DNA Topoisomerases

Bush, Natassja G.; Evans-Roberts, Katherine; Maxwell, Anthony

doi:10.1128/ecosalplus.esp-0010-2014

Cited by 203 publications

(236 citation statements)

References 314 publications

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“…These enzymes modulate bacterial chromosome topology by performing transient doublestrand DNA cleavage via a covalent link between a tyrosine side chain of the enzyme and a 5′ phosphate of DNA, followed by strand passage and religation (9,10), thereby either relaxing supercoils, decatenating, or introducing negative supercoils in DNA. The highly successful fluoroquinolone (FQ) class of antibiotics, exemplified by ciprofloxacin (Fig.…”

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confidence: 99%

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Chan

Germe

Bax

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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A paucity of novel acting antibacterials is in development to treat the rising threat of antimicrobial resistance, particularly in Gram-negative hospital pathogens, which has led to renewed efforts in antibiotic drug discovery. Fluoroquinolones are broad-spectrum antibacterials that target DNA gyrase by stabilizing DNA-cleavage complexes, but their clinical utility has been compromised by resistance. We have identified a class of antibacterial thiophenes that target DNA gyrase with a unique mechanism of action and have activity against a range of bacterial pathogens, including strains resistant to fluoroquinolones. Although fluoroquinolones stabilize double-stranded DNA breaks, the antibacterial thiophenes stabilize gyrase-mediated DNA-cleavage complexes in either one DNA strand or both DNA strands. X-ray crystallography of DNA gyrase–DNA complexes shows the compounds binding to a protein pocket between the winged helix domain and topoisomerase-primase domain, remote from the DNA. Mutations of conserved residues around this pocket affect activity of the thiophene inhibitors, consistent with allosteric inhibition of DNA gyrase. This druggable pocket provides potentially complementary opportunities for targeting bacterial topoisomerases for antibiotic development.

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confidence: 99%

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Chan

Germe

Bax

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…It can relax supercoiled DNA in an ATP- and Mg 2+ -dependent manner and represents one of the first proteins identified in the scaffold of mitotic chromosomes [51,52], demonstrating highly dynamic behavior during mitosis [53]. In meiotic cells, in particular, in diplotene oocytes of mice, topo II is abundant in the nucleoplasm, but absent in the central body of the mouse karyosphere [30].…”

Section: Discussionmentioning

confidence: 99%

The karyosphere capsule inRana temporariaoocytes contains structural and DNA-binding proteins

Ilicheva

Podgornaya

Bogolyubov

2018

Nucleus

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During the last stages of oogenesis, oocyte chromosomes condense and come close together, forming the so-called karyosphere. Karyosphere formation is accompanied by an essential decrease in transcriptional activity. In the grass frog Rana temporaria, the karyosphere is surrounded by an extrachromosomal capsule that separates the chromosomes from the rest of the nucleoplasm. The karyosphere capsule (KC) of R. temporaria has been investigated in detail at the ultrastructural level, but its protein composition remained largely unknown. We demonstrate here that nuclear actin, especially F-actin, as well as lamins A/C and B are the most abundant proteins of the KC. Key proteins of nuclear pore complexes, such as Nup93 and Nup35, are also detectable in the KC. New antibodies recognizing the telomere-binding protein TRF2 allowed us to localize TRF2 in nuclear speckles. We also found that the R. temporaria KC contains some proteins involved in chromatin remodeling, including topoisomerase II and ATRX. Thus, we believe that KC isolates the chromosomes from the rest of the nucleoplasm during the final period of oocyte growth (late diplotene) and represents a specialized oocyte nuclear compartment to store a variety of factors involved in nuclear metabolism that can be used in future early development.Abbreviations: BrUTP: 5-bromouridine 5’-triphosphate; CytD: cytochalasin D; IGCs: interchromatin granule clasters; IgG: immunoglobulin G; KC: karyosphere capsule; Mw: molecular weight; NE: nuclear envelope; PBS: phosphate buffered saline; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; Topo II: topoisomerase II

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“…Two topoisomerase enzymes are essential for DNA replication progression and/or DNA decatenation: DNA gyrase (Topoisomerase II) and Topoisomerase IV (Bush et al, 2015). The DNA gyrase, or topoisomerase II, is an ATP-dependent Type 2 topoisomerase that generates negative supercoils in the nucleoid and is important for the removal of positive supercoils in front of the replication forks.…”

Section: The Living Nucleoidmentioning

confidence: 99%

Impact of Chromosomal Architecture on the Function and Evolution of Bacterial Genomes

2018

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The bacterial nucleoid is highly condensed and forms compartment-like structures within the cell. Much attention has been devoted to investigating the dynamic topology and organization of the nucleoid. In contrast, the specific nucleoid organization, and the relationship between nucleoid structure and function is often neglected with regard to importance for adaption to changing environments and horizontal gene acquisition. In this review, we focus on the structure-function relationship in the bacterial nucleoid. We provide an overview of the fundamental properties that shape the chromosome as a structured yet dynamic macromolecule. These fundamental properties are then considered in the context of the living cell, with focus on how the informational flow affects the nucleoid structure, which in turn impacts on the genetic output. Subsequently, the dynamic living nucleoid will be discussed in the context of evolution. We will address how the acquisition of foreign DNA impacts nucleoid structure, and conversely, how nucleoid structure constrains the successful and sustainable chromosomal integration of novel DNA. Finally, we will discuss current challenges and directions of research in understanding the role of chromosomal architecture in bacterial survival and adaptation.

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DNA Topoisomerases

Cited by 203 publications

References 314 publications

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase

The karyosphere capsule inRana temporariaoocytes contains structural and DNA-binding proteins

Impact of Chromosomal Architecture on the Function and Evolution of Bacterial Genomes

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