A DNA tension-dependent tug-of-war between dimeric SMC motors governs loop extrusion directionality

Abstract

Structural maintenance of chromosome (SMC) complexes organize and regulate genomes by extruding DNA loops. During loop extrusion, DNA can be reeled into the growing loop from one or both sides, generating distinct extrusion directionality states whose physical basis remains unclear. Here, we combine single-molecule analysis and molecular dynamics simulations to investigate loop extrusion directionality across SMC complexes. We show that dimeric Smc5/6 and Wadjet predominantly perform two-sided loop extrusion during initial loop growth, whereas monomeric condensin exhibits one-sided extrusion, consistent with a relationship between stoichiometry and extrusion directionality. Surprisingly, however, cohesin predominantly exhibits one-sided extrusion despite functioning as a dimeric complex. Notably, dimeric Smc5/6 and Wadjet progressively transition from two-sided to one-sided extrusion as loop growth matures. Simulations and force-dependent analysis reveal that loop extrusion directionality is governed by a tension-dependent transition in dimeric motors. Increasing DNA tension erodes two-sided extrusion near the motor stalling force, driving a tug-of-war regime in which competing motors transiently dominate one another. This transition promotes one-sided extrusion during mature Smc5/6 and Wadjet-mediated loop extrusion and places cohesin, which has a comparatively low stalling force ([~]0.1 pN), constitutively near this regime. Together, our findings establish loop extrusion directionality as a dynamic emergent property governed by SMC stoichiometry, DNA tension, and stochastic motor competition.