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)

A Rhodopseudomonas capsulata nifH::lacZ gene fusion was used to isolate constitutive mutants of R. capsulata, unable to repress nif gene transcription anaerobically with every fixed-nitrogen source tested. When these nifc strains were grown aerobically, nif gene transcription was repressed. These results indicate that the regulation of nif gene transcription by fixed nitrogen is different from the regulation by oxygen. Under anaerobic conditions, nif gene transcription in both R. capsulata and Klebsiella pneumoniae is specifically prevented by inhibitors of DNA gyrase [DNA topoisomerase type II (ATP-hydrolyzing), EC 5.99.1.3]. A recent study has shown that anaerobically grown Salmonella typhimurium have high DNA gyrase activity, whereas aerobically grown cells have high DNA topoisomerase type I (EC 5.99.1.2) activity and DNA that is more relaxed [Yamamoto, N. & Droffner, M. L. (1985) Proc. Natl. Acad. Sci. USA 82, 2077-2081]. In view of these results, we suggest that the control of nif gene transcription in response to oxygen is determined by the action of DNA gyrase and DNA topoisomerase I. Thus, although nitrogen control of nif gene expression requires the products of regulatory genes for which constitutive mutations can be isolated, oxygen appears instead to prevent the adoption of a DNA conformation necessary, directly or indirectly, for nif gene transcription.
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PMID:Anaerobic regulation of nitrogen-fixation genes in Rhodopseudomonas capsulata. 301 47

Benzisoquinolinedione (nafidimide; NSC 308847) is an investigational drug currently in phase I clinical testing. We have studied the antileukemic activity in vitro, the cellular drug transport, and the molecular mechanism of action with DNA of this new compound. By agarose gel electrophoresis, we verified that nafidimide is an intercalating agent, through its alteration of the electrophoretic migration of DNA products produced by the relaxing action of DNA topoisomerase I. Concentrations of up to 100 microM of nafidimide did not produce topoisomerase I-mediated DNA cleavage. Nafidimide produced DNA single-strand breaks (SSB), double-strand breaks, and DNA-protein cross-links in human myeloid leukemia cells (measured with filter elution). The ratio of SSB/DNA-protein cross-links was 1.32 +/- 0.36, a value similar to that produced by 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), suggesting that nafidimide, like m-AMSA, produced protein-associated DNA-strand breaks through a topoisomerase II-mediated reaction. The production of double-strand breaks by nafidimide also suggests the involvement of topoisomerase II in the drug-induced DNA cleavage. The cytotoxic activity of nafidimide was quantified in human myeloid leukemia cell lines differing by a factor of 70 in their cytotoxic sensitivity to m-AMSA. The m-AMSA-resistant line was less than 2-fold resistant to nafidimide. Cellular drug uptake was rapid and reached a steady state level in 30 min at 37 degrees C. At the end of exposure, drug egress was rapid, as was the disappearance of the DNA SSB. Rapid cellular uptake of nafidimide, with low retention at the end of exposure and rapid rejoining of DNA SSB suggest that prolonged cellular exposure may be necessary for optimal antitumor effect. In vitro cloning data suggest that nafidimide may be a therapeutic option for patients with leukemia resistant to m-AMSA.
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PMID:In vitro toxicity and DNA cleaving capacity of benzisoquinolinedione (nafidimide; NSC 308847) in human leukemia. 302 21

Insertion and deletion mutagenesis within the gene topA of Escherichia coli encoding DNA topoisomerase I was carried out to test the existence of subdomains in the enzyme and the relationship between the slow-growth topA- phenotype and the known DNA relaxation activity of the enzyme. All mutants that show no detectable DNA relaxation activity in cell extracts fail to complement the temperature-sensitive growth defect of strain AS17 topAam harboring a plasmid-borne temperature-sensitive suppressor tRNA. All mutants that show partial or full levels of DNA relaxation activity in cell extracts (relative to activity in extracts of wild-type cells) can complement this defect. The carboxyl-proximal 25% of the enzyme appears to be in a domain that is dispensable both in terms of the catalytic function of the enzyme and its biological role. Analysis of the mutant enzyme also indicates that the formation of the covalent topoisomerase-DNA complex is correlated with the DNA relaxation activity, which supports the notion that the covalent complex is an obligatory intermediate in the catalysis of DNA topoisomerization.
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PMID:Probing the structural domains and function in vivo of Escherichia coli DNA topoisomerase I by mutagenesis. 302 80

We examined the roles of DNA topoisomerases in the replication of simian virus 40 (SV40) DNA in a cell-free system composed of an extract from HeLa cells supplemented with purified SV40 tumor antigen. When the activities of both topoisomerase I (EC 5.99.1.2) and topoisomerase II (EC 5.99.1.3) in the extract were blocked with specific inhibitors or antibodies, DNA synthesis was decreased by a factor of 15-20. Addition of purified HeLa DNA topoisomerase II to extracts immunologically depleted of both topoisomerases completely restored replication, and the replication products consisted largely of monomeric daughter molecules. Addition of purified HeLa DNA topoisomerase I to depleted extracts restored DNA synthesis, but the primary products were multiply intertwined, catenated daughter molecules. We conclude that DNA topoisomerases have at least two roles in the replication of SV40 DNA. Either topoisomerase I or topoisomerase II is sufficient to provide the unlinking activity necessary for fork propagation during SV40 DNA replication. However, topoisomerase II is uniquely required for the segregation of newly synthesized daughter molecules.
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PMID:Roles of DNA topoisomerases in simian virus 40 DNA replication in vitro. 302 65

We have previously shown that heparin is a potent inhibitor of a mammalian DNA topoisomerase I. We have now investigated the mechanism of its inhibition. This was carried out first by scrutinizing the structural features of heparin molecules responsible for the inhibition. Commercial heparin preparation was fractionated by antithrombin III-Sepharose into non-adsorbed, low-affinity and high-affinity fractions, of which only the high-affinity fraction of heparin is known to contain a specific oligosaccharide sequence responsible for the binding to antithrombin III. These fractions all exhibited essentially similar inhibitory activities. Furthermore, when chemically sulphated to an extent comparable with or higher than heparin, otherwise inactive glycosaminoglycans such as heparan sulphate, chondroitin 4-sulphate, dermatan sulphate and neutral polysaccharides such as dextran and amylose were converted into potent inhibitors. Sulphated dermatan sulphate, one of the model compounds, was further shown to bind competitively to the same sites on the enzyme as heparin. These observations strongly suggested that topoisomerase inhibition by heparin is attributable primarily, if not entirely, to the highly sulphated polyanionic nature of the molecules. In a second series of experiments we examined whether heparin inhibits only one or both of the topoisomerase reactions, i.e. nicking and re-joining. It was demonstrated that both reactions were inhibited by heparin, but the nicking reaction was more severely affected than was the re-joining reaction.
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PMID:Mechanism of inhibition of mammalian DNA topoisomerase I by heparin. 303 52

The fraction DE-B obtained by fractionating an extract from rat mammary adenocarcinoma cells on a DEAE-Sephadex column was used for transcribing linear and supercoiled rRNA gene (rDNA). This fraction, which is known to contain RNA polymerase I and essential transcription factors, also contains DNA topoisomerase I activity. Inhibition of this topoisomerase activity by the selective inhibitor camptothecin markedly diminished transcription of supercoiled rDNA, and at a concentration of 150 microM, camptothecin almost completely inhibited DNA topoisomerase I activity and supercoiled rDNA transcription. Addition of exogenous calf thymus DNA topoisomerase I to the sample containing the drug restored the ability of the extract to transcribe supercoiled rDNA. Camptothecin, even at a concentration of 500 microM, had no significant effect on the transcription of linear rDNA. These studies show that relaxation of supercoiled rDNA by DNA topoisomerase I is essential for its transcription. The preferential inhibition of rRNA synthesis in vivo following treatment with camptothecin is probably due to selective camptothecin inhibition of DNA topoisomerase I activity.
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PMID:Role of DNA topoisomerase I in the transcription of supercoiled rRNA gene. 303 39

Calf thymus DNA topoisomerase I, which belongs to the eukaryotic type I topoisomerases, is in a typical preparation purified as a set of five major polypeptides with Mr between 70000 and 100000. At least four of these proteins have binding affinity for DNA as was shown by incubating them with radioactive single-stranded DNA after separation in dodecylsulfate polyacrylamide gels and blotting onto nitrocellulose filters. That these polypeptides have DNA relaxing activity was directly demonstrated with protein extracted from single bands of dodecylsulfate/polyacrylamide gels. We consider the 100000-Mr protein to be the native enzyme. The smaller components are catalytically active fragments of the native topoisomerase most probably arising from limited proteolysis either within the nucleus or during the purification of the enzyme. In two-dimensional non-equilibrium pH-gradient electrophoresis gels the topoisomerase size variants exhibit apparent pI values between 8.1 and 8.3, with small but distinct differences between the components. The calf thymus topoisomerase I, upon binding to phage fd-DNA, protects a stretch of 15-25 nucleotides against digestion with DNase I.
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PMID:Characterisation of size variants of type I DNA topoisomerase isolated from calf thymus. 609 Jan 40

Chromatin-associated DNA topoisomerase I activity was measured in human diploid fibroblasts during in vitro aging. No difference was detected as a function of cell age in the nicking and the closing activities of the DNA-unwinding enzyme. The capacity of type-I topoisomerase to relax superhelical DNA molecules was, however, increased in aged cells. An age-related increase in nucleoprotein content was also observed.
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PMID:Increased DNA topoisomerase I activity in aging human cell chromatin. 609 22

Mutations in top, the structural gene for Escherichia coli DNA topoisomerase I, have been identified and mapped at 28 min on the chromosome, near cysB. Strains carrying deletions of the top gene are viable. The top mutations, however, do exert pleiotropic effects on transcription and transposition. Mutants lacking DNA topoisomerase I have a more rapid rate of induction and a higher level of catabolite-sensitive enzymes including tryptophanase and beta-galactosidase. This general activation of transcription by top mutations can be attributed to an increase in the negative superhelicity of the DNA in vivo when the topoisomerase activity is abolished. The frequency of transposition of Tn5, a transposon carrying kanamycin resistance, is decreased by a factor of 40 or more in top mutants. A direct or indirect role of the topoisomerase in transposition is discussed. The transposition frequency of Tn3, however, is not dependent on top. Based on the studies of the E. coli top mutants, it appears that the supX gene, which was originally studied in Salmonella typhimurium [Dubnau, E. & Margolin, P. (1972) Mol. Gen. Genet. 117, 91-112] is likely to be the structural gene for DNA topoisomerase I.
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PMID:Mutations in the gene coding for Escherichia coli DNA topoisomerase I affect transcription and transposition. 626 7

A DNA topoisomerase activity is found to be associated with the nucleosomes released by the Staphylococcal nuclease digestion of HeLa nuclei. Such an association is found to be salt dependent. A number of criteria have established that this DNA topoisomerase activity is due to HeLa topo I (Liu, L. F. and Miller, K. G. (1980) Proc. Natl. Acad. Sci. USA 78, 3489-3491). A similar association has been demonstrated from the in vitro studies using purified mononucleosomes and eukaryotic DNA topoisomerase I. Nonhistone HMG proteins and histone H1 are found to stimulate topoisomerase activity in vitro and form tight complexes with eukaryotic DNA topoisomerase I. The intimate interactions of topoisomerase I with chromosomal proteins and nucleosomes may be an essential feature of the topoisomerase function in vivo.
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PMID:Association of eukaryotic DNA topoisomerase I with nucleosomes and chromosomal proteins. 629 26


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