Theory and simulations of condensin mediated loop extrusion in DNA

Ryota Takaki,Atreya Dey,D Thirumalai,Guang Shi

doi:10.1038/s41467-021-26167-1

Abstract

Condensation of hundreds of mega-base-pair-long human chromosomes in a small nuclear volume is a spectacular biological phenomenon. This process is driven by the formation of chromosome loops. The ATP consuming motor, condensin, interacts with chromatin segments to actively extrude loops. Motivated by real-time imaging of loop extrusion (LE), we created an analytically solvable model, predicting the LE velocity and step size distribution as a function of external load. The theory fits the available experimental data quantitatively, and suggests that condensin must undergo a large conformational change, induced by ATP binding, bringing distant parts of the motor to proximity. Simulations using a simple model confirm that the motor transitions between an open and a closed state in order to extrude loops by a scrunching mechanism, similar to that proposed in DNA bubble formation during bacterial transcription. Changes in the orientation of the motor domains are transmitted over ~50 nm, connecting the motor head and the hinge, thus providing an allosteric basis for LE.

Highlights

Condensation of hundreds of mega-base-pair-long human chromosomes in a small nuclear volume is a spectacular biological phenomenon
When the results of structural studies are integrated with the observation that the hinge domain of the structural maintenance of chromosomes (SMC) complexes binds to DNA22–24, we conclude that both condensin and cohesin must use a similar mechanism to engage with DNA
Using a combination of simulations based on a simple model and theory, we have proposed that loop extrusion (LE) occurs by a scrunching mechanism

Summary

Introduction

Condensation of hundreds of mega-base-pair-long human chromosomes in a small nuclear volume is a spectacular biological phenomenon. Simulations using a simple model confirm that the motor transitions between an open and a closed state in order to extrude loops by a scrunching mechanism, similar to that proposed in DNA bubble formation during bacterial transcription. The only other theoretical study that predicts LE velocity as a function of an external load[16] is based on a four-state stochastic kinetic model, with minimally twenty parameters, for the catalytic cycle of the condensin that is coupled to loop extrusion[16]. By focusing on the motor activity of condensin through ATP-driven allosteric changes in the enzyme, our theory and simulations support "scrunching" as a plausible mechanism for loop extrusion. The theory and simulations show that for LE to occur there has to be an ATP-powered allosteric transition in condensin involving a large conformational change that brings distant parts (head and the hinge in Fig. 1) of the motor to proximity. Our work strongly suggests that the conformational transitions are driven by a scrunching mechanism in which the motor is relatively stationary, but DNA is reeled in by an allosteric mechanism

Methods

Results

Discussion

Conclusion