Protein-Mediated Loops in Supercoiled DNA Generate Large, Dynamic Topological Domains

Abstract

Proteins that act at a distance along DNA by binding at one site and contacting another create loops that form topological domains and influence regulation. Such loops are affected by the torsional state of DNA, which dramatically modulates topology, driving the DNA from extended and accessible, to more compact and genetically secured forms. Furthermore, the response of the DNA filament to supercoiling is biased by accessory factors. For example, small molecules like polyamines, which neutralize the negative charge repulsions along the phosphate backbone, enhance flexibility and promote writhe over twist in response to torsion. On the other hand, stiffer DNA antagonizes looping and bending. Recent experiments quantitatively reveal the extent to which negatively supercoiling DNA lowers the free energy of looping, and could therefore bias the operation of genetic switches. A new role for DNA supercoiling has emerged; it synergizes with protein-mediated looping to create large, dynamic topological domains that extend beyond the length of the loop. Such domains may coordinate gene regulation and other DNA transactions across spans in the genome that exceed the separation between the protein binding sites.