Symmetry and force response of cohesin loop extrusion are determined by diffusion of its motor and anchor domains

Abstract

Cohesin, a Structural Maintenance of Chromosomes (SMC) complex is thought to organize genomes by generating DNA loops, yet the molecular basis of loop extrusion remains incompletely understood. Here, we show that a single S. pombe cohesin complex extrudes DNA loops both symmetrically or asymmetrically, depending on the external force applied to DNA and that the mode and speed are controlled by stochastic switching of the cohesin motor between driving and diffusive states. We directly measured the weak forces generated during cohesin-mediated loop extrusion while simultaneously visualizing DNA loops and found that forces as low as 0.05 pN pull DNA out of cohesin loop without disrupting cohesin-DNA interaction. We further identified the Scc3 subunit as a diffusive DNA anchor required for loop extrusion and showed that its physical separation from the motor domain by unstructured regions of Scc1 promotes loop-extrusion initiation. Together, our results support a model in which cohesin loop extrusion is limited and tuned by diffusive motion of both anchor and motor modules, providing a mechanistic framework for how weak and diffusive cohesin-DNA interactions could modulate cohesin function in chromatin organization.