Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We characterized a DNA repair system in frog oocytes by comicroinjection of UV-irradiated pBR322 DNA and radiolabeled nucleotides. Repair synthesis was monitored by incorporation of label into recovered pBR322 DNA and by a novel method in which the removal of UV photoproducts was determined from the shift of DNA topoisomers that occurs during gel electrophoresis upon repair of these lesions. We investigated the effects of several drugs in the oocyte system and found that although novobiocin, an inhibitor of topoisomerase II, was an effective inhibitor of repair, VM-26, another inhibitor of topoisomerase II, was not. In addition, the topoisomerase I inhibitor camptothecin had no effect on repair in this system. Finally, circular DNA (either supercoiled or nicked circular) was repaired at least 50 times more rapidly than linear DNA.
Mol Cell Biol 1987 Dec
PMID:Repair of UV-induced lesions in Xenopus laevis oocytes. 283 Apr 88

We have found that type II topoisomerase inhibitors have two effects on replicating simian virus 40 genomes in vivo: production of catenated dimers and slowed replication of the last 5% of the genome. This suggests that type II topoisomerase simultaneously decatenates and facilitates replication fork movement at this stage of DNA replication. On the basis of this observation, a detailed model is proposed for the roles of topoisomerases I and II in simian virus 40 DNA replication.
Mol Cell Biol 1988 Feb
PMID:Swiveling and decatenation of replicating simian virus 40 genomes in vivo. 283 24

During the differentiation of the clonally distributed lymphocytes of mouse and man into mature resting B and T cells, their DNA becomes tightly packed into dense heterochromatin masses and exhibits very little transcriptional activity; it also becomes extensively nicked, containing some 3000-4000 single-strand breaks per diploid genome. The nuclear matrix is sparse and poorly organized and there are but trace amounts of the matrix-linked enzyme DNA topoisomerase II; the nucleus of these small cells is surrounded by a thin rim of cytoplasm. The resting cell can thus be considered (by analogy to a sperm cell) as a vector for transporting tightly packed and relatively inert genetic information to all parts of the body. When the lymphocyte is stimulated to enter a proliferative cycle by binding of appropriately presented antigen or mitogen to relevant membrane receptors, the cell enlarges, due to increased synthesis of protein; the dense heterochromatin is pulled out into very small clumps, as a result of an enormous growth in size as well as complexity of the nuclear matrix, and a great increase in transcriptional activity occurs. We have identified four nuclear matrix antigens that are very widely conserved in the evolution of eucaryotes and that occupy distinctive domains in interphase nuclei. Of particular interest is antigen P1, detected in organisms ranging from algae to mammals. By virtue of its location at the interface between nuclear envelope and chromatin, we propose that it plays a major and evolutionarily conserved role in chromatin organization and orientation in all eucaryotic cell types.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Evol 1987
PMID:Structural and evolutionary implications of the packaging of DNA for differentiation and proliferation in the lymphocyte. 283 58

Sites of an endogenous activity that has the properties of a DNA topoisomerase I have been identified on the palindromic ribosomal RNA genes of the slime mould Dictyostelium discoideum. This was done in vitro, by treating isolated nuclei with sodium dodecyl sulphate, which denatures topoisomerase during its cycle of nicking, strand passing and resealing, and hence reveals the DNA cleavages. It was also done in vivo using the drug camptothecin, which is believed to stabilize the cleavable complex of topoisomerase I plus DNA, hence increasing the chances of cleavage when sodium dodecyl sulphate is subsequently added. The cleavages in vitro and in vivo were mapped by indirect end-labelling. Both treatments cause what appear to be strong double-stranded cleavages at 200 and 2200 base-pairs and at 17 X 10(3) base-pairs upstream from the rRNA transcription start. The cleavage at 200 base-pairs was analysed in greater detail using RNA hybridization probes specific for single DNA strands. The cleavage is in fact composed of three closely spaced nicks on each DNA strand. The DNA sequence at each of the nicks is strongly homologous across 15 base-pairs. Sodium dodecyl sulphate-induced cleavage by eukaryotic topoisomerase I is known to yield enzyme covalently attached to the 3' cut end of the DNA. We show that protein-linked DNA restriction fragments with their 3' ends at the cleavage sites are selectively retarded on denaturing gels, which provides strong evidence that the unusual cluster of cleavages is caused by a topoisomerase I. Additionally, the camptothecin results revealed cleavages not only at the specific upstream sites, but also across the transcribed region. Interestingly, the zone of camptothecin-assisted cleavage does not extend as far at the 3' end of the gene as the zone of endogenous nuclease sensitivity.
J Mol Biol 1988 Mar 05
PMID:Topoisomerase I cleavage sites identified and mapped in the chromatin of Dictyostelium ribosomal RNA genes. 283 75

The PRL gene is expressed at a high basal level in rat pituitary tumor GH3 cells, and this basal level enhancement of PRL gene expression is maintained through a Ca2+-calmodulin-dependent mechanism. We have now examined whether the enzyme, DNA topoisomerase II, which has been shown to be phosphorylated by a Ca2+-calmodulin-dependent protein kinase, plays a role in the Ca2+-calmodulin-dependent basal level enhancement of PRL gene expression. The topoisomerase II inhibitor, novobiocin, at concentrations in the range of 35-140 microM, effectively blocked the ability of Ca2+ to increase PRL mRNA levels. Examination of the effects of novobiocin on the levels of protein synthesis, glucose-regulated protein (GRP) 78 mRNA, histone 3 mRNA, and 18S ribosomal RNA indicated that the drug selectivity inhibited PRL gene expression. Two other topoisomerase II inhibitors, m-AMSA and VM26, also diminished the Ca2+-induced levels of PRL mRNA at concentrations (100-400 nM) that did not lower total mRNA levels. We then examined whether topoisomerase II interacted nonrandomly with DNA from the 5' transcribed and 5'-flanking region of the rat PRL gene by in vitro mapping of topoisomerase II DNA cleavage sites. In initial assays with a 10.5 kilobase (kb) PRL genomic DNA fragment containing 3.5 kb of 5'-transcribed DNA and 7 kb of 5'-flanking DNA, we detected 4 major cleavage sites in the following regions: site 1, +1500 to +1600; site 2, +1 to -100; site 3, -1200 to -1300; and site 4, -2900 to -3000.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1988 Jan
PMID:Evidence for a role of topoisomerase II in the Ca2+-dependent basal level expression of the rat prolactin gene. 284 May 67

The type II topoisomerase of bacteriophage T4 is a central determinant of the frequency and specificity of acridine-induced frameshift mutations. Acridine-induced frameshift mutagenesis is specifically reduced in a mutant defective in topoisomerase activity. The ability of an acridine to promote topoisomerase-dependent cleavage at specific DNA sites in vitro is correlated to its ability to produce frameshift mutations at those sites in vivo. The specific phosphodiester bonds cleaved in vitro are precisely those at which frameshifts are most strongly promoted by acridines in vivo. The cospecificity of in vitro cleavage and in vivo mutation implicate acridine-induced, topoisomerase-mediated DNA cleavages as intermediates of acridine-induced mutagenesis in T4.
J Mol Biol 1988 Apr 20
PMID:Hotspot sites for acridine-induced frameshift mutations in bacteriophage T4 correspond to sites of action of the T4 type II topoisomerase. 284 8

Previous evidence suggests that epipodophyllotoxins, such as etoposide and teniposide, and the N-acyl anthracycline AD41 inhibit topoisomerase II resealing even though they apparently do not bind to DNA. Using experimental conditions designed to detect limited numbers of DNA binding sites, we now report that both epipodophyllotoxins and the N-acyl anthracyclines AD41 and AD32 bind to DNA. Binding was greater to kinetoplast DNA than to pUC18 plasmid DNA. There was also greater etoposide binding to single-stranded DNA than to double-stranded linear or supercoiled DNA. Based on binding competition experiments, etoposide and teniposide appear to have equal affinity for DNA, in spite of the fact that the latter is more potent as a topoisomerase inhibitor. This suggests that the difference in the drugs relates to protein interaction. There are 3- to 7-fold more binding sites for AD41 than for AD32, depending on the DNA substrate employed, and both drugs, unlike adriamycin, exhibit saturation of binding sites over a concentration range of 0-50 microM when kinetoplast DNA is the substrate. Evidence for DNA intercalation by AD41 is provided by the observation that the drug introduces positive supercoils into covalently closed plasmid DNA. Based on these data, a hypothesis is proposed that would provide a general mechanism whereby intercalating agents and epipodophyllotoxins alter topoisomerase function and presumably exert their antitumor effects.
Mol Pharmacol 1988 Oct
PMID:DNA binding by epipodophyllotoxins and N-acyl anthracyclines: implications for mechanism of topoisomerase II inhibition. 284 48

A novobiocin-resistant BHK cell line, designated as NovrA2, was found to exhibit cross-resistance to other topoisomerase II inhibitors such as 4'-dimethylepipodophyllotoxin-4-(4,6-O-ethylidine-beta-D-glu copyranoside) (VP-16), adriamycin, and 4'-(9-acridinyl-amino)methanesulfon-m-anisidide (m-AMSA), and also to different types of drugs such as vinblastine and arabinocytidine. Nalidixic acid-resistant cells (A2Nalr) of the NovrA2 cell line were phenotypically reverted to novobiocin sensitivity like wild-type cells and were also partially reverted to sensitivity to VP-16 and adriamycin, but not to vinblastine and arabinocytidine. When VP-16 was added to cell culture, the drug-induced DNA strand breaks were much fewer in NovrA2 cells than in BHK cells. This reduced level of strand breaks in NovrA2 cells was not due to reduced drug uptake, because the two cell lines accumulated similar levels of radiolabeled VP-16. VP-16 also induced fewer DNA breaks in isolated nuclei of NovrA2 cells than in those of BHK cells. There was no significant difference in the VP-16-induced DNA cleavage activities of partially purified topoisomerase II from BHK and Novr cells. These results show that the resistance of NovrA2 cells to various drugs is not acquired by a defense mechanism related to membrane permeability and suggest that the resistance of the NovrA2 cells to topoisomerase II inhibitors might be due in part to alteration in a topoisomerase II associated factor(s).
Somat Cell Mol Genet 1988 Sep
PMID:Cross-resistance of novobiocin-resistant BHK cell line to topoisomerase II inhibitors. 284 88

The budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe are both sensitive to camptothecin, an inhibitor of DNA topoisomerase I. An S. cerevisiae DNA repair mutant, rad52, is hypersensitive to the drug. In both species, topoisomerase I mutants totally lacking the enzyme are completely resistant to the drug. A strain with a mutation leading to a temperature-sensitive topoisomerase I exhibits temperature dependence in its in vivo response to camptothecin. A strain carrying a plasmid that overproduces topoisomerase I is hypersensitive to the drug. The rad52 mutant is killed by overproduction of the enzyme, even in the absence of the drug. The response of several of these strains to camptothecin analogs, to DNA topoisomerase II inhibitors, and to other drugs is reported. The cytotoxic effects of camptothecin are discussed in terms of the drug extending the lifetime of a topoisomerase I-DNA covalent intermediate, which is recognized as DNA damage by a DNA repair system.
Mol Pharmacol 1988 Dec
PMID:Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. 284 43

The structure of replicating simian virus 40 minichromosomes, extracted from camptothecin-treated infected cells, was investigated by biochemical and electron microscopic methods. We found that camptothecin frequently induced breaks at replication forks close to the replicative growth points. Replication branches were disrupted at about equal frequencies at the leading and the lagging strand sides of the fork. Since camptothecin is known to be a specific inhibitor of type I DNA topoisomerase, we suggest that this enzyme is acting very near the replication forks. This conclusion was supported by experiments with aphidicolin, a drug that blocks replicative fork movement, but did not prevent the camptothecin-induced breakage of replication forks. The drug teniposide, an inhibitor of type II DNA topoisomerase, had only minor effects on the structure of these replicative intermediates.
Mol Cell Biol 1988 Aug
PMID:Camptothecin, a specific inhibitor of type I DNA topoisomerase, induces DNA breakage at replication forks. 285 Apr 77


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