MYC modulates TOP2A diffusion to promote substrate detection and activity
Topoisomerases alleviate DNA supercoiling by cleaving and resealing DNA strands. Previously, we showed that the oncoprotein MYC recruits and stimulates topoisomerases to remove DNA entanglements generated by oncogenic transcription. Understanding this mechanism may suggest methods to inhibit MYC-driven topoisomerase activation, targeting tumor-specific transcription. Here, we demonstrate that the essential topoisomerase TOP2A in human cells exists in a dynamic equilibrium between sequestration in the nucleolus, substrate searching in transcription hubs, and active engagement on chromatin. This equilibrium is highly responsive to changes in DNA topology, allowing cells to regulate TOP2A levels. Using single molecule tracking, here we show that MYC accelerates TOP2A diffusion in cells. We explain this phenotype by demonstrating that MYC limits TOP2A self-interaction in vitro, while decreasing the size of TOP2A complexes in cells. By increasing TOP2A diffusion, MYC promotes substrate binding and increases TOP2A engagement on chromatin genome-wide, revealing the mechanism underlying MYC stimulation of TOP2A activity.
Authors
- Evanthia Iliopoulou (ORCID: https://orcid.org/0000-0002-2690-4820)
- Alessia Loffreda (ORCID: https://orcid.org/0000-0003-4523-5666)
- Andrej Paluda (ORCID: https://orcid.org/0000-0002-0716-0512)
- Laura Baranello (ORCID: https://orcid.org/0000-0001-6039-1849)
- Carl Möller (ORCID: https://orcid.org/0000-0001-9463-6402)
- Donald P. Cameron (ORCID: https://orcid.org/0000-0002-3175-6965)
- Vladislav Kuzin (ORCID: https://orcid.org/0000-0002-7139-1884)
- Ewa Pavlová (ORCID: https://orcid.org/0000-0002-6693-9040)
- Matteo Mazzocca (ORCID: https://orcid.org/0000-0003-2079-1535)
- Fredrik Westerlund (ORCID: https://orcid.org/0000-0002-4767-4868)
- Brian Saidel Lopez Duran (ORCID: https://orcid.org/0009-0006-4847-1858)
- Bea Jagodic (ORCID: https://orcid.org/0009-0005-0997-8130)
- Valérie Lamour
- Hallgerdur Kolbeinsdottir
- Davide Mazza
- Kathryn Jackson
Institutions
- Centre National de la Recherche Scientifique (FR)
- Vita-Salute San Raffaele University (IT)
- Inserm (FR)
- Karolinska Institutet (SE)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- IRCCS Ospedale San Raffaele (IT)
- Hôpitaux Universitaires de Strasbourg (FR)
- Génétique Moléculaire Génomique Microbiologie (FR)
- Massachusetts Institute of Technology (US)
- Chalmers University of Technology (SE)
- Université de Strasbourg (FR)
- The University of Tokyo (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-09
- DOI
- https://doi.org/10.1038/s41467-026-69232-3
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Agence Nationale de la Recherche
- Cancerfonden
- Fondation pour la Recherche Médicale
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- University of Tokyo
- Associazione Italiana per la Ricerca sul Cancro
- Science for Life Laboratory
- Erik och Edith Fernströms Stiftelse för Medicinsk Forskning
- French Infrastructure for Integrated Structural Biology