Molecular Evolution of DNA Topoisomerases: Mechanisms, Diversification, and Functional Adaptations

Abstract

Daksh Daksh

Topoisomerases are one of the essential enzymes that regulate DNA topology. They enable crucial processes such as replication, transcription and chromosomal segregation across bacteria, archaea and eukaryotes. This review traces their emergence from a hypothesized RNA world, where proto-enzymes may have managed RNA entanglements, to their pivotal role in DNA-based life following the RNA-to-DNA transition. Genomic and phylogenetic data suggest their diversification into Type I (IA, IB, IC) and Type II (IIA, IIB) families, likely resulting from independent evolutionary events driven by horizontal gene transfer (HGT), gene duplication, and modular innovation.The conserved Toprim domain in Type IA and IIA enzymes indicates a shared catalytic ancestry. However, HGT, particularly from viruses, introduced variants such as Type IB, thereby enhancing topological versatility.These adaptations-Type IA’s magnesium-driven simplicity for early cells, Type IIA’s ATP-powered catenation resolution for complex genomes, and unique forms such as reverse gyrase for extremophiles-mirror genomic complexity and ecological pressures. First elucidated by James Wang’s 1970s discovery in Escherichia coli, their universal presence suggests origins tied to the last universal common ancestor- Luca. Today, the evolutionary legacy of TOP2 proteins guides medical and biotechnological advancements. For instance, TOP2 inhibitors are employed as cancer treatments, while gyrase-specific antibiotics are utilized to combat bacterial infections. This article synthesizes molecular, phylogenetic, and functional insights to illuminate how topoisomerases evolved to overcome DNA’s topological challenges. By doing so, it provides a window into life’s ancient past and its modern applications.

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