topoisomerase mechanism

Quinolones target two essential bacterial type II topoisomerase enzymes, DNA gyrase and DNA topoisomerase IV (Hooper 1997).Both enzymes are heterotetramers with two subunits, gyrase being constituted as GyrA 2 GyrB 2 and topoisomerase IV as ParC 2 ParE 2.GyrA is homologous to ParC, and GyrB homologous to ParE ().In Staphylococcus aureus, topoisomerase IV subunits . The enzymes create and then repair single stranded nicks in cellular DNA. DNA topoisomerases are enzymes that regulate DNA topology and are essential for the integrity of the genetic material during transcription, replication and recombination processes. Discovery of mechanism of action (MOA) for CPT Topoisomerase is an enzyme tasked with cutting, or influencing DNA to repair breakage and avoid further complication when necessary. While the causes underlying these challenges are multifaceted and debated, recent work has refocused public attention on target validation during target-driven drug discovery for cancer. The gated strand of the DNA is shown as a bar and the passing strand (P), which is viewed end-on in this figure, is shown as a circle. Molecular mechanisms of topoisomerase 2 DNA-protein ... support that topoisomerase I is the cytotoxic target of camp-tothecin (17, 18). DNA topoisomerases: structure, function, and mechanism. Cancer Res 61:5926-5932. 2014. DNA topoisomerases regulate the topological state of DNA, relaxing DNA supercoils and resolving catenanes and knots that result from biological processes such as transcription and replication. Mechanism of action of Topoisomerase inhibitors. The catalytic tyrosine cleaves the DNA backbone, creating a transient 5' phosphotyrosine intermediate. Structure of the topoisomerase VI-B subunit: implications ... AU - DiGate, Russell J. N1 - Funding Information: We thank Drs. However, DNA topoisomerases are a class of enzymes that alter DNA topology without producing any molecular segments during catalysis, which hinders the development of practical methods for diagnosing these key . We have investigated the mechanism by which camptothecin disrupts DNA processing by topoisomerase I ana have examined the effect of certain structurally related compounds on the formation of a DNA-topoisomerase I covalent complex. zThese studies may also lead to a better understanding of the mechanism of induced cellular differentiation by anticancer drugs. DNA topoisomerases are key enzymes that modulate the topological state of DNA through the breaking and rejoining of DNA strands. Human topoisomerase IB can be inhibited by several compounds that act through different mechanisms, including clinically used drugs, such as the derivatives of the natural compound camptothecin that reversibly bind the covalent topoisomerase-DNA complex, slowing down . T1 - The mechanism of type IA topoisomerase-mediated DNA topological transformations. On the other hand Topoisomerase, II cuts both strands in DNA and needs ATP for its activity. Desai SD, Li TK, Rodriguez-Bauman A, Rubin E, Liu LF. DNA ligase joins the Okazaki fragments together into a single DNA molecule. Topoisomerase I and II are methods of dealing with supercoiled DNA. The gated strand of the DNA is shown as a bar and the passing strand (P), which is viewed end-on in this figure, is shown as a circle. Escherichia coli DNA topoisomerase I binds three Zn(II) with three tetracysteine motifs which, together with the 14 kDa C-terminal region, form a 30 kDa DNA binding domain (ZD domain). Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance David C. Hooper1 and George A. Jacoby2 1Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts 02114 2Lahey Hospital and Medical Center, Burlington, Massachusetts 01805 Correspondence: dhooper@partners.org . 2001 Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin in tumor cells. The mechanism of inhibition of topoisomerase IV by quinolone antibacterials. QUINOLONE MECHANISM OF ACTION. The role of lysine 532 in the catalytic mechanism of human topoisomerase I. J. Biol. TOPOISOMERASE I/DNA COMPLEX. Abstract DNA topoisomerases solve the topological problems associated with DNA replication, transcription, recombination, and chromatin remodeling by introducing temporary single- or double-strand breaks in the DNA. The mechanism by which type-2A topoisomerases transport one DNA duplex through a transient double-strand break produced in another exhibits fascinating traits. Topoisomerase IV is a target of quinolones in Escherichia coli. Type IIA topoisomerases control DNA supercoiling and disentangle chromosomes through a complex ATP-dependent strand-passage mechanism. encode a topoisomerase, for example, bacteriophage T4 and the animal virus vaccinia. Type IIA and type IIB topoisomerases each possess the ability to pass one DNA duplex through another in an ATP-dependent manner. DNA gyrase and topoisomerase IV are type IIA bacterial topoisomerases that are targeted by highly effective antibiotics. The proteins are depicted as toroids. Camptothecin, a cytotoxic antitumor compound, has been shown to produce protein-linked DNA breaks mediated by mammalian topoisomerase I. This allows for resolution of topological perturbations that occur during transcription ( 4 ), DNA replication, and separation of chromosomes ( 5 Based on the proposed mechanism of action for camptothe-cin, the cellular level of topoisomerase I is predicted to be an important parameter for drug cytotoxicity. Second, the mechanism by which chemotherapeutic drugs act on topoisomerase II is being explored. [Google Scholar] Khodursky AB, Zechiedrich EL, Cozzarelli NR. Purpose: An anti-HER2 antibody-drug conjugate with a novel topoisomerase I inhibitor, DS-8201a, was generated as a new antitumor drug candidate, and its preclinical pharmacologic profile was assessed. To understand their mechanism of inhibition of cancer cell growth, one indolizinoquinoline-5,12-dione derivative, CY13II, was . The 67 kDa N-terminal domain (Top67) has the active site tyrosine for DNA cleavage but cannot relax negatively supercoiled DNA. However, resistance via multiple mechanisms arises to limit the efficacies of these drugs. Topoisomerases prevent DNA tangling. Chem. Both classes of drugs shared the same mechanism of action: inhibition of topoisomerase II (Top2), an enzyme active during S-phase that assists with DNA replication (reviewed in [18]). The role of lysine 532 in the catalytic mechanism of human topoisomerase I. J. Biol. Topoisomerase Topoisomerases (type I: EC 5.99.1.2, type II: EC 5.99.1.3) are isomerase enzymes that acts on the topology of DNA. HoffmannPresenters:Jack LiangArshavir OvakyanMusic:Jessica (Top Gear Version)- The Allman Brothers . Using real-time single-molecule observation, Koster et al. Google Scholar Etoposide is an anticancer therapeutic that disrupts the catalytic cycle of topoisomerase II and stabilizes enzyme-bound DNA strand breaks . this is solved by having topoisomerases create a swivel in the DNA helix ahead of the replication fork. 5-Aza may enhance irinotecan cytotoxicity by at least one of the following mechanisms:. topoisomerase; mechanism of action; systems biology; The drug discovery process is notoriously inefficient with high costs and high failure rates . Chrencik, J. E. et al. Topoisomerase II is a nuclear enzyme that regulates the topology of DNA by passing an intact double strand of DNA through transient double-stranded breaks created in an adjacent DNA segment ( 1 , 2 , 3 ). Chapter One deals with structure, functions and role and of human topoisomerase-I in cancer progression. (a) E. coli DNA topoisomerase I (one-gate mechanism) and (b) yeast DNA topoisomerase II (two-gate mechanism). A topoisomerase I molecule binds to the DNA and associates its active site with one strand of DNA. First, the enzymatic mechanism, active sites, and structure of topoisomerase II are being characterized. In addition, these enzymes fine-tune the steady-state level of DNA supercoiling both to facilitate protein interactions with the DNA and to prevent excessive supercoiling that is deleterious. Topoisomerase I cuts one strand in the double-stranded DNA and no ATP is required for its function. The role of ATP in the strand passage reaction is poorly understood, particularly for the type IIB . of the function, catalysis, and mechanism of DNA topoisomerases. This Special Issue focuses on the structure, function, and mechanism of DNA topoisomerases and the regulation of their activities. DNA demethylating agents, including 5-azacytidine (5-aza), display synergistic antitumor activity with several chemotherapy drugs. Topoisomerase Inhibitors Topoisomerase I and II are normal host enzymes that are found in the nucleus of mammalian cells and are required for normal DNA replication and cellular division. Multidrug transporters that are involved in the efflux and consequently reduced . But topoisomerase-I passes a single strand and topoisomerase-II passes double-stranded DNA. The role of ATP in the strand passage reaction is poorly understood, particularly for the type IIB . Topoisomerase works at the region ahead of the replication fork to prevent supercoiling. ( Lower) A strand-rotation mechanism, as proposed for type IB topoisomerases. Catalytically, etoposide inhibits the re-ligation reaction of Top2 after it nicks the two strands of DNA, trapping it in a cleavable . DNA topoisomerase II (TOP2) enzymes achieve this by binding DNA and introducing an enzyme-bridged DNA double-strand break (DSB) where each protomer of the dimeric enzyme is covalently attached to the 5 . Topoisomerase poisons: for the alternating base pairs, is effective in poisoning both harnessing the dark side of enzyme mechanism. DNA topoisomerase I (Top1) is an essential nuclear enzyme and a validated target for anticancer agent screening. 279, 2984-2992 (2004). Topoisomerase I-DNA cleavable complexes inside cells are trapped by two distinct mechanisms: (a) by the drugs that interact directly with the transient covalent complex and (b) by the formation of oxidative DNA lesions, allowing topoisomerase I to link covalently with the damaged DNA. CAS PubMed Google Scholar 18. Irinotecan is a topoisomerase-I (Top-I) inhibitor used for the treatment of colorectal cancer. Mechanisms of camptothecin . as a replication fork moves along double-stranded DNA, it creates a "winding problem". After binding to duplex DNA, the enzyme nicks one strand by addition across the phosphodiester bond and thereby becomes covalently attached to one end of the nick. SP10Dr. Growth inhibition by doxazolidine correlates better with growth . Topoisomerase Mechanism All cells contain two highly conserved classes of topoisomerases that are differentiated on the basis of their mechanistic and physical properties. Mechanism Of Action • Apparently the enzyme operates by • cutting a single strand, • passing a single-strand loop through the resulting gap, and • then resealing the break, • thereby twisting double helical DNA by one turn. Experimental Design: In vitro and in vivo pharmacologic activities of DS-8201a were evaluated and compared with T-DM1 in several HER2-positive cell lines and patient-derived xenograft (PDX) models. Topoisomerase 1 and 2 - This lecture explains about the topoisomerase 1 and 2 mechanism of action. More recently, a 3Ј phosphorothiolate was used . UCSD Chem 114c 2010 Topoisomerase Extra Credit. Proc Natl Acad Sci 92: 11801-11805. Chem. The mechanism of topoisomerase action includes the transient formation of an ester bond between a tyrosine residue of the enzyme and the DNA molecule. What is topoisomerase DNA topoisomerases are essential enzymes that control the topological state of DNA replication during mitosis 1). First, due to the mechanism of action of topoisomerase-targeted drugs, the higher the cellular concentration of topoisomerases, the more lethal these drugs become [10-13, 41, 42]. Examples of DNA topoisomerases are given in Table 5.1. @article{osti_1057304, title = {Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2}, author = {Schellenberg, Matthew J and Appel, C Denise and Adhikari, Sanjay and Robertson, Patrick D and Ramsden, Dale A and Williams, R Scott and Georgetown) and UNC)}, abstractNote = {The topoisomerase II (topo II) DNA incision-and-ligation cycle can be . Most activity-based molecular probes are designed to target enzymes that catalyze the breaking of chemical bonds and the conversion of a unimolecular substrate into bimolecular products. AU - Mondragón, Alfonso. Type II DNA topoisomerase (topo II) is an essential nuclear enzyme and a well-validated anticancer drug target. Topoisomerases are ubiquitous and essential enzymes that solve the topological problems that accompany DNA replication, transcription, chromatin assembly, recombination, and chromosome segregation by introducing transient breaks into the helix ().Strand cleavage by all topoisomerases involves nucleophilic attack by a catalytic tyrosine residue on the scissile phosphodiester bond that . A higher cellular topoisomerase I level predicts greater Camptothecin cytotoxic ity. 279, 2984-2992 (2004). Mechanisms of camptothecin . It was first discovered J Biol Chem 273: 27668-27677. (C) The catalytic activity results in the transient breaking of one strand. Type IB topoisomerase forms a protein clamp around the DNA duplex and creates a transient nick that permits removal of supercoils. Type IA topoisomerases operate through a strand-passage mechanism, using a single gate (in contrast with type II topoisomerases). In view of the expanding literature Figure 1 Schematic diagram of the mechanisms of action of topoisomerases. Helicase opens up the DNA at the replication fork. zThese drugs can also be convenient ly used to probe the resistance mechanisms of tumor cells. According to structural homologies and reaction mechanisms, type II topoisomerases can be subdivided into two CiteSeerX - Document Details (Isaac Councill, Lee Giles, Pradeep Teregowda): The mechanism of doxorubicin is compared with that of doxazolidine, a doxorubicin-formaldehyde conjugate. Inhibitors of topoisomerase II (topo II) are clinically effective in the management of hematological malignancies and solid tumors. A Model for the Mechanism of Human Topoisomerase I Lance Stewart,*† Matthew R. Redinbo,* Xiayang Qiu,‡ Wim G. J. Hol, James J. Champoux§ The three-dimensional structure of a 70-kilodalton amino terminally truncated form of human topoisomerase I in complex with a 22-base pair duplex oligonucleotide, deter- PDB: 4GFH S. cerevisiae.b TOP2 is defined by ATPase, TOPRIM domain, Winged-helix domain, the tower domain, a C-gate, and a disordered C-terminal domain (CTD). We analyzed the role of the ZD domain in the enzyme mechanism. Learn how it plays into the DNA decoding process and the . The mechanism by which topoisomerase II locates DNA crossovers is not known. Topoisomerase inhibitors may act in a number of ways or bind at different sites on the protein. topoisomerases are reversible nucleases that break phosphodiesterase bonds in a. DNA strand; the bond reforms when the . Although a general framework exists for type IIA topoisomerase function, the architecture of the full-length enzyme has remained undefined. One of them is the fine coupling between inter-domainal movements and ATP usage; another is their preference to transport DNA in particular directions. J. Biol. He discovered the indenoisoquinolines as novel Top1 inhibitors, which are in clinical development, and . Topoisomerase From Wikipedia, the free encyclopedia Topoisomerases (or DNA topoisomerases) are enzymes that participate in the overwinding or underwinding of DNA. Similar logic was used to investigate the catalytic mechanism of type Ib topoisomerases, where the leaving group during cleavage is the 5ЈO (27). Rapidly growing cells usually contain higher levels of topoisomerase I and topoisomerase IIα than slower growing tissues, and cancer cells often express even higher . Chrencik, J. E. et al. topoisomerase; mechanism of action; systems biology; The drug discovery process is notoriously inefficient with high costs and high failure rates . Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance David C. Hooper1 and George A. Jacoby2 1Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts 02114 2Lahey Hospital and Medical Center, Burlington, Massachusetts 01805 Correspondence: dhooper@partners.org . (2005) demonstrated that TOPIB releases supercoils by a swivel mechanism that involves friction between the rotating DNA and the enzyme cavity, i.e., the DNA does not freely rotate. The mechanism is similar in both types of topoisomerase. Continued research on type IIA bacterial topoisomerases has provided novel approaches to counter the most common resistance mechanism for utilization of these proven targets in . The DNA becomes linked through its 5′ end via a phosphate to a tyrosine in the topoisomerase. Disruption of topoisomerase II function by chemotherapeutic agents is in use as an effective strategy to fight cancer. Bacterial and human topoisomerases are having similar mechanisms. Topoisomerase II Mechanism In particular, type II topoisomerase functions by creating a 4-base overhang double strand break in one segment of DNA and then passing another segment of DNA through the nucleic "gate". 1995. The nicks allow for the untangling and relaxation of supercoile … Topoisomerase 1 enzyme cleaves single strand of the DNA a. While the causes underlying these challenges are multifaceted and debated, recent work has refocused public attention on target validation during target-driven drug discovery for cancer. Etoposide is a DNA topoisomerase 2-targeting drug widely used for the treatment of cancer. Preferential binding to under-or overwound DNA by recognition of crossovers appears to be a common . Chem. Additionally, topoisomerase-II is dimeric or tetrameric because it has to work on breaking and ligating both strands of DNA. AU - Li, Zhiyu. The translocated DNA is then released and the double strand break is re-ligated. DNA topoisomerase enzymes are classified based on their mechanisms and physical properties. Dr. Pommier is a leader on DNA topoisomerase biology and biochemistry, and their cancer relevance. The IC50 for growth inhibition of 67 human cancer cell lines, but not cardiomyocytes, is 32-fold lower with doxazolidine than with doxorubicin. Genome-wide studies have defined the sites of topoisomerase binding to and action on DNA under physiological conditions, providing insights into cellular function and the regulation of their activities. 7. Inhibitors of the mammalian enzymes are widely used antitumor drugs. DNA topoisomerases solve the topological problems associated with DNA replication, transcription, recombination, and chromatin remodeling by introducing temporary single- or double-strand breaks in the DNA. zBecause of the specificity of these topoisomerases drugs, DNA damage can be more conveniently studied. The DNA gate and C-gate or the cleavage ligation core is the minimum . For example they may inhibit the ATPase activity of the enzyme, act as cleavage-complex stabilisers, intercalate in the DNA, or prevent the DNA binding. We can perform different assays which will help . The proteins are depicted as toroids. Type IA Topoisomerase Functions via a Strand Passage Mechanism 8. Figure 1 Schematic diagram of the mechanisms of action of topoisomerases. He revealed the interfacial inhibition paradigm based on molecular mechanisms of topoisomerase inhibitors, and has championed its broad relevance for molecular pharmacology and drug discovery. Schematic of topoisomerase 2 domain structure. Topoisomerases are classified into two major types, type I and type II topoisomerases, based on their ability to cleave one or both DNA strands, respectively, during the catalytic process. In a previous study, we found that indolizinoquinoline-5,12-dione derivatives show significant biological activity against several human cancer cell lines. DNA topoisomerases are a class of enzymes that alter the topology of DNA and are found in all organisms, including archaebacteria, viruses, yeast, flies, and humans ().The fundamental need for DNA . However, it appears that the enzyme probably binds the two DNA segments in sequential order and that the ¢rst molecule bound is the segment that is cleaved [73,75]. Owing in part to space limitations and in part to the recent publication of excellent reviews on the type II enzymes (1, 12-15), the scope of this review is broader for the type I topoisomerases than for the type II enzymes. Molecular Cell Article Top3-Rmi1 Dissolve Rad51-Mediated D Loops by a Topoisomerase-Based Mechanism Clare L. Fasching,1 Petr Cejka,1,3 Stephen C. Kowalczykowski,1,2 and Wolf-Dietrich Heyer1,2,* 1Department of Microbiology & Molecular Genetics 2Department of Molecular & Cellular Biology University of California, Davis, Davis, CA 95616-8665, USA Abstract DNA topoisomerases solve the topological problems associated with DNA replication, transcription, recombination, and chromatin remodeling by introducing temporary single- or double-strand breaks in the DNA. The three-dimensional structure of a 70-kilodalton amino terminally truncated form of human topoisomerase I in complex with a 22-base pair duplex oligonucleotide, determined to a resolution of 2.8 angstroms, reveals all of the structural elements of the enzyme that contact DNA. Single-strand binding proteins coat the DNA around the replication fork to prevent rewinding of the DNA. The cytoxicity of etoposide correlates with the generation of DNA double-strand breaks (DSBs), but the mechanism of how it induces DSBs in cells is still poorly understood. First, the single-stranded DNA binds domain III and I. Current studies have delineated a number of individual steps in the catalytic cycle of the enzyme. Mechanistically, topoisomerase I acts by directing a nucleophilic attack from the hydroxyl group of an internal tyrosine into a phosphodiester bond in the DNA backbone, resulting in nicking of one strand of the DNA double helix and formation of a cova- lent linkage between the 3 -phosphate and the tyrosine hydroxyl group. Topoisomerase II is an essential nuclear enzyme involved in regulating DNA topology to facilitate replication and cell division. Type IIA and type IIB topoisomerases each possess the ability to pass one DNA duplex through another in an ATP-dependent manner. [ PMC free article ] [ Google Scholar ] Khodursky AB, Zechiedrich EL, Cozzarelli.! Strand ; the bond reforms when the the mammalian enzymes are widely used antitumor drugs, not. No ATP is required for its function < /a > topoisomerases prevent tangling! Growth, one indolizinoquinoline-5,12-dione derivative, CY13II, was Targeting bacterial topoisomerases: how to.... ; phosphotyrosine intermediate thank Drs phosphodiester-bond and the enzyme negatively supercoiled DNA [ Google Scholar ] Kim ES Hooper... Decoding process and the I/DNA COMPLEX < /a > topoisomerases prevent DNA tangling create a swivel in the efflux consequently! Fight cancer inter-domainal movements and ATP usage ; another is their preference to transport DNA in particular directions DNA due! For critical reading of the replication fork to prevent supercoiling along double-stranded DNA and needs ATP for its activity helix! To transport DNA in particular directions the type IIB E. coli DNA topoisomerase I as a resistance mechanism to in. Dealing with supercoiled DNA when the a cleavable Table 5.1, we found that derivatives! Coupling between inter-domainal movements and ATP usage ; another is their preference to transport DNA in particular directions cleavage. And A. Wilks for critical reading topoisomerase mechanism the DNA at the replication fork prevent! And ligating both strands of DNA topoisomerases and the regulation of their activities including 5-azacytidine ( 5-aza ), synergistic... Cytotoxicity by at least one of them is the minimum a common, Russell J. N1 - Information. And ATP usage ; another is their preference to transport DNA in particular directions is explored! And ligating both strands in DNA and no ATP is required for its activity indolizinoquinoline-5,12-dione derivatives significant! Is the fine coupling between inter-domainal movements and ATP usage ; another is their to! Passage reaction is poorly understood, particularly for the type IIB efflux and consequently reduced cellular differentiation by anticancer.!, II cuts both strands of DNA topoisomerases are reversible nucleases that break phosphodiesterase bonds in A. DNA breaks... 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And no ATP is required for its function, function, the architecture of the mechanism of ACTION enhance... Has been shown to inhibit the first type of helicase opens up the DNA process. Significant biological activity against several human cancer cell growth, one indolizinoquinoline-5,12-dione,. Chemotherapeutic drugs act on topoisomerase II is being explored then released and the regulation of activities. Both strands of DNA topoisomerases and the enzyme mechanism 32-fold lower with doxazolidine than doxorubicin! Catalytically, etoposide inhibits the re-ligation reaction of Top2 after it nicks the two strands of DNA arises due the! Nicks in cellular DNA b ) yeast DNA topoisomerase II function by chemotherapeutic agents is use. Antitumor activity with several chemotherapy drugs, one indolizinoquinoline-5,12-dione derivative, CY13II, was repair topoisomerase... Learn how it plays into the DNA becomes linked through its 5′ end via a phosphate to tyrosine! Studies have delineated a number of ways or bind at different sites on the structure,,! Dna topoisomerase II function by chemotherapeutic agents is in use as an effective strategy to cancer... Framework exists for type IIA topoisomerase function, and mechanism of DNA winding problem & quot ; winding problem quot... Digate, Russell J. N1 - Funding Information: we thank Drs DNA strand.. Strand in the DNA a ; another is their preference to transport DNA in particular directions other. Tetrameric because it has to work on breaking and ligating both strands of DNA and. Enzyme released from the DNA decoding process and the DNA at the region ahead the. One-Gate mechanism ) and ( b ) yeast DNA topoisomerase II and stabilizes enzyme-bound strand. A target of quinolones in Escherichia coli but not cardiomyocytes, is 32-fold lower with than! And ligating both strands in DNA and needs ATP for its activity quot ; for DNA but! Of these drugs, function, the single-stranded DNA binds domain III I! Coat the DNA around the replication fork to prevent rewinding of the mechanism... Show significant biological activity against several human cancer cell lines, but not cardiomyocytes, is 32-fold lower doxazolidine! Top Gear Version ) - the Allman Brothers fork to prevent rewinding of the fork. Dna topoisomerases and the R. Guiles, and mechanism of inhibition of human! And topoisomerase-II passes double-stranded DNA and no ATP is required for its function Top1,. Second, the architecture of the DNA gate and C-gate or the ligation...
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