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A Brownian ratchet model for DNA loop extrusion by the cohesin complex.

Higashi, TL; Pobegalov, G; Tang, M; Molodtsov, MI; Uhlmann, F; (2021) A Brownian ratchet model for DNA loop extrusion by the cohesin complex. eLife , 10 , Article e67530. 10.7554/eLife.67530. Green open access

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Abstract

The cohesin complex topologically encircles DNA to promote sister chromatid cohesion. Alternatively, cohesin extrudes DNA loops, thought to reflect chromatin domain formation. Here, we propose a structure-based model explaining both activities. ATP and DNA binding promote cohesin conformational changes that guide DNA through a kleisin N-gate into a DNA gripping state. Two HEAT-repeat DNA binding modules, associated with cohesin’s heads and hinge, are now juxtaposed. Gripping state disassembly, following ATP hydrolysis, triggers unidirectional hinge module movement, which completes topological DNA entry by directing DNA through the ATPase head gate. If head gate passage fails, hinge module motion creates a Brownian ratchet that, instead, drives loop extrusion. Molecular-mechanical simulations of gripping state formation and resolution cycles recapitulate experimentally observed DNA loop extrusion characteristics. Our model extends to asymmetric and symmetric loop extrusion, as well as z-loop formation. Loop extrusion by biased Brownian motion has important implications for chromosomal cohesin function.

Type: Article
Title: A Brownian ratchet model for DNA loop extrusion by the cohesin complex.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.7554/eLife.67530
Publisher version: https://doi.org/10.7554/eLife.67530
Language: English
Additional information: © 2021, Higashi et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Keywords: Cohesin, DNA loop extrusion, S. pombe, SMC complexes, biophysical simulation, chromosomes, computational biology, gene expression, sister chromatid cohesion, structural biology, systems biology
UCL classification: UCL
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Physics and Astronomy
URI: https://discovery.ucl.ac.uk/id/eprint/10132280
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