Journal articles: 'Type II topoisomerase'

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Akasaka, Takaaki, Seiko Kurosaka, Yoko Uchida, Mayumi Tanaka, Kenichi Sato, and Isao Hayakawa. "Antibacterial Activities and Inhibitory Effects of Sitafloxacin (DU-6859a) and Its Optical Isomers against Type II Topoisomerases." Antimicrobial Agents and Chemotherapy 42, no. 5 (May 1, 1998): 1284–87. http://dx.doi.org/10.1128/aac.42.5.1284.

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ABSTRACT The in vitro inhibitory effects of sitafloxacin (DU-6859a) and its three stereoisomers on bacterial DNA gyrase from Escherichia coli, topoisomerase IV from Staphylococcus aureus, and topoisomerase II from human placenta were compared. No correlation was observed between the inhibitory activities of quinolones against bacterial type II topoisomerases and those against human topoisomerase II. Sitafloxacin showed the most potent inhibitory activities against bacterial type II topoisomerases and the lowest activity against human type II topoisomerase.

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Takei, Masaya, Hideyuki Fukuda, Tokutaro Yasue, Masaki Hosaka, and Yasuo Oomori. "Inhibitory Activities of Gatifloxacin (AM-1155), a Newly Developed Fluoroquinolone, against Bacterial and Mammalian Type II Topoisomerases." Antimicrobial Agents and Chemotherapy 42, no. 10 (October 1, 1998): 2678–81. http://dx.doi.org/10.1128/aac.42.10.2678.

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ABSTRACT We determined the inhibitory activities of gatifloxacin againstStaphylococcus aureus topoisomerase IV,Escherichia coli DNA gyrase, and HeLa cell topoisomerase II and compared them with those of several quinolones. The inhibitory activities of quinolones against these type II topoisomerases significantly correlated with their antibacterial activities or cytotoxicities (correlation coefficient [r] = 0.926 forS. aureus, r = 0.972 for E. coli, and r = 0.648 for HeLa cells). Gatifloxacin possessed potent inhibitory activities against bacterial type II topoisomerases (50% inhibitory concentration [IC50] = 13.8 μg/ml for S. aureustopoisomerase IV; IC50 = 0.109 μg/ml for E. coli DNA gyrase) but the lowest activity against HeLa cell topoisomerase II (IC50 = 265 μg/ml) among the quinolones tested. There was also a significant correlation between the inhibitory activities of quinolones against S. aureustopoisomerase IV and those against E. coli DNA gyrase (r = 0.969). However, the inhibitory activity against HeLa cell topoisomerase II did not correlate with that against either bacterial enzyme. The IC50 of gatifloxacin for HeLa cell topoisomerase II was 19 and was more than 2,400 times higher than that for S. aureus topoisomerase IV and that for E. coli DNA gyrase. These ratios were higher than those for other quinolones, indicating that gatifloxacin possesses a higher selectivity for bacterial type II topoisomerases.

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Garinther, W. I., and M. C. Schultz. "Topoisomerase function during replication-independent chromatin assembly in yeast." Molecular and Cellular Biology 17, no. 7 (July 1997): 3520–26. http://dx.doi.org/10.1128/mcb.17.7.3520.

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DNA topoisomerases I and II are the two major nuclear enzymes capable of relieving torsional strain in DNA. Of these enzymes, topoisomerase I plays the dominant role in relieving torsional strain during chromatin assembly in cell extracts from oocytes, eggs, and early embryos. We tested if the topoisomerases are used differentially during chromatin assembly in Saccharomyces cerevisiae by a combined biochemical and pharmacological approach. As measured by plasmid supercoiling, nucleosome deposition is severely impaired in assembly extracts from a yeast mutant with no topoisomerase I and a temperature-sensitive form of topoisomerase II (strain top1-top2). Expression of wild-type topoisomerase II in strain top1-top2 fully restored assembly-driven supercoiling, and assembly was equally efficient in extracts from strains expressing either topoisomerase I or II alone. Supercoiling in top1-top2 extract was rescued by adding back either purified topoisomerase I or II. Using the topoisomerase II poison VP-16, we show that topoisomerase II activity during chromatin assembly is the same in the presence and absence of topoisomerase I. We conclude that both topoisomerases I and II can provide the DNA relaxation activity required for efficient chromatin assembly in mitotically cycling yeast cells.

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Forterre, Patrick, Christiane Eue, Mouldy Sioud, and Abdellah Hamal. "Studies on DNA polymerases and topoisomerases in archaebacteria." Canadian Journal of Microbiology 35, no. 1 (January 1, 1989): 228–33. http://dx.doi.org/10.1139/m89-035.

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We have isolated DNA polymerases and topoisomerases from two thermoacidophilic archaebacteria: Sulfolobus acidocaldarius and Thermoplasma acidophilum. The DNA polymerases are composed of a single polypeptide with molecular masses of 100 and 85 kDa, respectively. Antibodies against Sulfolobus DNA polymerase did not cross react with Thermoplasma DNA polymerase. Whereas the major DNA topoisomerase activity in S. acidocaldarius is an ATP-dependent type I DNA topoisomerase with a reverse gyrase activity, the major DNA topoisomerase activity in T. acidophilum is a ATP-independent relaxing activity. Both enzymes resemble more the eubacterial than the eukaryotic type I DNA topoisomerase. We have found that small plasmids from halobacteria are negatively supercoiled and that DNA topoisomerase II inhibitors modify their topology. This suggests the existence of an archaebacterial type II DNA topoisomerase related to its eubacterial and eukaryotic counterparts. As in eubacteria, novobiocin induces positive supercoiling of halobacterial plasmids, indicating the absence of a eukaryotic-like type I DNA topoisomerase that relaxes positive superturns.Key words: archaebacteria, DNA topoisomerases, DNA polymerases, DNA topology, gyrase.

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Strumberg, Dirk, John L. Nitiss, Jiaowang Dong, Jerrylaine Walker, Marc C. Nicklaus, Kurt W. Kohn, Jonathan G. Heddle, Anthony Maxwell, Siegfried Seeber, and Yves Pommier. "Importance of the Fourth Alpha-Helix within the CAP Homology Domain of Type II Topoisomerase for DNA Cleavage Site Recognition and Quinolone Action." Antimicrobial Agents and Chemotherapy 46, no. 9 (September 2002): 2735–46. http://dx.doi.org/10.1128/aac.46.9.2735-2746.2002.

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ABSTRACT We report that point mutations causing alteration of the fourth alpha-helix (α4-helix) of the CAP homology domain of eukaryotic (Saccharomyces cerevisiae) type II topoisomerases (Ser740Trp, Gln743Pro, and Thr744Pro) change the selection of type II topoisomerase-mediated DNA cleavage sites promoted by Ca2+ or produced by etoposide, the fluoroquinolone CP-115,953, or mitoxantrone. By contrast, Thr744Ala substitution had minimal effect on Ca2+- and drug-stimulated DNA cleavage sites, indicating the selectivity of single amino acid substitutions within the α4-helix on type II topoisomerase-mediated DNA cleavage. The equivalent mutation in the gene for Escherichia coli gyrase causing Ser83Trp also changed the DNA cleavage pattern generated by Ca2+ or quinolones. Finally, Thr744Pro substitution in the yeast type II topoisomerase rendered the enzyme sensitive to antibacterial quinolones. This study shows that the α4-helix within the conserved CAP homology domain of type II topoisomerases is critical for selecting the sites of DNA cleavage. It also demonstrates that selective amino acid residues in the α4-helix are important in determining the activity and possibly the binding of quinolones to the topoisomerase II-DNA complexes.

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Kaufmann, S. H., and R. Hancock. "Topoisomerase II as a target for anticancer chemotherapy." Acta Biochimica Polonica 42, no. 4 (December 31, 1995): 381–93. http://dx.doi.org/10.18388/abp.1995_4892.

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Type II DNA topoisomerases are required for the segregation of genomic DNA at cell division in prokaryotic and eukaryotic cells, and inhibitors of these enzymes are potential cytotoxic agents in both prokaryotes and eukaryotes. The bacterial member of the topoisomerase II family, DNA gyrase, and the chemotherapeutic agents which target it are the subject of a recent review (Maxwell, A. et al., 1993, in Molecular Biology of DNA Topoisomerases, Andoh, T. et al., eds., pp. 21-30, CRC Press, Boca Raton). Here we present an overview of current knowledge of eukaryotic topoisomerase II and the anticancer agents which target this enzyme, focussing predominantly on new observations and recent reports and reviews.

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Blanche, F., B. Cameron, F. X. Bernard, L. Maton, B. Manse, L. Ferrero, N. Ratet, et al. "Differential behaviors of Staphylococcus aureus and Escherichia coli type II DNA topoisomerases." Antimicrobial Agents and Chemotherapy 40, no. 12 (December 1996): 2714–20. http://dx.doi.org/10.1128/aac.40.12.2714.

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Staphylococcus aureus gyrA and gyrB genes encoding DNA gyrase subunits were cloned and coexpressed in Escherichia coli under the control of the T7 promoter-T7 RNA polymerase system, leading to soluble gyrase which was purified to homogeneity. Purified gyrase was catalytically indistinguishable from the gyrase purified from S. aureus and did not contain detectable amounts of topoisomerases from the E. coli host. Topoisomerase IV subunits GrlA and GrlB from S. aureus were also expressed in E. coli and were separately purified to apparent homogeneity. Topoisomerase IV, which was reconstituted by mixing equimolar amounts of GrlA and GrlB, had both ATP-dependent decatenation and DNA relaxation activities in vitro. This enzyme was more sensitive than gyrase to inhibition by typical fluoroquinolone antimicrobial agents such as ciprofloxacin or sparfloxacin, adding strong support to genetic studies which indicate that topoisomerase IV is the primary target of fluoroquinolones in S. aureus. The results obtained with ofloxacin suggest that this fluoroquinolone could also primarily target gyrase. No cleavable complex could be detected with S. aureus gyrase upon incubation with ciprofloxacin or sparfloxacin at concentrations which fully inhibit DNA supercoiling. This suggests that these drugs do not stabilize the open DNA-gyrase complex, at least under standard in vitro incubation conditions, but are more likely to interfere primarily with the DNA breakage step, contrary to what has been reported with E. coli gyrase. Both S. aureus gyrase-catalyzed DNA supercoiling and S. aureus topoisomerase IV-catalyzed decatenation were dramatically stimulated by potassium glutamate or aspartate (500- and 50-fold by 700 and 350 mM glutamate, respectively), whereas topoisomerase IV-dependent DNA relaxation was inhibited 3-fold by 350 mM glutamate. The relevance of the effect of dicarboxylic amino acids on the activities of type II topoisomerases is discussed with regard to the intracellular osmolite composition of S. aureus.

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Delgado, Justine L., Chao-Ming Hsieh, Nei-Li Chan, and Hiroshi Hiasa. "Topoisomerases as anticancer targets." Biochemical Journal 475, no. 2 (January 23, 2018): 373–98. http://dx.doi.org/10.1042/bcj20160583.

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Many cancer type-specific anticancer agents have been developed and significant advances have been made toward precision medicine in cancer treatment. However, traditional or nonspecific anticancer drugs are still important for the treatment of many cancer patients whose cancers either do not respond to or have developed resistance to cancer-specific anticancer agents. DNA topoisomerases, especially type IIA topoisomerases, are proved therapeutic targets of anticancer and antibacterial drugs. Clinically successful topoisomerase-targeting anticancer drugs act through topoisomerase poisoning, which leads to replication fork arrest and double-strand break formation. Unfortunately, this unique mode of action is associated with the development of secondary cancers and cardiotoxicity. Structures of topoisomerase–drug–DNA ternary complexes have revealed the exact binding sites and mechanisms of topoisomerase poisons. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. It may also be possible to design catalytic inhibitors of topoisomerases by targeting certain inactive conformations of these enzymes. Furthermore, identification of various new bacterial topoisomerase inhibitors and regulatory proteins may inspire the discovery of novel human topoisomerase inhibitors. Thus, topoisomerases remain as important therapeutic targets of anticancer agents.

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Snapka, R. M., M. A. Powelson, and J. M. Strayer. "Swiveling and decatenation of replicating simian virus 40 genomes in vivo." Molecular and Cellular Biology 8, no. 2 (February 1988): 515–21. http://dx.doi.org/10.1128/mcb.8.2.515.

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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.

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Snapka, R. M., M. A. Powelson, and J. M. Strayer. "Swiveling and decatenation of replicating simian virus 40 genomes in vivo." Molecular and Cellular Biology 8, no. 2 (February 1988): 515–21. http://dx.doi.org/10.1128/mcb.8.2.515-521.1988.

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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.

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Thakur, Devendra Singh. "Topoisomerase II Inhibitors in Cancer Treatment." International Journal of Pharmaceutical Sciences and Nanotechnology 3, no. 4 (February 28, 2011): 1173–81. http://dx.doi.org/10.37285/ijpsn.2010.3.4.2.

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Topoisomerase II constitutes a family of nuclear enzymes essential to all living cells. These enzymes are capable of transferring one DNA double helix through a transient break in another DNA double helix. Type II topoisomerases play important roles in DNA metabolic processes, in which they are involved in DNA replication, transcription, chromosome condensation and de-condensation. Topoisomerase II is also the cellular target for a number of widely used anticancer agents currently in clinical use, such as the anthracyclines (daunorubicin and doxorubicin), the epipodophyllotoxins (etoposide and teniposide), and the aminoacridines. These agents stimulate the topoisomerase II-cleavable complex, which is a transient configuration of topoisomerase II on DNA in which topoisomerase II is covalently attached to DNA. This causes the accumulation of cytotoxic nonreversible DNA double-strand breaks generated by the processing of such complexes by DNA metabolic processes. As of present, the clinical use of catalytic topoisomerase inhibitors as antineoplastic agents is limited to aclarubicin and MST-16. Both of these compounds are preferentially active toward hematological malignancies and show limited activity toward solid tumors. This review explains the role of topoisomerase inhibitors in cancer therapy.

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Hicks, S., N. Labinskyy, B. Piteo, D. Laurent, J. E. Mathew, S. A. Gupte, and J. G. Edwards. "Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat." American Journal of Physiology-Heart and Circulatory Physiology 304, no. 7 (April 1, 2013): H903—H915. http://dx.doi.org/10.1152/ajpheart.00567.2012.

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Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic Goto-Kakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H2O2suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetes-induced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium.

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Wang, Xilan. "Structural study of Topoisomerase IV-DNA-Levofloxacin complexes from Streptococcus pneumoniae." E3S Web of Conferences 131 (2019): 01021. http://dx.doi.org/10.1051/e3sconf/201913101021.

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S. pneumoniae is an important pathogen causing pulmonary infection, acute otitis media and purulent meningitis in infants and children. Type II topoisomerases are enzymes that play essential roles in DNA replication, chromosome segregation and recombination throughout all living organisms. Topoisomerases IV can make a transient break in DNA strands in one chromosome. These enzymes are very important antibacterial as well as anticancer targets and potential anti-trypanosomal targets. Levofloxacin has shown efficient inhibition of Type II topoisomerases in S. pneumoniae. Its mechanism of action is to inhibit the activity of DNA topoisomerase, prevent bacterial DNA synthesis and replication leading to bacterial death. We focused on solving the key structures of topoisomerase IV-DNA-levofloxacin complexes by negative staining electron microscopy and the resulting model was obtained at 32 Å by 3D autorefine in Relion 3.0. This study was to try and obtain the structure of the whole complex with DNA bound in the G-gate and the T-gate in order to study DNA capture and transport in type II topoisomerases.

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Bronstein, Joel C., Stacey L. Olson, Kristin LeVier, Mark Tomilo, and Peter C. Weber. "Purification and Characterization of Recombinant Staphylococcus haemolyticus DNA Gyrase and Topoisomerase IV Expressed in Escherichia coli." Antimicrobial Agents and Chemotherapy 48, no. 7 (July 2004): 2708–11. http://dx.doi.org/10.1128/aac.48.7.2708-2711.2004.

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ABSTRACT The subunits of DNA gyrase and topoisomerase IV from Staphylococcus haemolyticus were expressed in Escherichia coli, purified to homogeneity, and used to reconstitute active enzymes that were sensitive to known topoisomerase inhibitors. This represents the first description of a method for isolating type II topoisomerases of a coagulase-negative staphylococcal species.

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Gruger, Thomas, John L. Nitiss, Anthony Maxwell, E. Lynn Zechiedrich, Peter Heisig, Siegfried Seeber, Yves Pommier, and Dirk Strumberg. "A Mutation in Escherichia coli DNA Gyrase Conferring Quinolone Resistance Results in Sensitivity to Drugs Targeting Eukaryotic Topoisomerase II." Antimicrobial Agents and Chemotherapy 48, no. 12 (December 2004): 4495–504. http://dx.doi.org/10.1128/aac.48.12.4495-4504.2004.

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ABSTRACT Fluoroquinolones are broad-spectrum antimicrobial agents that target type II topoisomerases. Many fluoroquinolones are highly specific for bacterial type II topoisomerases and act against both DNA gyrase and topoisomerase IV. In Escherichia coli, mutations causing quinolone resistance are often found in the gene that encodes the A subunit of DNA gyrase. One common site for resistance-conferring mutations alters Ser83, and mutations to Leu or Trp result in high levels of resistance to fluoroquinolones. In the present study we demonstrate that the mutation of Ser83 to Trp in DNA gyrase (GyrS83W) also results in sensitivity to agents that are potent inhibitors of eukaryotic topoisomerase II but that are normally inactive against prokaryotic enzymes. Epipodophyllotoxins, such as etoposide, teniposide and amino-azatoxin, inhibited the DNA supercoiling activity of GyrS83W, and the enzyme caused elevated levels of DNA cleavage in the presence of these agents. The DNA sequence preference for GyrS83W-induced cleavage sites in the presence of etoposide was similar to that seen with eukaryotic type II topoisomerases. Introduction of the GyrS83W mutation in E. coli strain RFM443-242 by site-directed mutagenesis sensitized it to epipodophyllotoxins and amino-azatoxin. Our results demonstrate that sensitivity to agents that target topoisomerase II is conserved between prokaryotic and eukaryotic enzymes, suggesting that drug interaction domains are also well conserved and likely occur in domains important for the biochemical activities of the enzymes.

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Blower, Tim R., Afif Bandak, Amy S. Y. Lee, Caroline A. Austin, John L. Nitiss, and James M. Berger. "A complex suite of loci and elements in eukaryotic type II topoisomerases determine selective sensitivity to distinct poisoning agents." Nucleic Acids Research 47, no. 15 (July 9, 2019): 8163–79. http://dx.doi.org/10.1093/nar/gkz579.

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AbstractType II topoisomerases catalyze essential DNA transactions and are proven drug targets. Drug discrimination by prokaryotic and eukaryotic topoisomerases is vital to therapeutic utility, but is poorly understood. We developed a next-generation sequencing (NGS) approach to identify drug-resistance mutations in eukaryotic topoisomerases. We show that alterations conferring resistance to poisons of human and yeast topoisomerase II derive from a rich mutational ‘landscape’ of amino acid substitutions broadly distributed throughout the entire enzyme. Both general and discriminatory drug-resistant behaviors are found to arise from different point mutations found at the same amino acid position and to occur far outside known drug-binding sites. Studies of selected resistant enzymes confirm the NGS data and further show that the anti-cancer quinolone vosaroxin acts solely as an intercalating poison, and that the antibacterial ciprofloxacin can poison yeast topoisomerase II. The innate drug-sensitivity of the DNA binding and cleavage region of human and yeast topoisomerases (particularly hTOP2β) is additionally revealed to be significantly regulated by the enzymes’ adenosine triphosphatase regions. Collectively, these studies highlight the utility of using NGS-based methods to rapidly map drug resistance landscapes and reveal that the nucleotide turnover elements of type II topoisomerases impact drug specificity.

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Kern, Gunther, Tiffany Palmer, David E. Ehmann, Adam B. Shapiro, Beth Andrews, Gregory S. Basarab, Peter Doig, et al. "Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914." Journal of Biological Chemistry 290, no. 34 (July 6, 2015): 20984–94. http://dx.doi.org/10.1074/jbc.m115.663534.

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We characterized the inhibition of Neisseria gonorrhoeae type II topoisomerases gyrase and topoisomerase IV by AZD0914 (AZD0914 will be henceforth known as ETX0914 (Entasis Therapeutics)), a novel spiropyrimidinetrione antibacterial compound that is currently in clinical trials for treatment of drug-resistant gonorrhea. AZD0914 has potent bactericidal activity against N. gonorrhoeae, including multidrug-resistant strains and key Gram-positive, fastidious Gram-negative, atypical, and anaerobic bacterial species (Huband, M. D., Bradford, P. A., Otterson, L. G., Basrab, G. S., Giacobe, R. A., Patey, S. A., Kutschke, A. C., Johnstone, M. R., Potter, M. E., Miller, P. F., and Mueller, J. P. (2014) In Vitro Antibacterial Activity of AZD0914: A New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-positive, Fastidious Gram-negative, and Atypical Bacteria. Antimicrob. Agents Chemother. 59, 467–474). AZD0914 inhibited DNA biosynthesis preferentially to other macromolecules in Escherichia coli and induced the SOS response to DNA damage in E. coli. AZD0914 stabilized the enzyme-DNA cleaved complex for N. gonorrhoeae gyrase and topoisomerase IV. The potency of AZD0914 for inhibition of supercoiling and the stabilization of cleaved complex by N. gonorrhoeae gyrase increased in a fluoroquinolone-resistant mutant enzyme. When a mutation, conferring mild resistance to AZD0914, was present in the fluoroquinolone-resistant mutant, the potency of ciprofloxacin for inhibition of supercoiling and stabilization of cleaved complex was increased greater than 20-fold. In contrast to ciprofloxacin, religation of the cleaved DNA did not occur in the presence of AZD0914 upon removal of magnesium from the DNA-gyrase-inhibitor complex. AZD0914 had relatively low potency for inhibition of human type II topoisomerases α and β.

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Lee, Joyce H., and James M. Berger. "Cell Cycle-Dependent Control and Roles of DNA Topoisomerase II." Genes 10, no. 11 (October 30, 2019): 859. http://dx.doi.org/10.3390/genes10110859.

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Type II topoisomerases are ubiquitous enzymes in all branches of life that can alter DNA superhelicity and unlink double-stranded DNA segments during processes such as replication and transcription. In cells, type II topoisomerases are particularly useful for their ability to disentangle newly-replicated sister chromosomes. Growing lines of evidence indicate that eukaryotic topoisomerase II (topo II) activity is monitored and regulated throughout the cell cycle. Here, we discuss the various roles of topo II throughout the cell cycle, as well as mechanisms that have been found to govern and/or respond to topo II function and dysfunction. Knowledge of how topo II activity is controlled during cell cycle progression is important for understanding how its misregulation can contribute to genetic instability and how modulatory pathways may be exploited to advance chemotherapeutic development.

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&NA;. "Cyclophosphamide/type II DNA topoisomerase inhibitors." Reactions Weekly &NA;, no. 1303 (May 2010): 16. http://dx.doi.org/10.2165/00128415-201013030-00045.

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Austin, Caroline, Ka Lee, Rebecca Swan, Mushtaq Khazeem, Catriona Manville, Peter Cridland, Achim Treumann, Andrew Porter, Nick Morris, and Ian Cowell. "TOP2B: The First Thirty Years." International Journal of Molecular Sciences 19, no. 9 (September 14, 2018): 2765. http://dx.doi.org/10.3390/ijms19092765.

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Type II DNA topoisomerases (EC 5.99.1.3) are enzymes that catalyse topological changes in DNA in an ATP dependent manner. Strand passage reactions involve passing one double stranded DNA duplex (transported helix) through a transient enzyme-bridged break in another (gated helix). This activity is required for a range of cellular processes including transcription. Vertebrates have two isoforms: topoisomerase IIα and β. Topoisomerase IIβ was first reported in 1987. Here we review the research on DNA topoisomerase IIβ over the 30 years since its discovery.

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Hirsch, Jana, and Dagmar Klostermeier. "What makes a type IIA topoisomerase a gyrase or a Topo IV?" Nucleic Acids Research 49, no. 11 (April 27, 2021): 6027–42. http://dx.doi.org/10.1093/nar/gkab270.

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Abstract Type IIA topoisomerases catalyze a variety of different reactions: eukaryotic topoisomerase II relaxes DNA in an ATP-dependent reaction, whereas the bacterial representatives gyrase and topoisomerase IV (Topo IV) preferentially introduce negative supercoils into DNA (gyrase) or decatenate DNA (Topo IV). Gyrase and Topo IV perform separate, dedicated tasks during replication: gyrase removes positive supercoils in front, Topo IV removes pre-catenanes behind the replication fork. Despite their well-separated cellular functions, gyrase and Topo IV have an overlapping activity spectrum: gyrase is also able to catalyze DNA decatenation, although less efficiently than Topo IV. The balance between supercoiling and decatenation activities is different for gyrases from different organisms. Both enzymes consist of a conserved topoisomerase core and structurally divergent C-terminal domains (CTDs). Deletion of the entire CTD, mutation of a conserved motif and even by just a single point mutation within the CTD converts gyrase into a Topo IV-like enzyme, implicating the CTDs as the major determinant for function. Here, we summarize the structural and mechanistic features that make a type IIA topoisomerase a gyrase or a Topo IV, and discuss the implications for type IIA topoisomerase evolution.

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Lin, Y. C. James, Jianhong Li, Chad R. Irwin, Heather Jenkins, Luke DeLange, and David H. Evans. "Vaccinia Virus DNA Ligase Recruits Cellular Topoisomerase II to Sites of Viral Replication and Assembly." Journal of Virology 82, no. 12 (April 16, 2008): 5922–32. http://dx.doi.org/10.1128/jvi.02723-07.

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ABSTRACT Vaccinia virus replication is inhibited by etoposide and mitoxantrone even though poxviruses do not encode the type II topoisomerases that are the specific targets of these drugs. Furthermore, one can isolate drug-resistant virus carrying mutations in the viral DNA ligase and yet the ligase is not known to exhibit sensitivity to these drugs. A yeast two-hybrid screen was used to search for proteins binding to vaccinia ligase, and one of the nine proteins identified comprised a portion (residue 901 to end) of human topoisomerase IIβ. One can prevent the interaction by introducing a C11-to-Y substitution mutation into the N terminus of the ligase bait protein, which is one of the mutations conferring etoposide and mitoxantrone resistance. Coimmunoprecipitation methods showed that the native ligase and a Flag-tagged recombinant protein form complexes with human topoisomerase IIα/β in infected cells and that this interaction can also be disrupted by mutations in the A50R (ligase) gene. Immunofluorescence microscopy showed that both topoisomerase IIα and IIβ antigens are recruited to cytoplasmic sites of virus replication and that less topoisomerase was recruited to these sites in cells infected with mutant virus than in cells infected with wild-type virus. Immunoelectron microscopy confirmed the presence of topoisomerases IIα/β in virosomes, but the enzyme could not be detected in mature virus particles. We propose that the genetics of etoposide and mitoxantrone resistance can be explained by vaccinia ligase binding to cellular topoisomerase II and recruiting this nuclear enzyme to sites of virus biogenesis. Although other nuclear DNA binding proteins have been detected in virosomes, this appears to be the first demonstration of an enzyme being selectively recruited to sites of poxvirus DNA synthesis and assembly.

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Pilati, P., D. Nitti, and S. Mocellin. "Cancer Resistance to Type II Topoisomerase Inhibitors." Current Medicinal Chemistry 19, no. 23 (July 1, 2012): 3900–3906. http://dx.doi.org/10.2174/092986712802002473.

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Douc-Rasy, S., A. Kayser, J. F. Riou, and G. Riou. "ATP-independent type II topoisomerase from trypanosomes." Proceedings of the National Academy of Sciences 83, no. 19 (October 1, 1986): 7152–56. http://dx.doi.org/10.1073/pnas.83.19.7152.

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Boritzki, Theodore J., Tammy S. Wolfard, Judith A. Besserer, Robert C. Jackson, and David W. Fry. "Inhibition of type II topoisomerase by fostriecin." Biochemical Pharmacology 37, no. 21 (November 1988): 4063–68. http://dx.doi.org/10.1016/0006-2952(88)90096-2.

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Lahiri, Sushmita D., Amy Kutschke, Kathy McCormack, and Richard A. Alm. "Insights into the Mechanism of Inhibition of Novel Bacterial Topoisomerase Inhibitors from Characterization of Resistant Mutants of Staphylococcus aureus." Antimicrobial Agents and Chemotherapy 59, no. 9 (June 15, 2015): 5278–87. http://dx.doi.org/10.1128/aac.00571-15.

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ABSTRACTThe type II topoisomerases DNA gyrase and topoisomerase IV are clinically validated bacterial targets that catalyze the modulation of DNA topology that is vital to DNA replication, repair, and decatenation. Increasing resistance to fluoroquinolones, which trap the topoisomerase-DNA complex, has led to significant efforts in the discovery of novel inhibitors of these targets. AZ6142 is a member of the class of novel bacterial topoisomerase inhibitors (NBTIs) that utilizes a distinct mechanism to trap the protein-DNA complex. AZ6142 has very potent activity against Gram-positive organisms, includingStaphylococcus aureus,Streptococcus pneumoniae, andStreptococcus pyogenes. In this study, we determined the frequencies of resistance to AZ6142 and other representative NBTI compounds inS. aureusandS. pneumoniae. The frequencies of selection of resistant mutants at 4× the MIC were 1.7 × 10−8forS. aureusand <5.5 × 10−10forS. pneumoniae. To improve our understanding of the NBTI mechanism of inhibition, the resistantS. aureusmutants were characterized and 20 unique substitutions in the topoisomerase subunits were identified. Many of these substitutions were located outside the NBTI binding pocket and impact the susceptibility of AZ6142, resulting in a 4- to 32-fold elevation in the MIC over the wild-type parent strain. Data on cross-resistance with other NBTIs and fluoroquinolones enabled the differentiation of scaffold-specific changes from compound-specific variations. Our results suggest that AZ6142 inhibits both type II topoisomerases inS. aureusbut that DNA gyrase is the primary target. Further, the genotype of the resistant mutants suggests that domain conformations and DNA interactions may uniquely impact NBTIs compared to fluoroquinolones.

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Mikulovich, Yu L., G. M. Sorokoumova, А. А. Selishcheva, and V. I. Shvets. "The antimicrobial activity of exogeno us anionic phospholipids against Mycobacterium tuberculosis and Escherichia coli." Fine Chemical Technologies 11, no. 3 (June 28, 2016): 64–73. http://dx.doi.org/10.32362/2410-6593-2016-11-3-64-73.

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The effect of anionic phospholipids, namely, cardiolipin, phosphatidylglycerol and phosphatidic acid, on the growth of gram-negative bacteria E. coli BL21(DE3), as well as gram-positive bacteria M. tuberculosis H37Rv was investigated in this study. The influence of all anionic phospholipids tested on the bacteria growth was shown to be dose-dependent. Lipids at concentrations below 335 μM didn’t affect, while at 335 μM and above they repressed bacteria growth and caused cellular death of both type of microorganisms. SOS response induction was observed by using strain E. coli CSH50 sfiA::lacZ during cultivation E. coli with cardiolipin, phosphatidylglycerol and phosphatidic acid. This indicates DNA damage through double-strand breaks. One reason of the DNA damage could be stabilization of transient complexes of DNA topoisomerase (types I and II) with DNA temporary broken by anionic phospholipids. However, neither phosphatidylglycerol nor phosphatidic acid affect the activity of types I and II DNA topoisomerases from E. coli in vitro. In contrast, cardiolipin inhibited DNA topoisomerase I and DNA gyrase (type II topoisomerase), but didn’t stabilize transient complexes of the enzyme with DNA. It indicates that DNA damage due to anionic phospholipids exposure didn’t result from inhibition of DNA topoisomerase activity through stabilization of the transient complex of the enzyme with DNA. The obtained results of cardiolipin, phosphatidylglycerol and phosphatidic acid bactericidal activity against grampositive M. tuberculosis and gram-negative E. coli make it possible to use anionic phospholipids as individual antimicrobial agents or as a matrix of effective and non-toxic liposomal drugs for tuberculosis treatment.

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Alpan, A. Selcen, H. Semih Gunes, and Zeki Topcu. "1H-Benzimidazole derivatives as mammalian DNA topoisomerase I inhibitors." Acta Biochimica Polonica 54, no. 3 (September 6, 2007): 561–65. http://dx.doi.org/10.18388/abp.2007_3229.

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Benzimidazole is one of the most important heterocyclic groups manifesting various biological properties, such as antibacterial, antifungal, antimicrobial, antiprotozoal and antihelmintic activities. Several benzimidazole derivatives are also active as inhibitors of type I DNA topoisomerases. In this study, three 1H-benzimidazole derivatives with different electronic characteristics at position 5-, namely 5-chloro-4-(1H-benzimidazole-2-yl)phenol (Cpd I), 5-methyl-4-(1H-benzimidazole-2-yl)phenol (Cpd II) and 4-(1H-benzimidazole-2-yl)phenol (Cpd III), were synthesized and evaluated for their effects on mammalian type I DNA topoisomerase activity using quantitative in vitro plasmid supercoil relaxation assays. For the structure elucidation of the compounds, melting points, UV, IR, 1H NMR, 13C NMR, mass spectral data and elemental analyses were interpreted. Among the compounds, 5-methyl-4-(1H-benzimidazole-2-yl)phenol (Cpd II) manifested relatively potent topoisomerase I inhibition.

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29

Morrissey, Ian, and John George. "Activities of Fluoroquinolones againstStreptococcus pneumoniae Type II Topoisomerases Purified as Recombinant Proteins." Antimicrobial Agents and Chemotherapy 43, no. 11 (November 1, 1999): 2579–85. http://dx.doi.org/10.1128/aac.43.11.2579.

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ABSTRACT Streptococcus pneumoniae topoisomerase IV and DNA gyrase have been purified from a fluoroquinolone-susceptibleStreptococcus pneumoniae strain, from first-step mutants showing low-level resistance to ciprofloxacin, sparfloxacin, levofloxacin, and ofloxacin, and from two clinical isolates showing intermediate- and high-level fluoroquinolone resistance by a gene cloning method that produces recombinant proteins fromEscherichia coli. The concentrations of ciprofloxacin, sparfloxacin, levofloxacin, or ofloxacin required to inhibit wild-type topoisomerase IV were 8 to 16 times lower than those required to inhibit wild-type DNA gyrase. Furthermore, low-level resistance to these fluoroquinolones was entirely due to the reduced inhibitory activity of fluoroquinolones against topoisomerase IV. For all the laboratory strains, the 50% inhibitory concentration for topoisomerase IV directly correlated with the MIC. We therefore propose that withS. pneumoniae, ciprofloxacin, sparfloxacin, levofloxacin, and ofloxacin target topoisomerase IV in preference to DNA gyrase. Sitafloxacin, on the other hand, was found to be equipotent against either enzyme. This characteristic is unique for a fluoroquinolone. A reduction in the sensitivities of both topoisomerase IV and DNA gyrase are required, however, to achieve intermediate- or high-level fluoroquinolone resistance in S. pneumoniae.

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Sanderson, Mark R., Ivan Laponogov, Xiaosu Pan, Dennis A. Veselkov, Isabelle M. T. Crevel, Jogitha Selvarajah, Art Branstrom, Ryan Cirz, Heinz E. Moser, and L. Mark Fisher. "Studies of prokaryotic Type II topoisomerase drug inhibition." Acta Crystallographica Section A Foundations and Advances 73, a2 (December 1, 2017): C633. http://dx.doi.org/10.1107/s2053273317089409.

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Lee, Joyce H., Timothy J. Wendorff, and James M. Berger. "Resveratrol: A novel type of topoisomerase II inhibitor." Journal of Biological Chemistry 292, no. 51 (October 26, 2017): 21011–22. http://dx.doi.org/10.1074/jbc.m117.810580.

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Ikeda, H. "Illegitimate recombination: Role of type II DNA topoisomerase." Advances in Biophysics 21 (1986): 149–60. http://dx.doi.org/10.1016/0065-227x(86)90020-1.

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Neuman, K. C., G. Charvin, D. Bensimon, and V. Croquette. "Mechanisms of chiral discrimination by topoisomerase IV." Proceedings of the National Academy of Sciences 106, no. 17 (April 9, 2009): 6986–91. http://dx.doi.org/10.1073/pnas.0900574106.

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Topoisomerase IV (Topo IV), an essential ATP-dependent bacterial type II topoisomerase, transports one segment of DNA through a transient double-strand break in a second segment of DNA. In vivo, Topo IV unlinks catenated chromosomes before cell division and relaxes positive supercoils generated during DNA replication. In vitro, Topo IV relaxes positive supercoils at least 20-fold faster than negative supercoils. The mechanisms underlying this chiral discrimination by Topo IV and other type II topoisomerases remain speculative. We used magnetic tweezers to measure the relaxation rates of single and multiple DNA crossings by Topo IV. These measurements allowed us to determine unambiguously the relative importance of DNA crossing geometry and enzymatic processivity in chiral discrimination by Topo IV. Our results indicate that Topo IV binds and passes DNA strands juxtaposed in a nearly perpendicular orientation and that relaxation of negative supercoiled DNA is perfectly distributive. Together, these results suggest that chiral discrimination arises primarily from dramatic differences in the processivity of relaxing positive and negative supercoiled DNA: Topo IV is highly processive on positively supercoiled DNA, whereas it is perfectly distributive on negatively supercoiled DNA. These results provide fresh insight into topoisomerase mechanisms and lead to a model that reconciles contradictory aspects of previous findings while providing a framework to interpret future results.

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Duguet, M. "When helicase and topoisomerase meet!" Journal of Cell Science 110, no. 12 (June 15, 1997): 1345–50. http://dx.doi.org/10.1242/jcs.110.12.1345.

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Several examples of direct interactions between helicases and topoisomerases have recently been described. The data suggest a possible cooperation between these enzymes in major DNA events such as the progression of a replication fork, segregation of newly replicated chromosomes, disruption of nucleosomal structure, DNA supercoiling, and finally recombination, repair, and genomic stability. A first example is the finding of a strong interaction between T antigen and topoisomerase I in mammalian cells, that may trigger unwinding of the parental DNA strands at the replication forks of Simian Virus 40. A second example is the reverse gyrase from thermophilic prokaryotes, composed of a putative helicase domain, and a topoisomerase domain in the same polypeptide. This enzyme may be required to maintain genomic stability at high temperature. A third example is the finding of an interaction between type II topoisomerase and the helicase Sgs1 in yeast. This interaction possibly allows the faithful segregation of newly replicated chromosomes in eukaryotic cells. A fourth example is the interaction between the same helicase Sgs1 and topoisomerase III in yeast, that may control recombination level and genetic stability of repetitive sequences. Recently, in humans, mutations in genes similar to Sgs1 have been found to be responsible for Bloom's and Werner's syndromes. The cooperation between helicases and topoisomerases is likely to be extended to many aspects of DNA mechanisms including chromatin condensation/decondensation.

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Stone, M. D., Z. Bryant, N. J. Crisona, S. B. Smith, A. Vologodskii, C. Bustamante, and N. R. Cozzarelli. "Chirality sensing by Escherichia coli topoisomerase IV and the mechanism of type II topoisomerases." Proceedings of the National Academy of Sciences 100, no. 15 (July 11, 2003): 8654–59. http://dx.doi.org/10.1073/pnas.1133178100.

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Sunter, Nicola J., Ian G. Cowell, Elaine Willmore, Gary P. Watters, and Caroline A. Austin. "Role of Topoisomerase IIβin DNA Damage Response following IR and Etoposide." Journal of Nucleic Acids 2010 (2010): 1–8. http://dx.doi.org/10.4061/2010/710589.

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The role of topoisomerase IIβwas investigated in cell lines exposed to two DNA damaging agents, ionising radiation (IR) or etoposide, a drug which acts on topoisomerase II. The appearance and resolution ofγH2AX foci in murine embryonic fibroblast cell lines, wild type and null for DNA topoisomerase IIβ, was measured after exposure to ionising radiation (IR) or etoposide. Topoisomerase II-DNA adduct levels were also measured. IR rapidly triggered phosphorylation of histone H2AX, less phosphorylation was seen in TOP2β-/-cells, but the difference was not statistically significant. IR did not produce topoisomerase II-DNA adducts above control levels. Etoposide triggered the formation of topoisomerase II-DNA adducts and the phosphorylation of histone H2AX, theγH2AX foci appeared more slowly with etoposide than with IR. Topoisomerase II-DNA complexes in WT cells but not TOP2β-/-cells increased significantly at 24 hours with the proteasome inhibitor MG132, suggesting topoisomerase IIβadducts are removed by the proteasome.

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Yi, Lanhua, and Xin Lü. "New Strategy on Antimicrobial-resistance: Inhibitors of DNA Replication Enzymes." Current Medicinal Chemistry 26, no. 10 (June 20, 2019): 1761–87. http://dx.doi.org/10.2174/0929867324666171106160326.

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Background:Antimicrobial resistance is found in all microorganisms and has become one of the biggest threats to global health. New antimicrobials with different action mechanisms are effective weapons to fight against antibiotic-resistance.Objective:This review aims to find potential drugs which can be further developed into clinic practice and provide clues for developing more effective antimicrobials.Methods:DNA replication universally exists in all living organisms and is a complicated process in which multiple enzymes are involved in. Enzymes in bacterial DNA replication of initiation and elongation phases bring abundant targets for antimicrobial development as they are conserved and indispensable. In this review, enzyme inhibitors of DNA helicase, DNA primase, topoisomerases, DNA polymerase and DNA ligase were discussed. Special attentions were paid to structures, activities and action modes of these enzyme inhibitors.Results:Among these enzymes, type II topoisomerase is the most validated target with abundant inhibitors. For type II topoisomerase inhibitors (excluding quinolones), NBTIs and benzimidazole urea derivatives are the most promising inhibitors because of their good antimicrobial activity and physicochemical properties. Simultaneously, DNA gyrase targeted drugs are particularly attractive in the treatment of tuberculosis as DNA gyrase is the sole type II topoisomerase in Mycobacterium tuberculosis. Relatively, exploitation of antimicrobial inhibitors of the other DNA replication enzymes are primeval, in which inhibitors of topo III are even blank so far.Conclusion:This review demonstrates that inhibitors of DNA replication enzymes are abundant, diverse and promising, many of which can be developed into antimicrobials to deal with antibioticresistance.

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Yuwen, Hao, Chu Chieh Hsia, Yutaka Nakashima, Amy Evangelista, and Edward Tabor. "Binding of Wild-Type P53 by Topoisomerase II and Overexpression of Topoisomerase II in Human Hepatocellular Carcinoma." Biochemical and Biophysical Research Communications 234, no. 1 (May 1997): 194–97. http://dx.doi.org/10.1006/bbrc.1997.6539.

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Stokes, Neil R., Helena B. Thomaides-Brears, Stephanie Barker, James M. Bennett, Joanne Berry, Ian Collins, Lloyd G. Czaplewski, et al. "Biological Evaluation of Benzothiazole Ethyl Urea Inhibitors of Bacterial Type II Topoisomerases." Antimicrobial Agents and Chemotherapy 57, no. 12 (September 16, 2013): 5977–86. http://dx.doi.org/10.1128/aac.00719-13.

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ABSTRACTThe type II topoisomerases DNA gyrase (GyrA/GyrB) and topoisomerase IV (ParC/ParE) are well-validated targets for antibacterial drug discovery. Because of their structural and functional homology, these enzymes are amenable to dual targeting by a single ligand. In this study, two novel benzothiazole ethyl urea-based small molecules, designated compound A and compound B, were evaluated for their biochemical, antibacterial, and pharmacokinetic properties. The two compounds inhibited the ATPase activity of GyrB and ParE with 50% inhibitory concentrations of <0.1 μg/ml. Prevention of DNA supercoiling by DNA gyrase was also observed. Both compounds potently inhibited the growth of a range of bacterial organisms, including staphylococci, streptococci, enterococci,Clostridium difficile, and selected Gram-negative respiratory pathogens. MIC90s against clinical isolates ranged from 0.015 μg/ml forStreptococcus pneumoniaeto 0.25 μg/ml forStaphylococcus aureus. No cross-resistance with common drug resistance phenotypes was observed. In addition, no synergistic or antagonistic interactions between compound A or compound B and other antibiotics, including the topoisomerase inhibitors novobiocin and levofloxacin, were detected in checkerboard experiments. The frequencies of spontaneous resistance forS. aureuswere <2.3 × 10−10with compound A and <5.8 × 10−11with compound B at concentrations equivalent to 8× the MICs. These values indicate a multitargeting mechanism of action. The pharmacokinetic properties of both compounds were profiled in rats. Following intravenous administration, compound B showed approximately 3-fold improvement over compound A in terms of both clearance and the area under the concentration-time curve. The measured oral bioavailability of compound B was 47.7%.

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Kaufmann, W. K., J. C. Boyer, L. L. Estabrooks, and S. J. Wilson. "Inhibition of replicon initiation in human cells following stabilization of topoisomerase-DNA cleavable complexes." Molecular and Cellular Biology 11, no. 7 (July 1991): 3711–18. http://dx.doi.org/10.1128/mcb.11.7.3711.

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Diploid human fibroblast strains were treated for 10 min with inhibitors of type I and type II DNA topoisomerases, and after removal of the inhibitors, the rate of initiation of DNA synthesis at replicon origins was determined. By alkaline elution chromatography, 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine), an inhibitor of DNA topoisomerase II, was shown to produce DNA strand breaks. These strand breaks are thought to reflect drug-induced stabilization of topoisomerase-DNA cleavable complexes. Removal of the drug led to a rapid resealing of the strand breaks by dissociation of the complexes. Velocity sedimentation analysis was used to quantify the effects of amsacrine treatment on DNA replication. It was demonstrated that transient exposure to low concentrations of amsacrine inhibited replicon initiation but did not substantially affect DNA chainelongation within operating replicons. Maximal inhibition of replicon initiation occurred 20 to 30 min after drug treatment, and the initiation rate recovered 30 to 90 min later. Ataxia telangiectasia cells displayed normal levels of amsacrine-induced DNA strand breaks during stabilization of cleavable complexes but failed to downregulate replicon initiation after exposure to the topoisomerase inhibitor. Thus, inhibition of replicon initiation in response to DNA damage appears to be an active process which requires a gene product which is defective or missing in ataxia telangiectasia cells. In normal human fibroblasts, the inhibition of DNA topoisomerase I by camptothecin produced reversible DNA strand breaks. Transient exposure to this drug also inhibited replicon initiation. These results suggest that the cellular response pathway which downregulates replicon initiation following genotoxic damage may respond to perturbations of chromatin structure which accompany stabilization of topoisomerase-DNA cleavable complexes.

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Kaufmann, W. K., J. C. Boyer, L. L. Estabrooks, and S. J. Wilson. "Inhibition of replicon initiation in human cells following stabilization of topoisomerase-DNA cleavable complexes." Molecular and Cellular Biology 11, no. 7 (July 1991): 3711–18. http://dx.doi.org/10.1128/mcb.11.7.3711-3718.1991.

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Diploid human fibroblast strains were treated for 10 min with inhibitors of type I and type II DNA topoisomerases, and after removal of the inhibitors, the rate of initiation of DNA synthesis at replicon origins was determined. By alkaline elution chromatography, 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine), an inhibitor of DNA topoisomerase II, was shown to produce DNA strand breaks. These strand breaks are thought to reflect drug-induced stabilization of topoisomerase-DNA cleavable complexes. Removal of the drug led to a rapid resealing of the strand breaks by dissociation of the complexes. Velocity sedimentation analysis was used to quantify the effects of amsacrine treatment on DNA replication. It was demonstrated that transient exposure to low concentrations of amsacrine inhibited replicon initiation but did not substantially affect DNA chainelongation within operating replicons. Maximal inhibition of replicon initiation occurred 20 to 30 min after drug treatment, and the initiation rate recovered 30 to 90 min later. Ataxia telangiectasia cells displayed normal levels of amsacrine-induced DNA strand breaks during stabilization of cleavable complexes but failed to downregulate replicon initiation after exposure to the topoisomerase inhibitor. Thus, inhibition of replicon initiation in response to DNA damage appears to be an active process which requires a gene product which is defective or missing in ataxia telangiectasia cells. In normal human fibroblasts, the inhibition of DNA topoisomerase I by camptothecin produced reversible DNA strand breaks. Transient exposure to this drug also inhibited replicon initiation. These results suggest that the cellular response pathway which downregulates replicon initiation following genotoxic damage may respond to perturbations of chromatin structure which accompany stabilization of topoisomerase-DNA cleavable complexes.

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Perez, Juan, Cecylia Lupala, and Patricia Gomez-Gutierrez. "Designing Type II Topoisomerase Inhibitors: A Molecular Modeling Approach." Current Topics in Medicinal Chemistry 14, no. 1 (December 31, 2013): 40–50. http://dx.doi.org/10.2174/1568026613666131113150046.

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Tennyson, Rachel B., and Janet E. Lindsley. "Type II DNA Topoisomerase fromSaccharomyces cerevisiaeIs a Stable Dimer†." Biochemistry 36, no. 20 (May 1997): 6107–14. http://dx.doi.org/10.1021/bi970152f.

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44

Mun Huang, Wai. "BACTERIAL DIVERSITY BASED ON TYPE II DNA TOPOISOMERASE GENES." Annual Review of Genetics 30, no. 1 (December 1996): 79–107. http://dx.doi.org/10.1146/annurev.genet.30.1.79.

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45

Pyke, K. A., J. Marrison, and R. M. Leech. "Evidence for a type II topoisomerase in wheat chloroplasts." FEBS Letters 242, no. 2 (January 2, 1989): 305–8. http://dx.doi.org/10.1016/0014-5793(89)80490-9.

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Mukherjee, A., S. Sen, and K. Agarwal. "Ciprofloxacin: mammalian DNA topoisomerase type II poison in vivo." Mutation Research Letters 301, no. 2 (February 1993): 87–92. http://dx.doi.org/10.1016/0165-7992(93)90029-u.

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Pocklington, Michael J., John R. Jenkins, and Elisha Orr. "The effect of novobiocin on yeast topoisomerase type II." Molecular and General Genetics MGG 220, no. 2 (January 1990): 256–60. http://dx.doi.org/10.1007/bf00260491.

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Bellon, Steven, Jonathan D. Parsons, Yunyi Wei, Koto Hayakawa, Lora L. Swenson, Paul S. Charifson, Judith A. Lippke, Robert Aldape, and Christian H. Gross. "Crystal Structures of Escherichia coli Topoisomerase IV ParE Subunit (24 and 43 Kilodaltons): a Single Residue Dictates Differences in Novobiocin Potency against Topoisomerase IV and DNA Gyrase." Antimicrobial Agents and Chemotherapy 48, no. 5 (May 2004): 1856–64. http://dx.doi.org/10.1128/aac.48.5.1856-1864.2004.

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ABSTRACT Topoisomerase IV and DNA gyrase are related bacterial type II topoisomerases that utilize the free energy from ATP hydrolysis to catalyze topological changes in the bacterial genome. The essential function of DNA gyrase is the introduction of negative DNA supercoils into the genome, whereas the essential function of topoisomerase IV is to decatenate daughter chromosomes following replication. Here, we report the crystal structures of a 43-kDa N-terminal fragment of Escherichia coli topoisomerase IV ParE subunit complexed with adenylyl-imidodiphosphate at 2.0-Å resolution and a 24-kDa N-terminal fragment of the ParE subunit complexed with novobiocin at 2.1-Å resolution. The solved ParE structures are strikingly similar to the known gyrase B (GyrB) subunit structures. We also identified single-position equivalent amino acid residues in ParE (M74) and in GyrB (I78) that, when exchanged, increased the potency of novobiocin against topoisomerase IV by nearly 20-fold (to 12 nM). The corresponding exchange in gyrase (I78 M) yielded a 20-fold decrease in the potency of novobiocin (to 1.0 μM). These data offer an explanation for the observation that novobiocin is significantly less potent against topoisomerase IV than against DNA gyrase. Additionally, the enzyme kinetic parameters were affected. In gyrase, the ATP Km increased ≈5-fold and the V max decreased ≈30%. In contrast, the topoisomerase IV ATP Km decreased by a factor of 6, and the V max increased ≈2-fold from the wild-type values. These data demonstrate that the ParE M74 and GyrB I78 side chains impart opposite effects on the enzyme's substrate affinity and catalytic efficiency.

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Austin, Caroline A., Jen-Hwei Sng, Sandhiya Patel, and L. Mark Fisher. "Novel HeLa topoisomerase II is the IIβ isoform: complete coding sequence and homology with other type II topoisomerases." Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression 1172, no. 3 (March 1993): 283–91. http://dx.doi.org/10.1016/0167-4781(93)90215-y.

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Hong, George, and Kenneth N. Kreuzer. "An Antitumor Drug-Induced Topoisomerase Cleavage Complex Blocks a Bacteriophage T4 Replication Fork In Vivo." Molecular and Cellular Biology 20, no. 2 (January 15, 2000): 594–603. http://dx.doi.org/10.1128/mcb.20.2.594-603.2000.

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ABSTRACT Many antitumor and antibacterial drugs inhibit DNA topoisomerases by trapping covalent enzyme-DNA cleavage complexes. Formation of cleavage complexes is important for cytotoxicity, but evidence suggests that cleavage complexes themselves are not sufficient to cause cell death. Rather, active cellular processes such as transcription and/or replication are probably necessary to transform cleavage complexes into cytotoxic lesions. Using defined plasmid substrates and two-dimensional agarose gel analysis, we examined the collision of an active replication fork with an antitumor drug-trapped cleavage complex. Discrete DNA molecules accumulated on the simple Y arc, with branch points very close to the topoisomerase cleavage site. Accumulation of the Y-form DNA required the presence of a topoisomerase cleavage site, the antitumor drug, the type II topoisomerase, and a T4 replication origin on the plasmid. Furthermore, all three arms of the Y-form DNA were replicated, arguing strongly that these are trapped replication intermediates. The Y-form DNA appeared even in the absence of two important phage recombination proteins, implying that Y-form DNA is the result of replication rather than recombination. This is the first direct evidence that a drug-induced topoisomerase cleavage complex blocks the replication fork in vivo. Surprisingly, these blocked replication forks do not contain DNA breaks at the topoisomerase cleavage site, implying that the replication complex was inactivated (at least temporarily) and that topoisomerase resealed the drug-induced DNA breaks. The replication fork may behave similarly at other types of DNA lesions, and thus cleavage complexes could represent a useful (site-specific) model for chemical- and radiation-induced DNA damage.

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Journal articles on the topic 'Type II topoisomerase'

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