Synergy of topoisomerase and structural-maintenance-of-chromosomes proteins creates a universal pathway to simplify genome topology

Significance

Vital biological processes such as gene transcription and cell division may be severely impaired by inevitable entanglements ensuing from the extreme length and confinement of the genome. The family of topoisomerase proteins has independently evolved in different organisms to resolve these topological problems, yet no existing model can explain how topoisomerase alone can reduce the topological complexity of DNA in vivo. We propose that a synergistic mechanism between topoisomerase and a family of slip-link–like proteins called structural maintenance of chromosomes (SMC) can provide a pathway to systematically resolve topological entanglements even under physiological crowding and confinement. Given the ubiquity of topoisomerase and SMC, we argue that the uncovered mechanism is at work throughout the cell cycle and across different organisms.

Abstract

Topological entanglements severely interfere with important biological processes. For this reason, genomes must be kept unknotted and unlinked during most of a cell cycle. Type II topoisomerase (TopoII) enzymes play an important role in this process but the precise mechanisms yielding systematic disentanglement of DNA in vivo are not clear. Here we report computational evidence that structural-maintenance-of-chromosomes (SMC) proteins—such as cohesins and condensins—can cooperate with TopoII to establish a synergistic mechanism to resolve topological entanglements. SMC-driven loop extrusion (or diffusion) induces the spatial localization of essential crossings, in turn catalyzing the simplification of knots and links by TopoII enzymes even in crowded and confined conditions. The mechanism we uncover is universal in that it does not qualitatively depend on the specific substrate, whether DNA or chromatin, or on SMC processivity; we thus argue that this synergy may be at work across organisms and throughout the cell cycle.