topoisomerases

Topoisomerases are essential enzymes that regulate DNA topology in cells. They relieve or introduce supercoils and tangles that arise during DNA replication, transcription, recombination, and chromosome condensation, by catalyzing transient breaks in the DNA backbone and passing a segment of DNA through the break. Their activity helps maintain genomic stability and proper chromosome architecture.

There are two main classes: type I and type II. Type I topoisomerases create single-strand breaks and change the DNA linking number by increments of one without requiring ATP in most cases. Type II topoisomerases create double-strand breaks and change the linking number by two, typically using ATP to power strand passage. In bacteria, gyrase is a unique type II enzyme that can introduce negative supercoils, while other type II enzymes include topo II in eukaryotes. Eukaryotes also possess topo I enzymes, and organisms often have multiple topo II isoforms (for example, α and β in vertebrates).

Mechanistically, a conserved active-site tyrosine forms a transient covalent bond with the DNA, generating a break. The enzyme then passes another DNA segment through the break and religates the strand, resolving the topological problem. For type II enzymes, two breaks are coordinated to allow passage of an intact double-stranded segment, powered by ATP hydrolysis.

In cells, topoisomerases participate in replication fork progression, transcription, chromatin remodeling, and chromosome segregation during mitosis and meiosis. They are targets for clinically important drugs: topo I inhibitors (e.g., camptothecin derivatives) and topo II inhibitors (e.g., doxorubicin, etoposide) for cancer therapy, and bacterial gyrase/topo IV inhibitors (quinolones) for antibiotics. Resistance and toxicity are active research areas in clinical use.