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)

Type IB DNA topoisomerases cleave and rejoin one strand of the DNA duplex, allowing for the removal of supercoils generated during replication and transcription. In addition, electron microscopy of cellular and viral TopIB-DNA complexes has suggested that the enzyme promotes long-range DNA-DNA crossovers and synapses. Here, we have used the atomic force microscope to visualize and quantify the interaction between vaccinia topoisomerase IB (vTopIB) and DNA. vTopIB was found to form filaments on nicked-circular DNA by intramolecular synapsis of two segments of a single DNA molecule. Measuring the filament length as a function of protein concentration showed that synapsis is a highly cooperative process. At high protein:DNA ratios, synapses between distinct DNA molecules were observed, which led to the formation of large vTopIB-induced DNA clusters. These clusters were observed in the presence of Mg2+, Ca2+ or Mn2+, suggesting that the formation of intermolecular vTopIB-mediated DNA synapsis is favored by screening of the DNA charge.
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PMID:Atomic force microscopy shows that vaccinia topoisomerase IB generates filaments on DNA in a cooperative fashion. 1623 28

The anti cancer drug methyl N-(4'-(9-acridinylamino)-3-methoxy-phenyl) methane sulfonamide (mAMSA) targets human DNA topoisomerase IIbeta. We report here the first selection with mAMSA of resistant human topoisomerase IIbeta. Random mutagenesis of human DNA topoisomerase IIbeta cDNA, followed by selection in yeast for resistance to mAMSA, identified betaP732L. This mutant was 10-fold less sensitive to mAMSA and cross-resistant to other chemotherapeutic agents such as etoposide, ellipticine, methyl N-(4'-(9-acridinylamino)-2-methoxy-phenyl) carbamate hydrochloride (mAMCA), methyl N-(4'-(9-acridinylamino)-phenyl) carbamate hydrochloride (AMCA), and doxorubicin. betaP732L is functional but has reduced strand passage activities and altered DNA binding compared with the wild-type protein. It has drastically altered cleavage properties compared with the wild-type enzyme. It cleaved a 40-base pair (bp) DNA substrate in the presence of magnesium but at positions different from that of the wild-type protein. More striking is that betaP732L was unable to cleave the 40-bp DNA substrate, a 500-bp linear substrate, or a 4.3-kilobase supercoiled substrate in the presence of calcium ions. This is the first report of a topoisomerase II mutation abolishing the ability of calcium to support DNA cleavage. This provides evidence for metal ion requirement for the phosphoryltransfer reaction of topoisomerase II and a possible mechanism for drug resistance.
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PMID:Mutation P732L in human DNA topoisomerase IIbeta abolishes DNA cleavage in the presence of calcium and confers drug resistance. 1623 2

Evidence is accumulating to suggest that some of the diverse functions associated with BRCA1 may relate to its ability to transcriptionally regulate key downstream target genes. Here, we identify S100A7 (psoriasin), S100A8, and S100A9, members of the S100A family of calcium-binding proteins, as novel BRCA1-repressed targets. We show that functional BRCA1 is required for repression of these family members and that a BRCA1 disease-associated mutation abrogates BRCA1-mediated repression of psoriasin. Furthermore, we show that BRCA1 and c-Myc form a complex on the psoriasin promoter and that BRCA1-mediated repression of psoriasin is dependent on functional c-Myc. Finally, we show that psoriasin expression is induced by the topoisomerase IIalpha poison, etoposide, in the absence of functional BRCA1 and increased psoriasin expression enhances cellular sensitivity to this chemotherapeutic agent. Therefore, we identified a novel transcriptional mechanism that is likely to contribute to BRCA1-mediated resistance to etoposide.
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PMID:BRCA1 and c-Myc associate to transcriptionally repress psoriasin, a DNA damage-inducible gene. 1628 14

Topoisomerase II plays an essential role in the segregation of chromosomes during cell division. It is also a major component of the nuclear matrix. Proteins that interact with and regulate this essential enzyme are of great interest. To investigate the role of proteins interacting with the N-terminal domain of the Saccharomyces cerevisiae topoisomerase II, we used a yeast two-hybrid protein interaction screen. We identified an interaction between the catalytic domain of the yeast protein kinase 1 enzyme (Pkc1) and the N-terminal domain of the S. cerevisiae topoisomerase II. The S. cerevisiae Pkc1 is the homologue of the mammalian calcium dependent PKC.
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PMID:The identification of a functional interaction between PKC and topoisomerase II. 1636 7

We previously demonstrated that mammalian spermatozoa contain a nuclease activity that cleaves DNA into loop-sized fragments. We show here that this activity is mediated by a nuclear matrix-associated topoisomerase IIB (TOP2B) interacting with an extracellular Mn2+/Ca2+-dependent nuclease. Together, these enzymes cleave all of the DNA into fragments of 50 kb, and this cleavage can be reversed by EDTA. If dithiothreitol is included, the nuclease digests the DNA, and if the protamines are removed the DNA is completely digested. A similar, TOP2B-mediated, chromatin fragmentation, which is reversible, followed by digestion of the DNA by an intracellular nuclease occurs in somatic cells during apoptosis. The extracellular location of the sperm nuclease made it possible to reconstitute the fragmentation activity in isolated spermatozoa, thus allowing us to identify two novel aspects of the mechanism. First, the fragmentation of all of the DNA to 50 kb by TOP2B required the addition of the extracellular nuclease or factor. Second, the subsequent, complete digestion of the DNA by the nuclease could be inhibited by etoposide, suggesting that the nuclease digestion requires TOP2B religation of the cleaved DNA. These data are the first demonstration of an active TOP2B in spermatozoa, suggesting this inert chromatin may be more active than previously thought. They also show that the unique chromatin structure of spermatozoa may provide an important model to study the regulated degradation of chromatin by TOP2B and associated nucleases.
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PMID:Topoisomerase IIB and an extracellular nuclease interact to digest sperm DNA in an apoptotic-like manner. 1691 90

A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Galphas), (b) calcium release (Galphaq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Galphao/i and Galphaq). BIM-46174 inhibits the growth of a large panel of human cancer cell lines, including anticancer drug-resistant cells. Exposure of cancer cells to BIM-46174 leads to caspase-3-dependent apoptosis and poly(ADP-ribose) polymerase cleavage. National Cancer Institute COMPARE analysis for BIM-46174 supports its novel pharmacologic profile compared with 12,000 anticancer agents. The growth rate of human tumor xenografts in athymic mice is significantly reduced after administration of BIM-46174 combined with either cisplatin, farnesyltransferase inhibitor, or topoisomerase inhibitors. Our data validate the feasibility of targeting heterotrimeric G-protein functions downstream the GPCRs to improve anticancer chemotherapy.
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PMID:Anticancer activity of BIM-46174, a new inhibitor of the heterotrimeric Galpha/Gbetagamma protein complex. 1698 67

The well known and accepted mode of action of cardiac glycosides is inhibition of the ubiquitous plasma membrane Na+, K+-ATPase that leads to increased intracellular Ca2+ ion concentrations. Ca2+ ions play pivotal role in many signaling pathways including those regulating apoptosis. It has been suggested that some forms of cardiac glycosides inhibit proliferation and induce apoptosis in prostate cancer cells in clinically relevant concentrations. It was also found out that the degree to which cardiac glycosides inhibited cancer cell growth was correlated to topoisomerase II-inhibiting activity. Digitoxin at concentrations found in cardiac patients induced levels of DNA-topoisomerase II cleavable complexes similar to etoposide, a topoisomerase II poison widely used in cancer chemotherapy. Cardiac glycosides can also regulate one of the most potent angiogenesis promoting substances, fibroblast growth factor-2 (FGF-2), and may inhibit activation of the transcription factor NF-kappaB. FGF-2 and NF-kappaB are relevant targets for anticancer drugs. There is growing interest in evaluating the oleander products and possibly other cardiac glycosides as antineoplastic agents. The first of these therapies to be developed in the United States is a patented, water-soluble oleander extract called Anvirzel.
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PMID:Cardiac glycosides in cancer research and cancer therapy. 1751 73

Simian virus 40 (SV40) nucleoprotein complexes extracted from nuclei of infected monkey cells (CV1) were precipitated with Ca2+, Mg2+, and Mn2+ divalent cations. Most of the viral chromatin but only a fraction of the proteins in the crude nuclear extracts were recovered after precipitation with 10 mM MgCl2. At this optimal concentration, DNA topoisomerase activity (nicking closing enzyme) coprecipitated with the SV40 nucleoprotein complexes.
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PMID:Coprecipitation of topoisomerase activity with simian virus 40 nucleoprotein complexes by divalent cations. 1794 Nov 82

Three derivatives of ouabain, digoxin and proscillaridin A containing the carboxylic group instead of the lactone moiety were synthesized and examined for cytotoxicity in human breast cancer cells. Evaluation of the cytotoxicity of these compounds employing an MTT assay and inhibition of [3H]thymidine incorporation into DNA in both MCF-7 and MDA-MB-231 breast cancer cells demonstrated that compound 3, the most active of the series, proved to be only slightly less potent than proscillaridin A. We evaluated the effects of these compounds 1-3 on change in intracellular Ca2+, appearance of apoptosis, inhibition of DNA topoisomerase I and II, and the activity of caspase-3 in breast cancer cells. These studies indicate that the increase in potency for 3 may be related, in part, to an activation of caspase-3, increasing free calcium concentration and topoisomerase II inhibition. All these data emphasize the potential usefulness of these derivatives of cardiac glycosides as anticancer agents.
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PMID:Antiproliferative activity of derivatives of ouabain, digoxin and proscillaridin A in human MCF-7 and MDA-MB-231 breast cancer cells. 1852 43

Human topoisomerase IIalpha utilizes a two-metal-ion mechanism for DNA cleavage. One of the metal ions (M(1)(2+)) is believed to make a critical interaction with the 3'-bridging atom of the scissile phosphate, while the other (M(2)(2+)) is believed to interact with a nonbridging oxygen of the scissile phosphate. Based on structural and mutagenesis studies of prokaryotic nucleic acid enzymes, it has been proposed that the active site divalent metal ions interact with type II topoisomerases through a series of conserved acidic amino acid residues. The homologous residues in human topoisomerase IIalpha are E461, D541, D543, and D545. To address the validity of these assignments and to delineate interactions between individual amino acids and M(1)(2+) and M(2)(2+), we individually mutated each of these acidic amino acid residues in topoisomerase IIalpha to either cysteine or alanine. Mutant enzymes displayed a marked loss of catalytic and DNA cleavage activity as well as a reduced affinity for divalent metal ions. Additional experiments determined the ability of wild-type and mutant topoisomerase IIalpha enzymes to cleave an oligonucleotide substrate that contained a sulfur atom in place of the 3'-bridging oxygen of the scissile phosphate in the presence of Mg2+, Mn2+, or Ca2+. On the basis of the results of these studies, we conclude that the four acidic amino acid residues interact with metal ions in the DNA cleavage/ligation active site of topoisomerase IIalpha. Furthermore, we propose that M(1)(2+) interacts with E461, D543, and D545 and M(2)(2+) interacts with E461 and D541.
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PMID:Metal ion interactions in the DNA cleavage/ligation active site of human topoisomerase IIalpha. 1969 56


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