Spontaneously directed loop extrusion in SMC complexes emerges from broken detailed balance and anisotropic DNA search

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Bonato, Andrea and Jang, Jae-Won and Kim, Do-Gyun and Moon, Kyoung-Wook and Michieletto, Davide and Ryu, Je-Kyung (2025) Spontaneously directed loop extrusion in SMC complexes emerges from broken detailed balance and anisotropic DNA search. Nucleic Acids Research, 53 (14). gkaf725. ISSN 1362-4962 (https://doi.org/10.1093/nar/gkaf725)

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Abstract

DNA loop formation by structural maintenance of chromosome (SMC) proteins, including cohesin, condensin, and the SMC5/6 complex, plays a pivotal role in genome organization. Despite its importance, the molecular mechanism underlying SMC-mediated loop formation, particularly how these complexes achieve persistent directionality (rectification) while minimizing backward steps during the formation of large loops, remains poorly understood. Here, we use atomic force microscopy (AFM) and computational simulation to uncover a key geometric feature of the yeast condensin SMC complex enabling rectified loop growth. Using AFM, we demonstrate that the hinge domain of yeast condensin exhibits a directional bias, extending orthogonally to the bound DNA and sampling an anisotropic region of space around the protein complex. By accounting for the geometric constraint on the hinge-mediated DNA-capture step, we computationally show that loop growth can spontaneously self-rectify. In contrast, an SMC model with broken detailed balance and isotropic search instead exhibited substantial loop shrinkage and random-walk-like behaviour. These findings reveal an overlooked, and potentially broadly conserved, anisotropic DNA capture mechanism through which SMC complexes form and stabilize DNA loops in vivo, in turn providing novel insights into the physical principles governing genome organization.

ORCID iDs

Bonato, Andrea ORCID logoORCID: https://orcid.org/0000-0002-5148-8590, Jang, Jae-Won, Kim, Do-Gyun, Moon, Kyoung-Wook, Michieletto, Davide and Ryu, Je-Kyung;
  • Item type:Article
    ID code:93788
    Dates:
    Date
    Event
    12 August 2025
    Published
    23 July 2025
    Accepted
    Subjects:Science > Physics
    Department:Faculty of Science > Physics
    Depositing user: Pure Administrator
    Date deposited:11 Aug 2025 15:17
    Last modified:17 Nov 2025 22:35
    URI:https://strathprints.strath.ac.uk/id/eprint/93788
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