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Substrate accessibility regulation of human TopIIa decatenation by cohesin

Author

Listed:
  • Erin E. Cutts

    (Du Cane Road
    University of Sheffield)

  • Sanjana Saravanan

    (Du Cane Road)

  • Paul Girvan

    (Du Cane Road
    Du Cane Road)

  • Benjamin Ambrose

    (Du Cane Road
    Du Cane Road)

  • Gemma L. M. Fisher

    (Du Cane Road)

  • David S. Rueda

    (Du Cane Road
    Du Cane Road)

  • Luis Aragon

    (Du Cane Road)

Abstract

Human topoisomerase II alpha (TOP2α) resolves DNA intertwines between sister chromatids during mitosis. How cohesin, an SMC complex that holds sister chromatids, affects TOP2α decatenation is unclear. To addres this, we developed a quadruple-trap optical tweezers assay to create DNA braids and study TOP2α decatenation at the single-molecule level in real-time. We show that TOP2α resolves both single and multiple braids but becomes inefficient at forces exceeding 28 pN. TOP2α is sensitive to DNA geometry, exhibiting a chiral preference for right-handed braid crossings, and requires loading directly at DNA crossovers to act. Pre-loading TOP2α onto individual DNA strands before braid formation, in the presence of ATP, prevents decatenation. Finally, we show that human cohesin, but not condensin I, binds stably to DNA braids and blocks TOP2α activity. Our study provides novel insights into the role of substrate accessibility in regulating TOP2α‘s activity and highlights cohesin as a barrier to decatenation.

Suggested Citation

  • Erin E. Cutts & Sanjana Saravanan & Paul Girvan & Benjamin Ambrose & Gemma L. M. Fisher & David S. Rueda & Luis Aragon, 2025. "Substrate accessibility regulation of human TopIIa decatenation by cohesin," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62505-3
    DOI: 10.1038/s41467-025-62505-3
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    References listed on IDEAS

    as
    1. Artur P. Kaczmarczyk & Anne-Cécile Déclais & Matthew D. Newton & Simon J. Boulton & David M. J. Lilley & David S. Rueda, 2022. "Search and processing of Holliday junctions within long DNA by junction-resolving enzymes," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Emily C. Dykhuizen & Diana C. Hargreaves & Erik L. Miller & Kairong Cui & Andrey Korshunov & Marcel Kool & Stefan Pfister & Yoon-Jae Cho & Keji Zhao & Gerald R. Crabtree, 2013. "BAF complexes facilitate decatenation of DNA by topoisomerase IIα," Nature, Nature, vol. 497(7451), pages 624-627, May.
    3. Ineke Brouwer & Gerrit Sitters & Andrea Candelli & Stephanie J. Heerema & Iddo Heller & Abinadabe J. Melo de & Hongshan Zhang & Davide Normanno & Mauro Modesti & Erwin J. G. Peterman & Gijs J. L. Wuit, 2016. "Sliding sleeves of XRCC4–XLF bridge DNA and connect fragments of broken DNA," Nature, Nature, vol. 535(7613), pages 566-569, July.
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