Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragmentation of the plasmid pBR322 DNA by a purified preparation of Ca/Mg-dependent endonuclease has been studied. It was shown that on the first steps of reaction the double-stranded cuts are introduced into the superhelical DNA independent of singlestranded ones. The doublestranded cuts are introduced into superhelical and linear DNA in 12 sites enriched with GC-pairs, 9 of them include pentanucleotide CGCGG(CCGCC) that is functionally significant. Relaxation of the plasmid DNA by topoisomerase I blocks the sitespecific action of the enzyme. Ca/Mg-dependent endonuclease is concluded to be topologically dependent enzyme, possibly, participating in the recombination processes.
Mol Gen Mikrobiol Virusol 1988 Sep
PMID:[Specificity of fragmentation of DNA from pBR322 plasmid by Ca,Mg-dependent endonuclease from cell nuclei of human lymphocytes]. 321 Nov 85

Cloning of an EcoRI restriction fragment, containing the 900 bp gamma-terminal sequence of transposon Tn1000, into pBR322, resulted in two plasmids, pICV63 and pICV64, which differed in the orientation of the cloned fragment within the replicon and in the level of ampicillin resistance conferred on the host cell. The DNAs of these plasmids differ in superhelicity and we suggest that a change in supercoiling of pICV63 DNA leads to this plasmid conferring resistance to only low levels of ampicillin, probably by reducing the expression of the bla gene. This hypothesis is supported by the fact that topA or supX mutations, which abolish topoisomerase I, reduce still further the level of resistance to ampicillin of pICV63-containing cells, whereas the gyrB226 compensatory mutation renders these cells more ampicillin resistant. Plasmid pICV63, therefore, enables mutant alleles of genes governing DNA topology to be recognized.
Mol Gen Genet 1987 Aug
PMID:Heterogeneity in the level of ampicillin resistance conferred by pBR322 derivatives with different DNA supercoiling. 331 57

The binding constants for interaction of several novel anthra[1,9-cd]pyrazol-6(2H)-ones (anthrapyrazoles) with DNA have been determined by an ethidium displacement method. The apparent binding constants range from less than 2 X 10(6) to 2.7 X 10(8) M-1. The binding is influenced not only by the nature of the side chains but also by the number and position of hydroxyl groups on the chromophore. Unwinding angles, determined by a topoisomerase I assay, ranged from 0 degrees to 29.2 degrees. The deshydroxy compound 1 gave the highest unwinding angle, and both substitution of hydroxyl groups in the chromophore and alterations in the side chains decrease the unwinding angle, consistent with a decreased or partial intercalation. Representative anthrapyrazoles cause an increase in sonicated DNA viscosity as expected for intercalators. Spectrophotometric examination of the binding of compound 1 to DNAs of different base composition show that the apparent binding to GC is approximately 3 times that of AT, a result which was paralleled by thermal denaturation studies. Certain of the anthrapyrazoles exhibit marked visible light photosensitization and induce DNA single-strand breakage upon illumination in the presence of NADH. The essential structural requirement for photosensitizing properties with these agents was the absence of hydroxyl groups in the chromophore. By employing 32P-labeled DNA of known sequence, it was possible to examine the anthrapyrazole 1-photosensitized cleavage of DNA at the individual base level employing denaturing polyacrylamide sequencing gels. Smooth sequence neutral photosensitized cleavage of DNA is observed analogous to hydroxyl radical "footprinting."
Mol Pharmacol 1988 Mar
PMID:Characteristics of the interaction of anthrapyrazole anticancer agents with deoxyribonucleic acids: structural requirements for DNA binding, intercalation, and photosensitization. 335 92

A strain of Escherichia coli K12 harboring simultaneously the temperature-sensitive dnaA46 mutation and a deletion of the trp-topA-cysB region plates with the same full efficiency at 30 degrees C and 42 degrees C. We have analyzed the possible involvement of the gene coding for topoisomerase I, topA, in this suppression phenomenon. The Ts phenotype was retrieved upon introduction of a plasmid-borne DNA fragment including an active topA gene into this strain, but not upon introduction of the same fragment harboring a topA::Tn1000 insertion. Replication seems to remain DnaA-dependent in the delta (topA) strain, however, since we have been unable to introduce a dnaA::Tn10 allele. We propose either that the dnaA46 gene product is overproduced and compensates for its thermal inactivation, or that initiation at oriC demands less DnaA protein in the absence of topoisomerase I.
Mol Gen Genet 1984
PMID:Genetic inactivation of topoisomerase I suppresses a defect in initiation of chromosome replication in Escherichia coli. 609 46

The antibiotic netropsin binds to DNA by a non-intercalative mechanism. It increases the linking number of DNA so that in the presence of topoisomerase I, positively supercoiled molecules are produced.
J Mol Biol 1983 Jun 15
PMID:Production of positively supercoiled DNA by netropsin. 630 51

An in vitro nucleosome assembly system has been established from cell-free extracts of the fungus Ustilago maydis. The extract catalyzed DNA supercoiling in the absence of exogenously added co-factors such as ATP and MgCl2 and was inhibited by moderate concentrations (200 mM) of KCl or NaCl. DNA supercoiling occurs via the formation of nucleosomes. Similar extracts, displaying the same activity, were prepared from Saccharomyces cerevisiae and Candida albicans, suggesting that the extract preparation protocol may be useful for many lower eukaryotic systems. An extract prepared from a strain of U. maydis lacking topoisomerase I failed to catalyze nucleosome assembly, clearly implicating this enzyme in this process. Addition of purified topoisomerase I, and, to a lesser extent, topoisomerase II, to the top1- extract regenerated the supercoiling activity. Our results provide a method for preparing assembly extracts from organisms, that are particularly amenable to genetic manipulation.
Mol Gen Genet 1995 Oct 25
PMID:Assembly of nucleosomal DNA in a cell-free extract from wild-type and top1- strains of Ustilago maydis. 747 70

The basic helix-loop-helix containing dioxin receptor mediates dioxin signal transduction. The ligand-activated receptor complex binds to specific sequences termed xenobiotic response elements and regulates transcription of target genes such as the gene for cytochrome P450IA1. This study demonstrates that induction of cytochrome P450IA1 and P450IB1 gene expression by a dioxin receptor ligand is repressed by camptothecin, an inhibitor of the topoisomerase I enzyme. However, a transiently transfected reporter construct under control of an xenobiotic response element-containing promoter was not affected by the topoisomerase inhibitor. In agreement with this observation, ligand-dependent activation of the dioxin receptor to its DNA-binding form is not altered by camptothecin as analyzed by electrophoretic mobility shift assay. Moreover, the inhibitory effect of camptothecin cannot be exerted once the P450IA1 gene has been activated. These results imply that topoisomerase I activity is necessary for the primary P450IA1 induction response, possibly involving dioxin-dependent alterations in chromatin structure of the P450IA1 promoter.
Mol Pharmacol 1995 Oct
PMID:Differential effects of a topoisomerase I inhibitor on dioxin inducibility and high-level expression of the cytochrome P450IA1 gene. 747 85

A compound with a novel structure, NSC 665517, was tested in the National Cancer Institute Preclinical Drug Discovery Screen. With the COMPARE algorithm, the pattern of differential cytotoxicity for NSC 665517 most closely resembled those of known topoisomerase II (top2) inhibitors. In vitro data showed that NSC 665517 induced DNA cleavage in the presence of top2 and topoisomerase I (top1) (at a higher concentration). The minimum concentration required to induce top2 cleavage was 0.5 microM. A substantial decrease in top2-induced cleavage by NSC 665517 was seen when the reaction mixtures were shifted to elevated temperature (55 degrees), suggesting that top2-induced cleavage occurs through the mechanism of stabilizing the reversible enzyme/DNA complex and inhibiting religation. The DNA cleavage pattern induced by NSC 665517 with top2 was different than that of other known top2 inhibitors, including etoposide, mitoxantrone, anthracyclines, amsacrine, and ellipticine. top2 cleavage sites induced by NSC 665517 showed strong preference for G located 3' to the top2-mediated DNA cleavage (position +1). NSC 665517 produced limited DNA unwinding at high drug concentration. DNA damage analyzed in KB cells by alkaline elution showed that NSC 665517 induced strand break. Data from the cytotoxicity in KB-V1 overexpressing P-glycoprotein and COMPARE analysis with rhodamine efflux assay indicated that NSC 665517 is a substrate of P-glycoprotein. These results strongly suggest that NSC 665517 is a novel topoisomerase-targeted drug. Preclinical evaluation of NSC 665517 as an antitumor agent is under way.
Mol Pharmacol 1995 Oct
PMID:Eukaryotic DNA topoisomerases mediated DNA cleavage induced by a new inhibitor: NSC 665517. 747 91

Pretreatment (4h) of human HL 60 leukemia cells with the topoisomerase I-inhibitor camptothecin (7-28 x 10(-9) Mol/l, single dose) enhanced vitamin D3-responsive CD 14 expression (10(-11)-10(-8) Mol/l vitamin D3) up to twofold, as measured by fluorescence activated flow cytometry after 1-3 days. Camptothecin by itself caused marginal effects. Hybridization of total RNA with oligonucleotides (bases 1358-1333 of CD 14 sequence) showed increased steady state levels of the 1.75 kb CD 14 mRNA after 24 h when normalized to beta-actin. The nuclear accumulation of [3H]-vitamin D3/receptor complexes (VDR) in a nuclear translocation assay was significantly enhanced (by 3 h) in the presence of camptothecin. We conclude that inhibition of topoisomerase I enhances vitamin D3-stimulated CD 14 expression. Topoisomerase I might either be a negatively active transcription factor itself or maintenance of DNA-bending, local supercoiling and accessibility of responsive elements might lead to reduction of VDR turnover and produce a stimulatory effect on vitamin D3-responsive transcription.
 ...
PMID:Topoisomerase I-inhibition enhances vitamin D-responsive expression of the receptor for lipopolysaccharide binding protein CD 14. 751 Sep 56

Camptothecin (CPT) has been shown to induce protein-linked DNA breaks (PLDB), which are stabilized intermediates of topoisomerase I (TOP1) activity. Due to the reversible nature of PLDB and the need for replication fork movement for CPT toxicity, both the time of CPT exposure and TOP1 levels are determinants of CPT toxicity. Therefore, the effects of CPT exposure on TOP1 over time were examined in an established human cell line, KB. Using an in vivo KCl-SDS co-precipitation assay, it was determined that 1 hr of CPT exposure resulted in a concentration-dependent increase in PLDB that reached a maximum at 5 microM CPT. However, prolonged incubations with CPT revealed a concentration- and time-dependent decrease in CPT-induced PLDB formation. The most rapid loss of PLDB was within 6 hr. Neither aphidicolin nor cycloheximide cotreatments altered the PLDB decrease induced by CPT. Immunoblot analysis revealed a reduction in TOP1 protein upon CPT exposure, whereas RNA analysis revealed no changes, which suggested a post-transciptional mechanism of TOP1 down-regulation. The CPT-induced reduction was specific for TOP1, because actin and tubulin levels were unaltered by CPT exposure. Finally, clonogenic assays revealed a small but statistically significant decrease in CPT toxicity throughout the CPT exposure period. Because PLDB formation based on TOP1 levels is an important step in the toxicity of CPT, the CPT-induced TOP1 reduction could be a transient mechanism of resistance for cells to avoid toxic levels of PLDB.
Mol Pharmacol 1995 May
PMID:Camptothecin induction of a time- and concentration-dependent decrease of topoisomerase I and its implication in camptothecin activity. 753 95


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