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. 2021 Jan-Mar;13(1):59-75.
doi: 10.32607/actanaturae.11058.

Diversity and Functions of Type II Topoisomerases

D A Sutormin  1   2 , A K Galivondzhyan  3   4 , A V Polkhovskiy  1   2 , S O Kamalyan  1   2 , K V Severinov  2   5   6 , S A Dubiley  1   2
Affiliations

Diversity and Functions of Type II Topoisomerases

D A Sutormin et al. Acta Naturae. 2021 Jan-Mar.

Abstract

The DNA double helix provides a simple and elegant way to store and copy genetic information. However, the processes requiring the DNA helix strands separation, such as transcription and replication, induce a topological side-effect - supercoiling of the molecule. Topoisomerases comprise a specific group of enzymes that disentangle the topological challenges associated with DNA supercoiling. They relax DNA supercoils and resolve catenanes and knots. Here, we review the catalytic cycles, evolution, diversity, and functional roles of type II topoisomerases in organisms from all domains of life, as well as viruses and other mobile genetic elements.

Keywords: DNA segregation; decatenation; replication; spatial chromosome organization; supercoiling; topoisomerases; transcription.

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Figures

Fig. 1
Fig. 1
DNA topology. (A) Linking number of a circular DNA molecule and changes in the linking number resulting from strand cleavage and transfer. (B) Spatial structures, plectoneme and solenoid, arising from DNA supercoiling
Fig. 2
Fig. 2
Type II topoisomerase structure. Left – variants of the enzyme domain architecture. Homologous domains are shown in the same colors. In the WHD, the catalytic tyrosine residue responsible for DNA cleavage is depicted by a yellow circle. Right – domain organization of type IIA (DNA gyrase) and IIB (Topo VI) topoisomerases
Fig. 3
Fig. 3
Catalytic cycles of the topoisomerases IIA (A) and IIB (B) and the effect of topoisomerase activity on DNA topology (C). The scheme shows the following steps: binding of the DNA G-segment (blue) and T-segment (green); binding and hydrolysis of ATP molecules (ATP – red circle, ADP – green circle, if the bound nucleotide state is unknown (ATP/ADP), it is depicted by a purple circle); cleavage and ligation of the G-segment and passage of the T-segment through the enzymatic complex. A scheme for G-segment cleavage is shown in the center of each cycle (Y – catalytic tyrosine residue of the WHD). Type II topoisomerases are able to change DNA supercoiling, as well as unlink (decatenate) or link (catenate) DNA molecules
Fig. 4
Fig. 4
DNA gyrase and its function. (A) Structure of a DNA gyrase complex with DNA. (B) a twin-domain model illustrating positive supercoiling upstream of the elongating RNA-polymerase and negative supercoiling downstream [62]. Co-transcriptional positive, and negative, supercoiling moves along the DNA molecule and influences the initiation of transcription from adjacent promoters (indicated by arrows). Depending on the promoter, the effect can be either activating or inhibiting. DNA gyrase promotes transcription elongation through relaxation of positive supercoiling ahead of RNA polymerase. (C) Changes in genome supercoiling during E. coli culture transition from the exponential to stationary growth phase promote switching of the cell from a mainly anabolic to catabolic physiological state [63]. OriC – origin of replication, dif – site recognized by XerC/XerD recombinases. (D) Circadian oscillations of the S. elongatus genome supercoiling level (at the bottom) correlate with changes in the gene transcriptional profile (at the top). A sharp decrease in the genome supercoiling level (indicated by the orange arrow) in the presence of the DNA gyrase inhibitor novobiocin causes rapid change in the transcriptional profile (2), making it similar to the profile of bacteria in the physiologically relaxed genome state (1) [64]. (E) DNA gyrase is essential for the spatial organization of the Mu prophage and its transposition. The prophage DNA is shown in dark blue, and bacterial genome DNA is in blue
Fig. 5
Fig. 5
Topoisomerase IV and its function. (A) Structure of the Topo IV complex with DNA. (B) Comparison of the GyrA CTD (PDB ID: 1zi0) and Topo IV ParC CTD (PDB ID: 1zvt) structures. A putative position of DNA is shown as a dashed line. (C) Proteins interacting with Topo IV. The effect of each protein on Topo IV activity is depicted as “+” (activation), “–” (inhibition), or “?” (interaction is not confirmed). (D) Topological effects associated with DNA replication. Positive supercoils formed in front of the moving replisome are relaxed by DNA gyrase and, presumably, Topo IV. Accumulation of DNA supercoiling leads to replisome rotation, thereby producing DNA pre-catenanes. In E. coli, the SeqA protein binds to the hemimethylated GATC sites of newly replicated DNA molecules. Dam methylates GATC sites and displaces SeqA; so, the SeqA concentration gradient extends 100–400 kb over the replisome and moves together with it. Topo IV cannot interact with SeqA-bound DNA regions, which explains the temporary cohesion of daughter chromosomes during replication in E. coli; however, when all GATC sites are methylated and SeqA is no longer associated with DNA, topoisomerase removes pre-catenanes, enabling daughter chromosome separation [110]
Fig. 6
Fig. 6
Function of eukaryotic Top2. (A) Relaxation of supercoils during transcription. Promoters are depicted by purple arrows. (B) Top2 is involved in transcription initiation. (C) Top2, CTCF, and cohesin are colocalized at the TAD boundaries. Pink arrows display the direction of loop extrusion, mediated by CTCF and cohesin. Red-blue squares depict CTCF binding sites. Top2 facilitates cohesin- mediated DNA translocation through the relaxation of topological stress. (D) Top2-mediated introduction of DNA double-strand breaks in the promoter region induces transcription. (E) Decatenation of daughter chromosomes
Fig. 7
Fig. 7
Cellular localization of type II topoisomerases and homologues proteins in A. thaliana
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