Synergy of Topoisomerase and Structural-Maintenance-of-Chromosomes Proteins Creates a Universal Pathway to Simplify Genome Topology

TL;DR

This study reveals a universal mechanism where SMC proteins and Topoisomerase II cooperate to simplify genome topology, preventing entanglements that interfere with vital biological processes across different organisms and cell cycle stages.

Contribution

It uncovers a novel synergistic pathway involving SMC proteins and TopoII that facilitates genome disentanglement through loop extrusion and crossing localization.

Findings

SMC proteins assist TopoII in resolving DNA entanglements.

The mechanism is effective in crowded and confined environments.

It is universal across different substrates and organism types.

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 localisation of essential crossings in turn catalysing 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.