Year: 2026
Type: article
Abstract: 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.
Source: Nature Communications
Institutions: Karolinska Institutet, The University of Tokyo, IRCCS Ospedale San Raffaele, Chalmers University of Technology, Massachusetts Institute of Technology, Centre National de la Recherche Scientifique, Inserm, Institut de génétique et de biologie moléculaire et cellulaire, Université de Strasbourg, Hôpitaux Universitaires de Strasbourg, Vita-Salute San Raffaele University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Japan Agency for Medical Research and Development, Agence Nationale de la Recherche, Cancerfonden, Fondation pour la Recherche Médicale, Karolinska Institutet, 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, Uppsala Multidisciplinary Center for Advanced Computational Science, HORIZON EUROPE European Research Council
Awards: G1190173965, G1305553894, G1373546608, G142144760, G1441096865, G156594879, Par-delà les frontières, l'Université de Strasbourg, G237047288, G2565930076, G2659019386, Façonner les talents en formation et en recherche à l'Université de Strasbourg, G3309697758, G3321450376, G4104961128, G4377315820, G4399195447, G4474667827, Integrative Molecular and Cellular Biology, G471331628, Real-Time Visualization of DNA Repair - One Molecule at a Time, G5296751580, G5612705525, Understanding how MYC drives transcriptional amplification via regulation of DNA topology, Targeting Topoisomerase Regulation of Oncogenic Growth, Mechanism and targeting of topoisomerase regulatory interactions to arrest MYC-driven tumors, G6803667113, G6832510969, G712881263, G7240651115, G7259097847, G7367701772, G74440900, G796431723, Infrastructure Française pour la Biologie Structurale Intégrée
OpenAlex ID: W7128436754