Topoisomerase Functions in DNA Dynamics

Topoisomerases are essential enzymes that manage the topological state of DNA by introducing transient breaks and rejoining strands to regulate supercoiling, knotting and catenation. Through distinct catalytic mechanisms, type I topoisomerases cleave single strands and permit passage of another DNA segment, whereas type II enzymes cleave both strands to enable double-strand passage. This dynamic control of torsional stress is critical during replication, transcription and recombination, preventing replication fork stalling, R-loop accumulation and chromosome entanglements. Malfunction of these enzymes compromises genome integrity and has been linked to cancer, neurological disorders and infectious disease. Moreover, topoisomerases are prominent drug targets: inhibitors that stabilise cleavage intermediates or interfere with gate dynamics serve as effective antibacterials and anticancer agents. Recent advances have further elucidated the structural basis for enzyme regulation, the role of co-factors in homeostasis and the impact of topoisomerase dysregulation on cellular physiology, underscoring their global significance in biology and medicine.

Research from Nature Portfolio

Recent studies have elucidated mechanisms of topoisomerase regulation and inhibition. One investigation characterised how a protein complex protects a dual‐activity topoisomerase from ubiquitin-mediated degradation, thereby preventing harmful cleavage complexes in both DNA and RNA. Another effort synthesised and evaluated bisbenzimidazole derivatives that intercalate at the enzyme–DNA interface, stabilising the gate in a closed conformation and blocking negative supercoil relaxation. These compounds exhibited potent activity against multidrug-resistant bacteria and provide a molecular framework for designing next-generation antimicrobials targeting type IA topoisomerases.

Topoisomerase Functions in DNA Dynamics publication trend

The graph below shows the total number of articles in topoisomerase functions in dna dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Topoisomerase: Enzyme that transiently cleaves and rejoins DNA strands to regulate its topology.

DNA supercoiling: Over- or under-winding of the double helix generating torsional stress.

Catenation/Decatenation: Interlinking or unlinking of DNA circles, crucial for chromosome segregation.

Strand passage: Mechanism by which topoisomerases transfer one DNA segment through a break in another.

R-loop: Three-strand structure formed by RNA hybridising to one DNA strand, displacing the other.

References

1. The TDRD3-USP9X complex and MIB1 regulate TOP3B homeostasis and prevent deleterious TOP3B cleavage complexes. Nature Communications (2023).
2. Unraveling topoisomerase IA gate dynamics in presence of PPEF and its preclinical evaluation against multidrug-resistant pathogens. Communications Biology (2023).
3. Variation of Structure and Cellular Functions of Type IA Topoisomerases across the Tree of Life. Cells (2024).
4. What’s on the Other Side of the Gate: A Structural Perspective on DNA Gate Opening of Type IA and IIA DNA Topoisomerases. International Journal of Molecular Sciences (2023).
5. Loss of TOP3B leads to increased R-loop formation and genome instability. Open Biology (2019).