Hence, CcdB-binding would promote the formation of a DSB [241]. Structural studies revealed the presence of an hTop 2-specific methionine residue that may be exploitable for this purpose [124,199]. An official website of the United States government. Camptothecin (Fig. Genet. Commun. Neurosci. 29, 740748 (2010). (Textbook of pharmacology and therapeutics; mentions that irinotecan and topotecan are the only camptothecin analogues approved for clinical use and have activity in colorectal, ovarian and small cell lung cancer, and both can cause elevations in serum aminotransferase levels). Nucleic Acid. The strand breakage site-specific drug binding physically blocks the religation reaction [136,137]. sharing sensitive information, make sure youre on a federal (1988), Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q2122, Austin CA, Sng JH, Patel S, Fisher LM (1993), Novel HeLa topoisomerase II is the II beta isoform: complete coding sequence and homology with other type II topoisomerases, Construction, characterization, and complementation of a conditional-lethal DNA topoisomerase II mutant human cell line, McClendon AK, Rodriguez AC, Osheroff N (2005), Human topoisomerase II rapidly relaxes positively supercoiled DNA - Implications for enzyme action ahead of replication forks, Plk1-dependent phosphorylation regulates functions of DNA topoisomerase II in cell cycle progression, Ramamoorthy M, Tadokoro T, Rybanska I, Ghosh AK, Wersto R, May A, et al. The main pathway for ROS formation by anthracyclines is the formation of semiquinone radicals resulting in redox cycling [283,285]. Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Tuduri, S. et al. Targeting of an antitumor agent ICRF-159, Catalysis of ATP hydrolysis by two NH(2)-terminal fragments of yeast DNA topoisomerase II, Steady-state and Rapid Kinetic Analysis of Topoisomerase II Trapped as the Closed-clamp Intermediate by ICRF-193, Sehested M, Jensen PB, Srensen BS, Holm B, Friche E, Demant EJ (1993), Antagonistic effect of the cardioprotector (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187) on DNA breaks and cytotoxicity induced by the topoisomerase II directed drugs daunorubicin and etoposide (VP-16), Hasinoff BB, Kushchak TI, Yalowich JC, Creighton AM (1995), A QSAR study comparing the cytotoxicity and DNA topoisomerase inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane), DNA gyrase: subunit structure and ATPase activity of the purified enzyme, Sugino A, Higgins NP, Brown PO, Peebles CL, Cozzarelli NR (1978), Energy coupling in DNA gyrase and the mechanism of action of novobiocin, Lewis RJ, Singh OM, Smith CV, Skarzynski T, Maxwell A, Wonacott AJ, et al. Structural analysis of the catalytic core (the 55-kDa DNA breakage-reunion domain of the ParC subunit plus the 30-kDa Toprim domain of the ParE subunit) of Streptococcus pneumoniae Top 4 complexed with DNA and fluoroquinolones (including moxifloxacin, clinafloxacin, and levofloxacin) provided the first visualization of drug-stabilized type IIA topoisomerase cleavage complexes [33]. Several toxins and regulatory proteins that target DNA gyrase have been identified and characterized in bacteria [26,219,220]. It is used to treat ALL, AML, chronic myelogenous leukemia (CML), and Kaposis sarcoma [314317]. (2003), Genomic anatomy of the specific reciprocal translocation t(15;17) in acute promyelocytic leukemia, Hasan SK, Mays AN, Ottone T, Ledda A, La Nasa G, Cattaneo C, et al. Nature 522, 8993 (2015). It has been demonstrated that the E-ring exists in equilibrium between lactone (closed-ring) and carboxylate (open-ring) forms under physiological condition [138]. 42, 72597267 (2014). (2016), Destruction of vasculogenic mimicry channels by targeting epirubicin plus celecoxib liposomes in treatment of brain glioma, Frederick CA, Williams LD, Ughetto G, Van der Marel GA, Van Boom JA, Rich A (1990), Structural comparison of anticancer drug-DNA complexes: adriamycin and daunomycin, Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, et al. Unlike bisdioxopiperazine compounds that act as uncompetitive inhibitors, the aminocoumarin antibiotic novobiocin (Fig. B. Nat. 2). Where do topoisomerase bind? Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Type IIA topoisomerase (Top 2) poisons. 1192-3. FOIA This information should facilitate the development of new type IB topoisomerase poisons. 2) [16,41], the catalytic cycle of type IIA topoisomerases starts from the binding of the G-segment DNA to the enzyme, a process corresponding to the assembly of the so-called DNA gate [44,113]. (2011), Use of divalent metal ions in the DNA cleavage reaction of topoisomerase IV, GHKL, an emergent ATPase/kinase superfamily, Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187, Bellon S, Parsons JD, Wei YY, Hayakawa K, Swenson LL, Charifson PS, et al. Proc. Thus, it seems reasonable to develop hTop 2-specific poisons as anticancer drugs to prevent the therapy-related leukemia and cardiotoxicity. Natl Acad. The Cleavage of the G-segment followed by pulling the broken DNA ends apart creates a path that allows the T-segment to go through. Despite their effectiveness, these drugs have limitations due to their instability and severe side effects, as well as drug resistance caused by P-glycoprotein [175,176]. Sci. They are essential during transcription and replication, and topoisomerase inhibitors are among the most effective and most commonly used anticancer and antibacterial drugs. 3) is an asymmetric molecule with only one methyl group present in the 2-carbon linker that connects the two piperazinedione moieties [242,243]. Telomerase activity is exhibited in gametes and stem and tumor cells. The https:// ensures that you are connecting to the 13th ed. Conceivably, this weak protein-DNA interface can be easily ruptured by the stored superhelical tension, and the downstream DNA can then rotate about the cleavage site by one or more turns until all torsional strains are released or the break is resealed. Proc. Lyu, Y. L. & Wang, J. C. Aberrant lamination in the cerebral cortex of mouse embryos lacking DNA topoisomerase II. In addition, it is also required for development and the survival of some neural cells [8587]. (2013), Negative regulation of mitochondrial transcription by mitochondrial topoisomerase I, Douarre C, Sourbier C, Dalla Rosa I, Brata Das B, Redon CE, Zhang H, et al. (2015), Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin, Blower TR, Williamson BH, Kerns RJ, Berger JM (2016), Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis, Laponogov I, Pan XS, Veselkov DA, Cirz RT, Wagman A, Moser HE, et al. (1996), Differential expression of the topoisomerase II and genes in human breast cancer, Regulation of the human topoisomerase IIalpha gene promoter in confluence-arrested cells, The cell cycle-coupled expression of topoisomerase IIalpha during S phase is regulated by mRNA stability and is disrupted by heat shock or ionizing radiation, Turley H, Comley M, Houlbrook S, Nozaki N, Kikuchi A, Hickson ID, et al. Once the DNA torsional strain has been relieved, the topoisomerase reseals the relaxed double helix. NB-506 is a DNA intercaltor that can poison hTop 1 [142,143]. Importantly, the A. baumannii Top 4 structure revealed the chelation of a Mg2+ molecule by the C-3, C-4 diketo moiety of moxifloxacin (Fig. Its cardioprotective mechanism is attributed to the chelation of iron by dexrazoxane, thus decreasing the production of ROS during anthracycline treatment [340,341]. 3) is an anthracycline antibiotic originally isolated from Streptomyces peucetius [303,304]. Dexrazoxane: how it works in cardiac and tumor cells. On the other hand Topoisomerase, II cuts both strands in DNA and needs ATP for its activity. Sci. Chem. Moreover, the C-terminal tail of YacG fits into a hydrophobic pocket on the surface of GyrB that is also targeted by the oxathiolo-pyridine group of NBTIs [191], which further stabilizes the inhibitory complex. Human cells also contain two type IA topoisomerases, hTop 3 and hTop 3. https://doi.org/10.1038/nrn.2016.101, DOI: https://doi.org/10.1038/nrn.2016.101. DNA topoisomerase-I works in the unwinding of double-stranded DNA. 4) [240]. Therefore, it would be clinically desirable to have an anticancer drug that preferentially targets hTop 2. Thus, a heterotetrameric type II topoisomerase can be converted into a homodimeric type II topoisomerase by gene fusion. Yang, X., Li, W., Prescott, E. D., Burden, S. J. mTop 1 plays critical roles in transcription and DNA replication of circular mitochondrial DNA [64,65]. The swivel function of eukaryotic Top 1 is essential for removing DNA superhelical tension that arises during both DNA replication and transcription [4752]. We apologize to the many colleagues whose work is only briefly discussed or excluded due to space limitations. Irinotecan and topotecan are derived from camptothecins, cytotoxic compounds which were initially isolated from the bark of the Chinese tree, Camptotheca acuminata. First, it binds to the parental DNA ahead of the replication fork. Unfortunately, this unique mode of action is . Interestingly, many clinically successful inhibitors of hTop 1 and hTop 2, as well as bacterial type IIA topoisomerase inhibitors, utilize mechanism 3, which is often referred to as topoisomerase poisoning [6, 2431]. Topoisomerases serve to maintain both the transcription and replication of DNA. Thus, topoisomerases remain as important therapeutic targets of anticancer agents. What is the difference between topoisomerase and gyrase? Doxorubicin (Fig. 16, 15231529 (2013). In the absence of topoisomerase, supercoiling tension would increase to the point where DNA could fragment. The bound G-segment is primarily anchored by interacting with the helix-turn-helix motifs of the WHD domains and is bent into a U-shape by a pair of conserved isoleucine residues that intercalate into DNA at sites 12 base pairs apart [126]. Biochemical and structural studies suggest that these DNA-mimicking proteins may interact with the primary DNA-binding groove of DNA gyrase (and perhaps Top 4), thereby blocking the binding of the G-segment (Fig. A large number of small molecules have been identified as inhibitors of hTop 1 or hTop 2. Gan To Kagaku Ryoho. Topoisomerase activity is particularly increased in rapidly dividing and in cancer cells. Despite the lack of structural similarities between hTop 1, a type IB topoisomerase, and hTop 2s, type IIA topoisomerases, some small molecules, including our novel quinolones, have been shown to act as dual catalytic inhibitors of hTop 1 and hTop 2s. Although simocyclinone D8 can bind to the GyrB subunit of gyrase [231], it binds primarily to the GyrA subunit of gyrase (Fig. Chen, S. H., Chan, N. L. & Hsieh, T. S. New mechanistic and functional insights into DNA topoisomerases. It is not clear, however, if the effect of camptothecins on mTop 1 contribute to the anticancer activities of these drugs. and transmitted securely. The exit gate corresponds to the C-terminal dimerization interface that is usually observed in the closed state [33,4244,113,123,128,129]. Linka, R. M. et al. Genet. Neurosci. Nat. Studies from the authors laboratories were supported in part by National Institutes of Health grants GM59465, AI087671, and T326M008365, and Ministry of Science and Technology grants 1062113-M-002021-MY3 and 1042911-I-002302. Unable to load your collection due to an error, Unable to load your delegates due to an error, LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. C. Type IB topoisomerase (Top 1) poisons. Irinotecan (CPT-11, Campostar) (Fig. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. What is the function of Primase in DNA replication? In contrast, elevated levels of topoisomerases would increase the potency of topoisomerase poisons [39]. This duplex passage event is likely driven by the hydrolysis of one ATP and a clockwise rotation of the N-gate, which not only pushes the T-segment through the DNA-gate but also causes the upper cavity enclosed by the N-gate to collapse to prevent the T-segment from moving backward. Dexrazoxane is the only drug approved to treat cardiotoxicity caused by anthracyclines [337339]. Top 2 is required for DNA replication and chromosome segregation [7780], and its expression is significantly elevated in proliferating and cancer cells [8184]. sharing sensitive information, make sure youre on a federal 16, 144154 (2015). Chem. Maintaining genome stability in the nervous system. Sugino, K. et al. Nature 461, 674678 (2009). King, I. F. et al. Upon the binding of an NBTI, the two cohesive DNA ends can no longer slide against one another. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, Camptothecin and taxol: discovery to clinic-thirteenth Bruce F. Cain Memorial Award Lecture, Hsiang YH, Hertzberg R, Hecht S, Liu LF (1985), Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I, Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin, Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin, Tsao YP, Russo A, Nyamuswa G, Silber R, Liu LF (1993), Interaction between Replication Forks and Topoisomerase I-DNA Cleavable Complexes: Studies in a Cell-free SV40 DNA Replication System, Chrencik JE, Staker BL, Burgin AB, Pourquier P, Pommier Y, Stewart L, et al. MfpA and Qnr adopt a quadrilateral -helix fold, with overall dimensions and distribution of negatively charged groups on their protein surface markedly resembling features of B-form DNA [222225]. I am currently continuing at SunAgri as an R&D engineer. Natl Acad. (2005), Molecular basis of gyrase poisoning by the addiction toxin CcdB, A strand-passage conformation of DNA gyrase is required to allow the bacterial toxin, CcdB, to access its binding site, Herman EH, Witial DT, Hellmann K, Waravdekar VS (1982), Biological properties of ICRF-159 and related bis(dioxopiperazine) compounds, Ishida R, Miki T, Narita T, Yui R, Sato M, Utsumi KR, et al. DNA Repair (Amst.) 3) is a potent anticancer drug that can be used to treat many cancers. Given that ICRF-187 on its own does not exhibit appreciable affinity toward the ATPase domain, it appears that the ATP-induced closure of the entry gate is required prior to the binding of ICRF-187. (2011), Genz-644282, a novel non-camptothecin topoisomerase I inhibitor for cancer treatment, Houghton PJ, Lock R, Carol H, Morton CL, Gorlick R, Anders Kolb E, et al. (2000), Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus T 6040. The development of either isoform-specific hTop 2 poisons or potent hTop 2 catalytic inhibitors may provide safer therapeutic options for cancer patients. Natl Acad. A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. What role do topoisomerases play in replication? Easily accessible podophyllotoxin is used in the synthesis of etoposide (Etopophos, VePesid, VP-16) and teniposide (Vumon, VM-26) [296]. A major incentive for developing new compounds against bacterial type IIA topoisomerases is to overcome the growing resistance to quinolone antibacterial agents. The function of DNA polymerase is essential for passing on genetic information. Learn Test Match Created by Margaret_Iaccarino Terms in this set (12) effect of moving polymerase on supercoiling of DNA -causes positive supercoiling in front of opening fork --> piling up of supercoils --> creates resistance, hinders helix opening solution to resistance to DNA opening -topoisomerase topoisomerase The DNA damage response: making it safe to play with knives. Aguilera, A. Neurosci. However, more conformational states of type IIA topoisomerases, such as the opening of DNA gate, would be required to understand how the opening and closing of these gates are coordinated. Repair of topoisomerase I-mediated DNA damage. Topoisomerase II is required for proper retinal development and survival of postmitotic cells. The structure of hTop 1 in complex with a DNA duplex containing an 8-oxoG lesion suggests the enzyme may adopt an inactive conformation in which the catalytic tyrosine bends away from the active site [149]. Lyu, Y. L. et al. Cell 160, 367380 (2015). As the name suggests, it helps in changing the DNA topology. Teniposide is less water soluble and has higher plasma protein binding than etoposide [301,302]. Precisely how topoisomerases regulate genome dynamics within the nervous system is therefore a crucial research question. It is often used to treat ovarian and small cell lung cancer [153155,169].
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