Theory and simulations of condensin mediated loop extrusion in DNA

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.

Condensin extrudes DNA loops in steps up to hundreds of base pairs that are generated by ATP binding events

“…We suggest that such steps result from the hinge domain grabbing proximate DNA during every DNA loop-extrusion cycle. Indeed, our current as well as recently published model simulations indicate that this scenario can result in large step sizes ( 37 ).…”

“…Notably, the simulation value of ∼110 bp at 0.2 pN still deviated significantly from the corrected experimental median step size value of ∼200 bp. This quantitative difference suggests that future modelling work on SMC loop extrusion needs to account for additional effects such as enthalpic penalty for grabbing and bending short DNA segments compared to longer ones ( 37 ) or other potential non-specific condensin–DNA interactions ( 38 ).…”

Transcriptional Regulation and Implications for Controlling Hox Gene Expression

“…The loop-extrusion model postulates that DNA is squeezed out into a loop aided by Structural Maintenance of Chromosome (SMC) proteins, such as cohesin and condensin. They clasp DNA and these proteins stop moving DNA through the loop when they reach properly oriented CTCF sites [ 122 , 143 ]. This mechanism also allows for loops to form within the TADs, and dynamic enhancer contacts can thus be envisioned as the formation of different loop conformations to activate or inhibit transcription.…”

DNA tension-modulated translocation and loop extrusion by SMC complexes revealed by molecular dynamics simulations

“…The basic DNA-segment-capture mechanism (41) qualitatively explains existing experiments on SMCC translocation along DNA, and subsequent theoretical work incorporating similar mechanisms involving binding at one DNA site with capture of a second, distant DNA (45, 46) has led to concordant results. An alternative ‘scrunching’ model has also been proposed, based on the idea that DNA might be handed over from the hinge to the heads (or vice versa) via folding of the SMCC at an “elbow” joint (35, 47, 48, 49).…”

“…Left: Composite structural model of bsSMC (19), showing the two SMC proteins in cyan and green, the dimerization "hinge" domain (top, PDB structure 4RSJ), the long coiled-coiled arms (PDB 5XG2 and 5NNV) with putative "elbow" domain, and ATP-binding/ATPase "heads" (PDB 5XEI). The basic DNA-segment-capture mechanism (41) qualitatively explains existing experiments on SMCC translocation along DNA, and subsequent theoretical work incorporating similar mechanisms involving binding at one DNA site with capture of a second, distant DNA (45,46) has led to concordant results. An alternative 'scrunching' model has also been proposed, based on the idea that DNA might be handed over from the hinge to the heads (or vice versa) via folding of the SMCC at an "elbow" joint (35,47,48,49).…”