The dynamic interplay between DNA topoisomerases and DNA topology

Abstract

Topological properties of DNA influence its structure and biochemical interactions. Within the cell, DNA topology is constantly in flux. Transcription and other essential processes, including DNA replication and repair, not only alter the topology of the genome but also introduce additional complications associated with DNA knotting and catenation. These topological perturbations are counteracted by the action of topoisomerases, a specialized class of highly conserved and essential enzymes that actively regulate the topological state of the genome. This dynamic interplay among DNA topology, DNA processing enzymes, and DNA topoisomerases is a pervasive factor that influences DNA metabolism in vivo. Building on the extensive structural and biochemical characterization over the past four decades that has established the fundamental mechanistic basis of topoisomerase activity, scientists have begun to explore the unique roles played by DNA topology in modulating and influencing the activity of topoisomerases. In this review we survey established and emerging DNA topology-dependent protein-DNA interactions with a focus on in vitro measurements of the dynamic interplay between DNA topology and topoisomerase activity.

Allele-specific collateral and fitness effects determine the dynamics of fluoroquinolone-resistance evolution

“…Although the resistant strains varied in their responses, we observed extensive and conserved CS towards the majority of the antibiotics tested, consistent with earlier results derived from laboratory-evolved strains of Enterococcus faecalis (7), Pseudomonas aeruginosa (8,9) and Escherichia coli (5,13). FQ-resistance mutations in gyrA and parC result in three-dimensional structural changes of the DNA gyrase and the topoisomerase IV that are associated with the modification of 15 DNA topology (23) and subsequently the global reprogramming of gene expression (24,25), which in turn leads to collateral effects in Salmonella enterica serovar Typhimurium (26). Hence, we hypothesize that this gene expression reprogramming is responsible for the observed extensive collateral effects in S. pneumoniae as well, although this remains to be elucidated.…”

Genome-wide mapping of Topoisomerase I activity sites reveal its role in chromosome segregation

“…Supercoiling is an indispensable component and inevitable consequence of DNA and RNA metabolism (3). The excess of supercoiling, both positive and negative, generated during replication and transcription have to be removed by the activity of topoisomerases to manage normal cellular function (1–3,55). We recently provided experimental demonstration for the co-localization of DNA gyrase and TopoI with RNAP by analysing the genome-wide binding profile of DNA gyrase, TopoI and RNAP in Mtb as a validation of the twin supercoiled domain model (22).…”

Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance

“…Replication fork progression causes positive supercoils to build up ahead of the fork [71,72]. These positive supercoils need to be resolved, as a build-up will cause a large amount of torsional stress [73] that can stall replication. To relieve the torsional stress, the replication fork may rotate causing the development of precatenanes behind the fork [71,[74][75][76].…”