• With the exception of reverse gyrase, this unique type IA topoisomerase does require ATP and generates positive DNA supercoils rather than unwinding them. (jove.com)
  • DNA gyrase supports replication and transcription with its unique supercoiling activity, whereas Topo IV preferentially relaxes (+) supercoils and is a decatenating enzyme required for chromosome segregation. (rcsb.org)
  • Here we report the crystal structure of the C-terminal domain of Topo IV ParC subunit (ParC-CTD) from Bacillus stearothermophilus and provide a structure-based explanation for how Topo IV and DNA gyrase execute distinct activities. (rcsb.org)
  • Although the topological connectivity of ParC-CTD is similar to the recently determined CTD structure of DNA gyrase GyrA subunit (GyrA-CTD), ParC-CTD surprisingly folds as a previously unseen broken form of a six-bladed beta-propeller. (rcsb.org)
  • Propeller breakage is due to the absence of a DNA gyrase-specific GyrA box motif, resulting in the reduction of curvature of the proposed DNA binding region, which explains why ParC-CTD is less efficient than GyrA-CTD in mediating DNA bending, a difference that leads to divergent activities of the two homologous enzymes. (rcsb.org)
  • The first type II topoisomerase to be discovered was DNA gyrase from bacteria, by Martin Gellert and coworkers in 1976, and also characterized by Nicholas Cozzarelli and co-workers. (wikipedia.org)
  • DNA gyrase catalyzes the introduction of negative supercoils into DNA and is the only type II enzyme to do this, all the others catalyze DNA relaxation. (wikipedia.org)
  • The exception among the type I topoisomerases, reverse gyrase, which contains a helicase domain (EC 3.6.4.12) and introduces positive supercoiling in an ATP-dependent manner. (wikipedia.org)
  • In the case of gyrase, a substantial amount of the free energy from ATP hydrolysis is transduced into torsional stress in DNA, i.e. supercoiling is an energy-requiring process. (wikipedia.org)
  • Further, in the absence of ATP, gyrase is able to remove negative supercoils in a slower DNA relaxation reaction. (wikipedia.org)
  • eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. (embl.de)
  • So there are many different types of topoisomerases but we'll be looking at topoisomerase II, also called DNA gyrase, and topoisomerase IV. (osmosis.org)
  • It inhibits bacterial topoisomerase IV and DNA gyrase (topoisomerases type II), enzymes required for DNA replication, transcription, repair, and recombination. (medscape.com)
  • The targets of quinolone activity are the bacterial DNA gyrase and topoisomerase IV, enzymes essential for DNA replication and transcription. (cdc.gov)
  • DNA gyrase and topoisomerase IV. (cdc.gov)
  • In this study we focused our attention on the behavior of four nuclear matrix proteins during the various stages of apoptosis in the HL-60 cell line exposed to the DNA topoisomerase I inhibitor, camptothecin. (nih.gov)
  • 3,5] The additive/synergistic effect of sequential topoisomerase I and II inhibitor administration has been examined in vivo in several phase I and II human trials that explored their sequential administration. (cancernetwork.com)
  • Topotecan is a novel topoisomerase I inhibitor that may have a role in the adjuvant chemotherapy of several solid tumors, including malignant glioma. (aspetjournals.org)
  • We are using this deletion set to identify all yeast genes that confer sensitivity to drugs targeting DNA topoisomerase II. (aacrjournals.org)
  • Interestingly, all three mutants also showed only modest effects on sensitivity to the topoisomerase I targeting agent camptothecin. (aacrjournals.org)
  • Our results may also provide important clues to the differences in cellular responses to drugs targeting such as camptothecin, that target topoisomerase I and drugs such as etoposide that target topoisomerase II. (aacrjournals.org)
  • Camptothecin (CPT) analogues and derivatives serve as a novel class of effective anticancer agents that exert their action against DNA topoisomerase I. This paper presents procedures for the rapid, high frequency regeneration of a camptothecin producing plant, Ophiorrhiza prostrata D. Don from leaf and internode explants via shoot organogenesis. (ejbiotechnology.info)
  • 3] This antagonism might be related to topoisomerase I inhibition of DNA synthesis, which is required for the cytotoxic effect of topoisomerase II-induced cleavable complexes. (cancernetwork.com)
  • High micromolar concentrations of topotecan, which are unlikely to be achieved in plasma in human patients in vivo , were cytotoxic within 48 hr, induced DNA fragmentation, did not induce major cell cycle changes, failed to consistently alter BCL-2 or BAX protein levels but inhibited RNA synthesis and induced cleavable DNA/topoisomerase I complex formation. (aspetjournals.org)
  • Prolonged exposure for 72 hr to high nanomolar to low micromolar concentrations of topotecan augmented p21 protein levels and induced G2/M arrest but failed to consistently alter BCL-2 and BAX protein levels, did not induce significant DNA/topoisomerase I complex formation and did not inhibit RNA synthesis. (aspetjournals.org)
  • Quinolones inhibit two enzymes that are required for bacterial DNA synthesis, i.e. (cdc.gov)
  • The unbroken DNA strand is then passed through the gap in the broken strand into the upper cavity of the enzyme. (jove.com)
  • Finally, the enzyme ligates the broken ends of the DNA strands back together and produces a locally relaxed DNA molecule. (jove.com)
  • The enzyme creates a double strand break in one loop of the DNA double helix before helping the unbroken loop to pass through this break via an ATP-dependent reaction. (jove.com)
  • The enzyme rotates the cut single-strand around the opposite strand, untwisting the DNA in the process. (jove.com)
  • the enzyme responsible, eukaryotic topo I, has a distinct mechanism and is representative of the type IB family. (wikipedia.org)
  • This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. (cancerindex.org)
  • This enzyme catalyzes the transient breaking and rejoining of a single strand of DNA which allows the strands to pass through one another, thus altering the topology of DNA. (cancerindex.org)
  • The crystal structures of human topoisomerase I comprising the core and carboxyl-terminal domains in covalent and noncovalent complexes with 22-base pair DNA duplexes reveal an enzyme that 'clamps' around essentially B-form DNA. (embl.de)
  • The core domain and the first eight residues of the carboxyl-terminal domain of the enzyme, including the active-site nucleophile tyrosine-723, share significant structural similarity with the bacteriophage family of DNA integrases. (embl.de)
  • Type-II DNA topoisomerases resolve DNA entanglements such as supercoils, knots and catenanes by passing one segment of DNA duplex through a transient enzyme-bridged double-stranded break in another segment. (elsevierpure.com)
  • These results are consistent with a scenario where the enzyme binds to one DNA for a period of ~10 s, waiting for multiple diffusional encounters with the other DNA to transport it across the break ~10 times, and then dissociates from the binding site without waiting for the exhaustion of transportable DNA segments. (elsevierpure.com)
  • The major source of transcription-associated damage in yeast is Topoisomerase I (Top1), an enzyme that removes torsional stress that accumulates when DNA strands are separated. (duke.edu)
  • Most, however, reflect enzyme incision at ribonucleotides, which are the most abundant noncanonical component of DNA. (duke.edu)
  • Under high-transcription conditions, most Top1-dependent events arise when the enzyme cleaves the non-transcribed strand of DNA. (duke.edu)
  • There are plenty of processes and enzymes involved that we can target and the quinolones and fluoroquinolones inhibit an enzyme called DNA topoisomerase. (osmosis.org)
  • Base damage and topoisomerase I (Top1)-linked DNA breaks are abundant forms of endogenous DNA breakage, contributing to hereditary ataxia and underlying the cytotoxicity of a wide range of anti-cancer agents. (whiterose.ac.uk)
  • Top1 relieves torsional stress by nicking and resealing one DNA strand, and some Top1-dependent mutations are due to trapping and processing of the covalent cleavage intermediate. (duke.edu)
  • Recent studies have demonstrated that Top1-dependent mutations exhibit a strand bias, with the nature of the bias differing depending on the transcriptional status of the underlying DNA. (duke.edu)
  • In the case of Escherichia coli DNA topoisomerase I, it has been suggested that a 30 kDa fragment moves away from the rest of the protein to create an entrance into the central hole in the protein. (rcsb.org)
  • We found that several genes also confer high levels of sensitivity to mAMSA including strains with mutations in HPR5, a helicase involved in funneling DNA lesion into recombination-repair pathways, ASF1, a chromatin assembly factor that is required for gene silencing, and CTF4, a DNA polymerase alpha binding protein important for genome stability. (aacrjournals.org)
  • This protein plays a pivotal role in DNA recombination and repair. (medscape.com)
  • Type IA forms a covalent bond with 5' end of the cleaved DNA strand and removes negative supercoils. (jove.com)
  • DNA topology refers to the crossing of the two DNA strands that alters the twist of the double helix and gives rise to tertiary conformations of DNA, such as supercoils, knots and catenanes. (wikipedia.org)
  • Type II topoisomerases resolve problematic DNA topologies such as knots, catenanes, and supercoils that arise as a consequence of DNA replication and recombination. (utmb.edu)
  • When enough supercoils are induced, the DNA condenses. (osmosis.org)
  • Topoisomerases are enzymes that relax overwound DNA molecules during various cell processes, including DNA replication and transcription. (jove.com)
  • Topological issues in DNA arise due to the intertwined nature of its double-helical structure, which, for example, can lead to overwinding of the DNA duplex during DNA replication and transcription. (wikipedia.org)
  • Since the overall chemical composition and connectivity of the DNA do not change, the DNA substrate and product are chemical isomers, differing only in their topology. (wikipedia.org)
  • T opoisomerase enzymes I and II play a critical role in preserving DNA topology by producing transient single- and double-strand DNA breaks that relieve supercoiling during replication, recombination, chromosomal decondensation, and RNA transcription. (cancernetwork.com)
  • Then, using the energy from a second ATP, Type II topoisomerase reseals the broken ends of the DNA strands and finally detaches from the DNA- leaving behind an untangled DNA helix. (jove.com)
  • They do this by binding to DNA and cutting the sugar-phosphate backbone of either one (type I topoisomerases) or both (type II topoisomerases) of the DNA strands. (wikipedia.org)
  • Type II enzymes are mechanistically distinct from type I in being ATP-dependent and transiently cleaving both DNA strands rather than just one. (wikipedia.org)
  • The double-helical structure of DNA involves the intertwining of the two polynucleotide strands around each other, which potentially gives rise to topological problems. (wikipedia.org)
  • Type-1B topoisomerases interact with duplex DNA and break one of the strands allowing one severed DNA end to pivot about the uncleaved strand. (rocabosch.com)
  • A post-translational modification with SUMO (SUMOylation) can regulate various cellular events such as DNA replication, repair, transcription and cell cycle regulation. (ku.edu)
  • The involvement of viral DNA-binding proteins in the regulation of virulence genes, transcription, DNA replication, and repair make them significant targets. (mdpi.com)
  • High levels of transcription stimulate mutation rates in microorganisms, and this occurs primarily through an enhanced accumulation of DNA damage. (duke.edu)
  • Our group has identified DNA topoisomerase IIα (Topo IIα) as one of the important mitotic proteins for SUMOylation. (ku.edu)
  • Stabilization of covalent complexes, converting topoisomerases into DNA damage, is an essential aspect of cell killing by these drugs. (aacrjournals.org)
  • Both diseases involve the BRAFT and FANCM complexes, which are important in DNA repair. (medscape.com)
  • Type I topoisomerases are ATP-independent and act by cutting a bond between nucleotides on a single strand of double stranded DNA. (jove.com)
  • Type I Topoisomerases act on one strand of double-stranded DNA, and they are further divided into three categories: IA, IB, and IC. (jove.com)
  • It creates a single-strand breakthrough which the opposite strand can pass, resulting in a locally untangled DNA molecule. (jove.com)
  • Type IB forms a covalent bond with the 3' end of the broken DNA strand and can relax both positively and negatively supercoiled DNA. (jove.com)
  • 1] The DNA strand breaks are followed by strand passage and reannealing with relief of DNA torsional strain. (cancernetwork.com)
  • [ 7 , 8 ] Sister chromatid exchanges are considered a sensitive indicator for cell genome instability, as they are thought to be the outcome of DNA double-strand breaks resulting from homologous recombination repair. (medscape.com)
  • Here we directly observed the strand passage by human topoisomerase IIα, after winding a pair of fluorescently stained DNA molecules with optical tweezers for 30 turns into an X-shaped braid. (elsevierpure.com)
  • Both types of topoisomerases cause double strand breaks in DNA, but at different points during mitosis . (osmosis.org)
  • Topoisomerase II plays a role in condensing the chromosomes by making a double strand break in the DNA so that it can be more tightly wound, causing a supercoil. (osmosis.org)
  • Topoisomerase IV plays a role later on, after the chromosome has been replicated, where it causes a double strand break in the DNA so the new DNA strand can be disentangled from the original. (osmosis.org)
  • Hin-Mediated DNA Knotting and Recombination Promote Replicon Dysfunction and Mutation , Richard W. Deibler * , Jennifer K. Mann * , De Witt L. Sumners and E. Lynn Zechiedrich. (utexas.edu)
  • DNA overwinding in a clockwise direction results in positively supercoiled DNA, whereas underwinding in a counterclockwise direction produces negatively supercoiled DNA. (jove.com)
  • Thus, when topoisomerase I inhibition occurs with agents such as SN-38 in cell lines, the cells compensate by increasing expression of topoisomerase II and vice versa. (cancernetwork.com)
  • We have found that vectors that overexpress topoisomerase II, or vectors that express a topoisomerase II mutant that is hypersensitive to DNA intercalating agents confers a high enough level of sensitivity to mAMSA to allow efficient screening of the yeast deletion strains. (aacrjournals.org)
  • Transfer of a mutant p53 gene enhanced topotecan sensitivity in wild-type p53 LN-229 but not mutant p53 LN-18 cells. (aspetjournals.org)
  • Failure to remove problematic DNA topologies prohibits cell division and can result in cell death or genetic mutation. (utmb.edu)
  • Despite their biological and clinical importance, little is understood about how a topoisomerase differentiates DNA topologies in a molecule that is significantly larger than the topoisomerase itself. (utmb.edu)
  • Now, quinolones are created to target bacterial topoisomerases, but it was soon discovered that by adding a fluorine molecule to the quinolones, they become more effective. (osmosis.org)
  • Neither short-term nor long-term topotecan toxicity was blocked by ectopic expression of bcl -2 or wild-type p53. (aspetjournals.org)
  • Closed-circular double-stranded DNA can be described by 3 parameters: Linking number (Lk), Twist (Tw) and Writhe (Wr) (Fig. 1). (wikipedia.org)
  • These enzymes regulate positive and negative DNA supercoiling without changing the nucleotide sequence. (jove.com)
  • In cell lines, the cytotoxic effect of topoisomerase I and II is scheduledependent. (cancernetwork.com)
  • Type II topoisomerases were subsequently identified from bacterial viruses and eukaryotes. (wikipedia.org)
  • This entry represents the C-terminal region of DNA topoisomerase I enzymes from eukaryotes (type IB enzymes). (embl.de)
  • While the antibody to the nucleolar isoform of DNA topoisomerase II gave a fluorescent pattern that was well-maintained until the late phases of apoptosis, the other three nuclear antigens showed marked modifications in their distribution. (nih.gov)
  • It was identified that the nuclear division cycle 80, cyclin B2 and topoisomerase 2‑α may serve important roles in adrenocortical tumor development. (cancerindex.org)
  • Palmer C, Diehn M, Alizadeh AA, Brown PO "Cell-type specific gene expression profiles of leukocytes in human peripheral blood. (openwetware.org)
  • BML mutations thus result in defects in DNA repair and genomic instability in the somatic cells, predisposing the patients to cancer development. (medscape.com)
  • Despite their frequency, the overlapping mechanisms that repair these forms of DNA breakage are largely unknown. (whiterose.ac.uk)
  • It has been proposed that type II topoisomerases recognize angle and curvature between two DNA helices characteristic of knotted and catenated DNA to account for the enzyme's preference to unlink instead of link DNA. (utmb.edu)
  • Such catastrophic consequences make topoisomerases an effective target for antibiotics and anticancer agents. (utmb.edu)
  • Additionally, supercoiling can occur when the DNA twists back on itself due to the inability of the DNA ends to freely rotate to relieve the torsional stress. (jove.com)
  • DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. (wikipedia.org)
  • Crystal structure of the Bloom syndrome helicase BLM in complex with DNA (PDB ID: 4CGZ). (medscape.com)
  • The unwinding of the DNA double helix during replication results in overwinding in regions ahead of the replication fork. (jove.com)
  • If left unchanged, this torsion would eventually stop the DNA or RNA polymerases involved in these processes from continuing along the DNA helix. (wikipedia.org)
  • We have taken advantage of newly developed yeast genomic tools to identify genes encoding DNA repair or DNA damage tolerance functions that play key roles in sensitivity to drugs targeting topoisomerases. (aacrjournals.org)
  • Unfortunately, most drugs that target DNA topoisomerase II do not accumulate in wild type yeast cells to high enough. (aacrjournals.org)
  • Here, we report that depletion of Tyrosyl DNA phosphodiesterase 1 (TDP1) sensitizes human cells to alkylation damage and the additional depletion of apurinic/apyrimidinic endonuclease I (APE1) confers hypersensitivity above that observed for TDP1 or APE1 depletion alone. (whiterose.ac.uk)
  • Agents targeting DNA topoisomerases are active against a wide range of human tumors. (aacrjournals.org)