A kinetic proofreading mechanism for disentanglement of DNA by topoisomerases

Cells must remove all entanglements between their replicated chromosomal DN As to segregate them during cell division. Entanglement removal is done by ATP-driven enzymes that pass DNA strands through one another, called type I I topoisomerases. In vitro, some type II topoisomerases can reduce entangle ments much more than expected, given the assumption that they pass DNA segm ents through one another in a random way(1). These type II topoisomerases ( of less than 10 nm in diameter) thus use ATP hydrolysis to sense and remove entanglements spread along flexible DNA strands of up to 3,000 nm long. He re we propose a mechanism for this, based on the higher rate of collisions along entangled DNA strands, relative to collision rates on disentangled DN A strands. We show theoretically that if a type II topoisomerase requires a n initial 'activating' collision before a second strand-passing collision, the probability of entanglement may be reduced to experimentally observed l evels. This proposed two-collision reaction is similar to 'kinetic proofrea ding' models of molecular recognition(2,3).