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. 2016 Sep;8(3):221-231.
doi: 10.1007/s12551-016-0206-x. Epub 2016 Jul 2.

The Dynamic Interplay Between DNA Topoisomerases and DNA Topology

Yeonee Seol  1 , Keir C Neuman  1
Affiliations

The Dynamic Interplay Between DNA Topoisomerases and DNA Topology

Yeonee Seol et al. Biophys Rev. 2016 Sep.

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, alter the topology of the genome, while introducing 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 established the fundamental mechanistic basis of topoisomerase activity, the unique roles played by DNA topology in modulating and influencing the activity of topoisomerases have begun to be explored. 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.

Keywords: DNA supercoiling; DNA topology; cancer therapy; protein; topoisomerase.

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Conflict of interest statement

Conflict of interest

Yeonee Seol declares that she has no conflict of interest.

Keir C. Neuman declares that he has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Figures

Fig. 1
Fig. 1
Graphical overview of DNA topology. Linking number differences (∆Lk) arise due to cellular processes, such as DNA transcription and replication. Differences in the linking number are accommodated by a combination of twist (torsion) (Tw) and writhe (Wr), which change the structure and mechanics of DNA. Knotting within a DNA molecule and links between DNA molecules (catenanes) represent higher order topological conformations of DNA
Fig. 2
Fig. 2
The mechanical and geometrical effects of DNA twist (Tw) and writhe (Wr). Left half of graph Underwound DNA (ΔTw <0) can result in local DNA melting, facilitating single-strand DNA (ssDNA) binding by proteins such as transcription factor IID (TFIID) and TATA box binding protein (TATA), and wrapping of DNA by nucleosomes. On the other hand, overwound DNA (ΔTw >0) increases DNA torsion, thereby hindering enzymatic activities associated with opening of the DNA duplex, including initiation and elongation by RNA polymerase. Increased torsion also hinders and can reverse DNA wrapping interactions of nucleosomes. Right half of graph The formation of writhe facilitates the interactions among distal sites of DNA and promotes local DNA bending. In addition, geometric differences between positive and negative Wr or DNA juxtapositions within knotted or catenated DNA are subject to chiral- and geometric-dependent activities of some Type II topoisomerases. For example, topoisomerase IV has been shown to be sensitive to the DNA crossing angle α depicted in the figure
Fig. 3
Fig. 3
Overview of DNA topoisomerase (Topo) activities and the effects of DNA twist (Tw) and writhe (Wr) on Topo activity. Top 2 rows During a catalytic cycle, Topo IA creates a break in the ssDNA (inset: green circle indicates the enzyme–DNA bond) and passes the intact ssDNA through the gap, resulting in a change of Lk of +1. As the ssDNA region is required for Topo IA binding, underwound DNA facilitates enzymatic activity. Topo IA can only relax negatively supercoiled DNA, whereas reverse gyrases, a combination of a Type IA Topo and a helicase found in hyperthermophiles, can generate positive supercoils with ATP. The rate and degree of positive supercoiling by reverse gyrase are limited by the torque in the DNA. Middle row Topo IB generates a ssDNA nick (inset: green circle indicates the enzyme–DNA bond) and relaxes both positive and negative supercoils via a controlled rotation mechanism, resulting in an a random change in Lk before religation. The rate of relaxation is proportional to the stored torque, i.e., ΔTw. Although not shown, the mechanism of Topo V is similar to that of Topo IB. Bottom 2 rows Topo IIA generates a double-strand break (inset: green circle indicates the enzyme–DNA bond) and passes the other duplex through a DNA gate formed by the enzyme and DNA bridge. Positive DNA torsion decreases the catalytic activity of Topo IIA. Some Topo IIA (Topo IV, gyrase, and human Topo IIα) are affected by the chirality of DNA Wr
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