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

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journal contribution
posted on 30.07.2021, 10:36 by Torahiko L Higashi, Georgii Pobegalov, Minzhe Tang, Maxim I Molodtsov, Frank Uhlmann
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.

Funding

Crick (Grant ID: 10750, Grant title: Molodtsov FC001750) Crick (Grant ID: 10198, Grant title: Uhlmann FC001198) European Research Council (Grant ID: 670412 - ChromatidCohesion, Grant title: ERC 670412 - ChromatidCohesion)

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