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

By Enzo Orlandini, Davide Marenduzzo, Davide Michieletto

Posted 05 Sep 2018
bioRxiv DOI: 10.1101/410019 (published DOI: 10.1073/pnas.1815394116)

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.

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