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.
Highlights
Cohesin is a member of the Structural Maintenance of Chromosomes (SMC) family of ring-shaped chromosomal protein complexes that are central to higher order chromosome organization (Hirano, 2016; Uhlmann, 2016; Yatskevich et al, 2019)
Our study provides a molecular proposal for both topological entry into the cohesin ring as well as for DNA loop extrusion
ATP binding to the ATPase heads opens up a kleisin N-gate, allowing DNA to enter and reach the top of the engaged ATPase heads
Summary
Cohesin is a member of the Structural Maintenance of Chromosomes (SMC) family of ring-shaped chromosomal protein complexes that are central to higher order chromosome organization (Hirano, 2016; Uhlmann, 2016; Yatskevich et al, 2019). Both of cohesin’s roles have to do with how DNA is organised in the cell, it remains unclear how a single protein complex can engage in two such different activities To answer this question, Higashi et al used a structure of cohesin from yeast cells gripping onto DNA to build a model that simulates how the complex interacts with chromosomes and chromatin. In addition to topologically entrapping DNA, in vitro experiments have revealed the ability of human cohesin to translocate along DNA in a directed motion, as well as its ability to extrude DNA loops (Davidson et al, 2019; Kim et al, 2019) These activities are reminiscent of those previously observed with a related SMC complex, condensin, a central mediator of mitotic chromosome condensation (Terakawa et al, 2017; Ganji et al, 2018). This suggests that loop extrusion does not involve topological DNA entry into the cohesin ring
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
