Tax protein in human T-cell leukemia virus type-I leukemogenicity. 1531 Apr 5


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