Giant proteins that move DNA: bullies of the genomic playground

Key Points Five major ideas regarding the highly specialized proteins that move DNA are discussed in this review. Proteins move DNA. A protein can be thought of as moving on DNA, or alternatively, DNA can be moving past the protein. Depending on what moves, the consequences are dramatically different. Movement of DNA within the cell has to be regulated and must be accurate with respect to cell division. This is one of a number of occasions that require the DNA to be moved, not the protein. DNA movers are large. Many of the DNA-moving proteins have a total molecular mass of over a million Daltons, whereas more passive DNA-binding proteins are uniformly small. These enzymes are large because they need large surfaces to multimerize and interact with DNA, and because they are often composites of multiple activities. Enzymes use energy to enforce reaction directionality. Nucleotide binding and release is often as important in luring enzymes into catalytically proficient states as ATP hydrolysis itself. DNA motors such as topoisomerases often employ the binding of ATP to produce specific structural changes in the enzyme that ensure reaction directionality. Topoisomerases use energy to reduce topological entanglements to sub-equilibrium levels. Directed stochasticity. Counter-intuitively, DNA-moving enzymes often act stochastically rather than in a deterministic fashion. Their action at a given instant is not always in the direction of the overall process. The DNA translocase FtsK, DNA-replication forks and microtubule polymerization all have this property. The ability to 'capture' molecules that have successfully reached their precise location following movement presumably allowed this simple and robust strategy to arise several times throughout the course of evolution. Moving DNA has topological consequences. A common but unexpected feature of all DNA translocases is that motion of the DNA leads to changes in its topology. They produce changes in twist (which is convertible to writhe), ahead of and behind the protein, that require removal by topoisomerases. Only recently have single-molecule biophysical techniques allowed these important changes to be measured.