Type IA DNA topoisomerases: Strictly one step at a time

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Abstract
During DNA replication and transcription, the winding of the DNA helix undergoes dramatic changes that give rise to DNA supercoiling. Additionally, both DNA replication and recombination can leave the DNA in a tangled, catenated, or interwound state. DNA topoisomerases are the enzymes charged with resolving these topological problems in the DNA (for reviews, see refs. 1–3). In addition, in bacteria two or more DNA topoisomerases act in concert to maintain a fixed global level of helical tension in the DNA that is critical for its proper function. Topoisomerases alter the topological state of the DNA by either passing one strand of the helix through the other strand (type I family) or by passing a region of duplex DNA through another region of duplex DNA (type II family). The two families of enzymes carry out this molecular sleight of hand by reversibly cleaving one or both strands of the DNA, respectively. The reversibility of the reaction is ensured by the covalent attachment of the enzyme to a DNA end (or ends) through a phosphodiester linkage involving a tyrosine residue in the enzyme. The type I family is further subdivided into two subfamilies depending on the polarity of attachment of the topoisomerase to the DNA; members of the type IA subfamily become attached to 5′ phosphate termini, whereas members of the type IB subfamily attach to 3′ phosphates. The requirement for a type IA enzyme to bind a short single-stranded region in the substrate further distinguishes the type IA enzymes from the type IB enzymes, which prefer completely duplex DNA. What happens after cleavage to effect the strand passage reaction has long fascinated investigators working on the type I enzymes. The experiments described by Dekker et al. (4) in this issue of PNAS provide an elegant and convincing test of a model …