DNA Recognition/Processing | DNA Topoisomerases: Type II

Dalvie, Esha D.; Osheroff, Neil

doi:10.1016/b978-0-12-809633-8.21378-2

Cited by 7 publications

(12 citation statements)

References 18 publications

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“…These enzymes carry out their functions as homodimers and require the presence of divalent metal ions, in addition to adenosine triphosphate (ATP), for total catalytic activity [ 16 ]. The type IIB subfamily is found in the archaea and the bacteria domain of life [ 17 ], while the type IIA subfamily is found in bacteria and mammals. The topoisomerase IIa (Top2a) and topoisomerase IIb (Top2b) isoforms are found in humans.…”

Section: Dna Topoisomerasesmentioning

confidence: 99%

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Matias-Barrios

Dong

2023

Pharmaceuticals

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DNA topoisomerase II (Top2) is essential for all eukaryotic cells in the regulation of DNA topology through the generation of temporary double-strand breaks. Cancer cells acquire enhanced Top2 functions to cope with the stress generated by transcription and DNA replication during rapid cell division since cancer driver genes such as Myc and EZH2 hijack Top2 in order to realize their oncogenic transcriptomes for cell growth and tumor progression. Inhibitors of Top2 are therefore designed to target Top2 to trap it on DNA, subsequently causing protein-linked DNA breaks, a halt to the cell cycle, and ultimately cell death. Despite the effectiveness of these inhibitors, cancer cells can develop resistance to them, thereby limiting their therapeutic utility. To maximize the therapeutic potential of Top2 inhibitors, combination therapies to co-target Top2 with DNA damage repair (DDR) machinery and oncogenic pathways have been proposed to induce synthetic lethality for more thorough tumor suppression. In this review, we will discuss the mode of action of Top2 inhibitors and their potential applications in cancer treatments.

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Section: Dna Topoisomerasesmentioning

confidence: 99%

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Matias-Barrios

Dong

2023

Pharmaceuticals

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“…Gepotidacin targets both DNA gyrase and topoisomerase IV. These bacterial type II topoisomerases are essential enzymes that modulate the topological state of the chromosome. ,,− Gyrase controls DNA under- and overwinding and works ahead of replication forks and transcription complexes to remove positive supercoils that accumulate as a result of these DNA processes. It is the only enzyme that can actively underwind (i.e., negatively supercoil) DNA. − Although topoisomerase IV can relax negative and positive DNA supercoils, its primary function is to decatenate, or remove tangles between, daughter chromatids that are created during replication and eliminate knots that are generated during recombination. ,,,, To carry out their catalytic activities, these enzymes use a double-stranded DNA passage mechanism. ,,,,, During this reaction, gyrase and topoisomerase IV generate a transient double-stranded DNA break in one segment of DNA and pass an intact double helix through the DNA gate.…”

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confidence: 99%

Interactions between Gepotidacin and Escherichia coli Gyrase and Topoisomerase IV: Genetic and Biochemical Evidence for Well-Balanced Dual-Targeting

Oviatt,

Gibson,

Huang

et al. 2024

ACS Infect. Dis.

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Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical issue. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial in clinical development. Recently, phase III clinical trials for gepotidacin treatment of uncomplicated urinary tract infections caused by uropathogens, including Escherichia coli, were stopped for demonstrated efficacy. Because of the clinical promise of gepotidacin, it is important to understand how the compound interacts with its cellular targets, gyrase and topoisomerase IV, from E. coli. Consequently, we determined how gyrase and topoisomerase IV mutations in amino acid residues that are involved in gepotidacin interactions affect the susceptibility of E. coli cells to the compound and characterized the effects of gepotidacin on the activities of purified wild-type and mutant gyrase and topoisomerase IV. Gepotidacin displayed well-balanced dual-targeting of gyrase and topoisomerase IV in E. coli cells, which was reflected in a similar inhibition of the catalytic activities of these enzymes by the compound. Gepotidacin induced gyrase/topoisomerase IV-mediated single-stranded, but not double-stranded, DNA breaks. Mutations in GyrA and ParC amino acid residues that interact with gepotidacin altered the activity of the compound against the enzymes and, when present in both gyrase and topoisomerase IV, reduced the antibacterial activity of gepotidacin against this mutant strain. Our studies provide insights regarding the well-balanced dual-targeting of gyrase and topoisomerase IV by gepotidacin in E. coli.

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“…Ciprofloxacin and other members of the fluoroquinolone class target the bacterial type II topoisomerases, gyrase and topoisomerase IV. − Gyrase maintains the superhelical state of the bacterial genome and relieves torsional stress generated ahead of replication forks and transcription complexes. − Topoisomerase IV can relax DNA supercoils but primarily unlinks (decatenates) replicated daughter chromosomes and removes knots from the genetic material. − These type II enzymes capture, bend, and cleave a DNA segment and carry out their essential catalytic functions by passing a separate double helix through this transient double-stranded break. ,,,,− To initiate the DNA cleavage reaction, active site tyrosine residues launch a nucleophilic attack on the DNA backbone, generating a covalent linkage between the enzyme and the newly created 5′-terminal phosphate of the cleaved DNA. ,,,, This covalent enzyme-cleaved DNA complex is known as the “cleavage complex”. ,,,,,, …”

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confidence: 99%

“…6,12,14,15,18−21 To initiate the DNA cleavage reaction, active site tyrosine residues launch a nucleophilic attack on the DNA backbone, generating a covalent linkage between the enzyme and the newly created 5′-terminal phosphate of the cleaved DNA. 6,12,14,15,19 This covalent enzyme-cleaved DNA complex is known as the "cleavage complex". 6,8,12,14,15,19,20 Fluoroquinolones stabilize the cleavage complex by inserting into the cleaved scissile bonds on both strands of the DNA (one drug molecule per DNA strand), thereby inhibiting DNA ligation and increasing levels of DNA scission.…”

mentioning

confidence: 99%

“…6,12,14,15,19 This covalent enzyme-cleaved DNA complex is known as the "cleavage complex". 6,8,12,14,15,19,20 Fluoroquinolones stabilize the cleavage complex by inserting into the cleaved scissile bonds on both strands of the DNA (one drug molecule per DNA strand), thereby inhibiting DNA ligation and increasing levels of DNA scission. 3,[6][7][8][9]22 When replication forks, transcription complexes, and other DNA tracking machinery approach drug-stabilized gyrase/topoisomerase IV-DNA complexes, the cut DNA can no longer be rejoined by the type II enzymes and is converted into persistent chromosomal breaks.…”

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confidence: 99%

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Target-Mediated Fluoroquinolone Resistance in Neisseria gonorrhoeae: Actions of Ciprofloxacin against Gyrase and Topoisomerase IV

Collins,

Oviatt,

Chan

et al. 2024

ACS Infect. Dis.

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Fluoroquinolones make up a critically important class of antibacterials administered worldwide to treat human infections. However, their clinical utility has been curtailed by target-mediated resistance, which is caused by mutations in the fluoroquinolone targets, gyrase and topoisomerase IV. An important pathogen that has been affected by this resistance is Neisseria gonorrhoeae, the causative agent of gonorrhea. Over 82 million new cases of this sexually transmitted infection were reported globally in 2020. Despite the impact of fluoroquinolone resistance on gonorrhea treatment, little is known about the interactions of this drug class with its targets in this bacterium. Therefore, we investigated the effects of the fluoroquinolone ciprofloxacin on the catalytic and DNA cleavage activities of wildtype gyrase and topoisomerase IV and the corresponding enzymes that harbor mutations associated with cellular and clinical resistance to fluoroquinolones. Results indicate that ciprofloxacin interacts with both gyrase (its primary target) and topoisomerase IV (its secondary target) through a water−metal ion bridge that has been described in other species. Moreover, mutations in amino acid residues that anchor this bridge diminish the susceptibility of the enzymes for the drug, leading to fluoroquinolone resistance. Results further suggest that ciprofloxacin primarily induces its cytotoxic effects by enhancing gyrase-mediated DNA cleavage as opposed to inhibiting the DNA supercoiling activity of the enzyme. In conclusion, this work links the effects of ciprofloxacin on wildtype and resistant gyrase to results reported for cellular and clinical studies and provides a mechanistic explanation for the targeting and resistance of fluoroquinolones in N. gonorrhoeae.

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DNA Recognition/Processing | DNA Topoisomerases: Type II

Cited by 7 publications

References 18 publications

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy

Interactions between Gepotidacin and Escherichia coli Gyrase and Topoisomerase IV: Genetic and Biochemical Evidence for Well-Balanced Dual-Targeting

Target-Mediated Fluoroquinolone Resistance in Neisseria gonorrhoeae: Actions of Ciprofloxacin against Gyrase and Topoisomerase IV

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