Topoisomerases (type I: EC 5.99.1.2, type II: EC 5.99.1.3) are enzymes that act on the topology of DNA. The double-helical configuration that DNA strands naturally reside in makes them difficult to separate, and yet they must be separated by helicase proteins if other enzymes are to transcribe the sequences that encode proteins, or if chromosomes are to be replicated. In so-called circular DNA, in which double helical DNA is bent around and joined in a circle, the two strands are topologically linked, or knotted. Otherwise identical loops of DNA having different numbers of twists are topoisomers, and cannot be interconverted by any process that does not involve the breaking of DNA strands. Topoisomerases catalyze and guide the unknotting of DNA.
The insertion of viral DNA into chromosomes and other forms of recombination can also require the action of topoisomerases.
Many drugs operate through interference with the topoisomerases. The broad-spectrum fluoroquinolone antibiotics act by disrupting the function of bacterial type II topoisomerases. Some chemotherapy drugs work by interfering with topoisomerases in cancer cells: type 1 is inhibited by irinotecan and topotecan , while type 2 is inhibited by etoposide and teniposide .
Type I topoisomerases
Both type I and type II topoisomerases change the supercoiling of DNA. Type I topoisomerases function by nicking one strand of the DNA double helix, twisting it around the other strand, and religating (reconnecting) the nicked strand. (For this reason, these isomerases are sometimes described as nickases.) Type I topisomerases change the linking number of a circular DNA strand by 1.
Type II topoisomerases
Type II topoisomerases cut both strands of the DNA helix simultaneously. One free end is twisted, and the severed strands are reattached. Type II topoisomerases change the linking number of a DNA loop by 2. For example, DNA gyrase is a type II isomerase observed in E. coli and most other prokaryotes. Gyrase introduces negative supercoils and decreases the link number by 2. Gyrase is able to relieve knots in the bacterial chromosome.
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