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 found that Chlamydomonas reinhardtii cells contain an ATP-dependent topoisomerase activity that supercoils circular DNA in vitro. Subsequent addition of a type I topoisomerase eliminates the supercoils. Like bacterial gyrase, this activity is inhibited by low concentrations of novobiocin (less than 0.1 microM) and by nalidixic acid (less than 0.1 microM). We have examined the effects of these topoisomerase inhibitors on accumulation of various chloroplast transcripts in vivo. Novobiocin differentially affected such transcripts; some transcripts became more abundant while many others were reduced in the presence of this drug. Nalidixic acid on the other hand caused many transcripts to become more abundant albeit to varying degrees. Inhibitors of this algal topoisomerase specifically stimulate a family of related transcripts which we have previously shown to be under light-dark control. We discuss how the inhibitors of this topoisomerase might exert their in vivo effects.
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PMID:An ATP-dependent supercoiling topoisomerase of Chlamydomonas reinhardtii affects accumulation of specific chloroplast transcripts. 298 13

T6 DNA topoisomerase has been purified from bacteriophage T6 infected Escherichia coli. Unlike the T4 DNA topoisomerase which has three subunits, it consists of two subunits of molecular weights 75,000 and 51,000. They are the products of T6 genes 39 and 52, respectively. The purified T6 enzyme can stimulate in vitro T6 DNA replication. It has an ATP-dependent DNA relaxation activity similar to the T4 enzyme. Either ATP or dATP can be used in both reactions. Using a "Western blotting" and radioimmuno-detection methods, we show that T6 39 subunit contains protein sequences specified by both the T4 39 and 60 genes. The 52-proteins of both phages appear to be identical. The T4 and T6 topoisomerase genes represent a naturally occurring example of gene separation or fusion.
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PMID:Relationship between bacteriophage T4 and T6 DNA topoisomerases. T6 39-protein subunit is equivalent to the combined T4 39- and 60-protein subunits. 299 Dec 31

A topoisomerase activity is associated with herpes simplex virus type 1. The enzyme was recovered from purified virions which were disrupted with 6 M-guanidine-HCl followed by renaturation of extracted proteins. Based upon the following observations, the virion activity is classified as a type I topoisomerase: (i) the linking number of a unique DNA topoisomer is altered in steps of one; (ii) ATP and MgCl2 are not required for activity; (iii) the enzyme can be trapped in a covalent complex with DNA; (iv) the covalent linkage to DNA is through a 3' phosphoryl bond. A number of lines of evidence strongly indicate that the topoisomerase is external to the nucleocapsid. For example, the activity was released by treatment of intact virions with NP40, and subsequent washing steps extracted most residual activity. When guanidine extracts were prepared from nucleocapsids, topoisomerase activity was not detectable. Finally, DNA within the virion did not appear to contain covalently attached proteins with properties similar to topoisomerases. Thus, the enzyme appears to be a component of the envelope or tegument structure of the virion.
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PMID:Association of type I DNA topoisomerase with herpes simplex virus. 299 29

Topoisomerase-II activity was analyzed in various human leukemic and lymphoblastoid cell-lines with comparison to normal human peripheral blood lymphocytes. All of the examined tumor cells contained this enzyme in both the nuclear and cytoplasmic fractions, whereas no appreciable activity of the enzyme was detected in either fraction of the resting normal lymphocytes. Using pBR322 plasmid as a substrate, undialyzed extracts of the tumor cells exhibited the typical ATP-dependent relaxation of supercoiled circles and formation of linear and catenated structures, as well as the ATP-independent knotting activity. On the other hand, dialyzed extracts exerted only the ATP-dependent supercoil relaxation. Novobiocin inhibited the linearization and catenation but not the supercoil relaxing or knotting activities. This study provides indications for an excessive level of a structurally abnormal topoisomerase-II in these tumor cell-lines.
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PMID:Topoisomerase-II activity in human leukemic and lymphoblastoid cells. 299 64

We have undertaken a study of DNA topoisomerases in mitochondria from human acute leukemia cells. Two activities have been detected in these organelles. One of the enzymes is presumably a type II topoisomerase, i.e., in ATP-dependent reactions it can catenate closed circular plasmid DNA, and decatenate closed circular kinetoplast DNA. A second topoisomerase is presumably a type I enzyme since, it can relax positive as well as negative supercoils in an ATP-independent reaction, it is unable to catenate plasmid DNA or decatenate kinetoplast DNA, and it is inhibited, rather than stimulated, by ATP.
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PMID:The presence of two mitochondrial DNA topoisomerases in human acute leukemia cells. 299 88

Novobiocin inhibits DNA topoisomerases. It also inhibits excision repair of DNA photodamage, blocking both repair synthesis and the earlier step of incision at u.v. damage sites (as measured by the accumulation of DNA strand breaks in u.v.-irradiated interphase cells treated with DNA synthesis inhibitors such as hydroxyurea or cytosine arabinoside). It has been supposed, therefore, that novobiocin affects repair by blocking a putative topoisomerase step prior to incision. But we find that novobiocin also has a marked dose- and time-dependent effect on mitochondria: in cells exposed to novobiocin, mitochondria swell and their cristae become disrupted, and the intracellular ATP:ADP ratio is lowered, though the membrane potential is maintained as judged by rhodamine 123 fluorescence. Mitotic cells are more resistant to mitochondrial disruption by novobiocin than are interphase cells. This correlates with a relative resistance of u.v.-irradiated mitotic cells to the inhibition of incision by novobiocin. The chromosomal decondensation that results from the accumulation of DNA breaks due to incision when u.v.-irradiated mitotic cells are treated with hydroxyurea and cytosine arabinoside is largely suppressed by novobiocin. Furthermore, the suppression of induced strand break accumulation is partly due to a suppression by novobiocin of the uptake and phosphorylation of cytosine arabinoside; breaks accumulated in u.v.-irradiated cells in the presence of aphidicolin, an inhibitor of DNA polymerase alpha that does not require phosphorylation, are less novobiocin-sensitive. We conclude that the effects of novobiocin on excision repair are more likely to be due to a non-specific effect on ATP metabolism than to a specific effect on a repair-related topoisomerase.
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PMID:Novobiocin inhibition of DNA excision repair may occur through effects on mitochondrial structure and ATP metabolism, not on repair topoisomerases. 299 34

The receptor for epidermal growth factor (EGF) is a single-chain transmembrane polypeptide of relative molecular mass (Mr) 170,000 (170K) which has been implicated in the regulation of both normal and abnormal cell proliferation. It has an externally facing EGF-binding domain and a cytoplasmically facing tyrosine-specific protein kinase site. Although the receptor has been well characterized, the mechanism by which it transmits the growth stimulatory signal from the plasma membrane to the nucleus is unclear. EGF binding to cells has been shown to enhance topoisomerase activity within the cells. Topoisomerases catalyse the interconversion of topological isomers of DNA and thus may influence replication and transcription. Mroczkowski et al. reported that purified EGF receptors of both human and murine origin can nick supercoiled double-stranded (ds) DNA in an ATP-dependent fashion, an activity related to those of topoisomerases. Another related tyrosine kinase, pp60src, has also been reported to have a similar DNA-nicking activity. We have now characterized the EGF receptor-associated DNA-nicking activity by sucrose gradient centrifugation. Our results, presented here, indicate that the DNA-nicking activity is not intrinsic to the EGF receptor, but is found in a distinct molecular species.
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PMID:EGF receptor-associated DNA-nicking activity is due to a Mr-100,000 dissociable protein. 299 1

Using an assay which measures catenation of a supercoiled DNA template, we have characterized and quantitated a potent activity identified in crude fractions of HeLa cell nuclei. Catenation requires Mg-ATP and a DNA-condensing agent, polyvinyl alcohol. A filter-binding or agarose gel assay can be used to quantitate activity. In this reaction, DNA topoisomerase I relaxes the input supercoiled DNA to provide DNA topoisomerase II, a strongly favored template for catenation. DNA topoisomerase II preferentially catenates relaxed DNA over supercoiled DNA by a factor of 100. One molecule of DNA topoisomerase II is able to catenate about 20 circles of relaxed DNA/min at 30 degrees C but only 0.16 circle of supercoiled DNA/min at 30 degrees C. The purified HeLa topoisomerase I can also catenate DNA under these assay conditions, yet in an ATP-independent fashion. It is much less efficient than topoisomerase II; one molecule of topoisomerase I catenates only about 3.8 X 10(-3) molecules of supercoiled DNA/min at 30 degrees C with a DNA template containing 5% nicked circles. This remarkable difference between the two enzymes allows quantitation of DNA topoisomerase II activity seen in the presence of excess topoisomerase I. Unlike Escherichia coli topoisomerase I (omega), catenation by the HeLa topoisomerase I is not stimulated by gapped circles.
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PMID:Characterization of a potent catenation activity of HeLa cell nuclei. 299 11

We have found that purified T4 DNA topoisomerase promotes recombination between two phage lambda DNA molecules in an in vitro system. In this cross, T4 DNA topoisomerase alone is able to catalyze the recombination and produce a linear monomer recombinant DNA that can be packaged in vitro. ATP is not required for this recombination, while oxolinic acid stimulates it. The recombinant DNA molecules contain duplications or deletions, and the crossovers take place between nonhomologous and nonspecific sequences of lambda DNA. Therefore, the recombination mediated by the T4 DNA topoisomerase is an illegitimate recombination that is similar to that mediated by Escherichia coli DNA gyrase. A model was proposed previously in which DNA gyrase molecules that are bound to DNA associate with each other and lead to the exchange of DNA strands through the exchange of DNA gyrase subunits. This model is also applicable to the recombination mediated by T4 DNA topoisomerase.
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PMID:Bacteriophage T4 DNA topoisomerase mediates illegitimate recombination in vitro. 300 33

Type I topoisomerases have been purified from nuclei and mitochondria of human acute lymphoblastic leukemia cells. Both of these ATP-independent enzymes are actually found to be inhibited by ATP at physiologically significant concentrations. Other adenine nucleotides showed varying effects: ADP inhibited only at high concentrations; AMP had no effect on either topoisomerase. Both enzymes were also inhibited by dATP. The importance of the adenine ring structure was confirmed by the lack of an inhibitory effect observed with equivalent levels of GTP, UTP, CTP, or their deoxy counterparts. Assays performed in the presence of nonhydrolyzable analogs of ATP suggest that hydrolysis of ATP does not accompany this enzyme inhibition. This was supported by direct determination of the ATPase activity of the purified enzymes. Type I topoisomerase from calf thymus and HeLa cells were also found to be sensitive to ATP. These results suggest that mammalian type I topoisomerases in general may possess a nucleotide-binding site that may be involved in regulation of enzyme activity.
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PMID:ATP inhibits nuclear and mitochondrial type I topoisomerases from human leukemia cells. 300 64


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