Topo2008: DNA Topoisomerases in Biology and Medicine

The DNA topoisomerases are a group of fascinating enzymes that play an essential but dangerous game with DNA. They break and rejoin either one or both strands of the double helix to solve the problems of tangling and linking that occur as a result of DNA manipulations (replication, transcription and recombination) in all cells. This basic problem with the DNA structure was recognized by Watson and Crick almost as soon as the double helix was described (1). As the parental DNA strands are separated at a replication fork, the double-helical turns are compressed and overwound ahead of the fork; the resulting torsional stress will prevent further replication if it is not relieved. This overwinding corresponds to positive supercoiling. Alternatively, any rotation of the replication fork leads to interwinding of the replicated regions, ultimately resulting in linking (catenation) of the daughter chromosomes, which must be removed if partition is to occur without breaking the DNA (2). Transcription can also result in the generation of both positive and negative supercoiling (3), and other processes, particularly recombination, can lead to the knotting of DNA strands. These complexities of double-helical DNA are grouped together under the label of DNA topology (4). The topological problems of the DNA helix must have arisen very early in evolution, as soon as DNA genomes became long enough that a simple rotation of the entire molecule to remove supercoiling became impracticable. The only viable solution to these difficulties is to untwist, unlink and unknot the DNA by breaking one or both strands, permitting strands to pass through one another or allowing rotation at the break point. These strategies are adopted by the different classes of topoisomerase enzymes, discovered during the 1970s. The type I enzymes break and rejoin one strand of the helix, and either pass single strands through one another (type IA) or allow one broken end to rotate about the intact strand (type IB). Type I enzymes can remove supercoiling from DNA. In contrast, type II topoisomerases pass one double-helical segment through a double-stranded break in another, in an ATP-dependent reaction, and can thus unlink (decatenate) linked chromosomes, and remove knots. One subset of these enzymes, DNA gyrases, can introduce negative supercoiling (unwinding) into DNA. Most cell types express a suite of topoisomerase enzymes to regulate the topology of their DNA. However, these manipulations of the DNA helix come at a cost; the broken DNA strands must …