Temporospatial control of topoisomerases by essential cellular processes

Abstract

Topoisomerases are essential, ubiquitous enzymes that break and rejoin the DNA strand to control supercoiling. Because topoisomerases are DNA scissors, these enzymes are highly regulated to avoid excessive DNA cleavage, a vulnerability exploited by many antibiotics. Topoisomerase activity must be co-ordinated in time and space with transcription, replication, and cell division or else these processes stall, leading to genome loss. Recent work in Escherichia coli has revealed that topoisomerases do not act alone. Most topoisomerases interact with the essential process that they promote, a coupling that may stimulate topoisomerase activity precisely when and where cleavage is required. Surprisingly, in E. coli and most other bacteria, gyrase is not apparently regulated in this manner. We review how each E. coli topoisomerase is regulated, propose possible solutions to ‘the gyrase problem’, and conclude by highlighting how this regulation may present opportunities for antimicrobial development.