MYC modulates TOP2A diffusion to promote substrate detection and activity
Journal article, 2026
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.
Author
Donald P. Cameron
Karolinska Institutet
Kathryn Jackson
Karolinska Institutet
Alessia Loffreda
IRCCS Osped San Raffaele
Carl Ivar Möller
Chalmers, Life Sciences, Chemical Biology
Vladislav Kuzin
Karolinska Institutet
Matteo Mazzocca
Massachusetts Institute of Technology (MIT)
IRCCS Osped San Raffaele
Evanthia Iliopoulou
Karolinska Institutet
Hallgerdur Kolbeinsdottir
Karolinska Institutet
Andrej Paluda
University of Tokyo
Evgeniya Pavlova
Molecular Bioscience
Bea Jagodic
Karolinska Institutet
Brian Saidel Lopez Duran
University of Strasbourg
Valerie Lamour
University of Strasbourg
Hop Univ Strasbourg
Fredrik Westerlund
Molecular Bioscience
Davide Mazza
Università Vita-Salute San Raffaele
IRCCS Osped San Raffaele
Laura Baranello
Karolinska Institutet
Nature Communications
2041-1723 (ISSN) 20411723 (eISSN)
Vol. 17 1 2527Subject Categories (SSIF 2025)
Cell and Molecular Biology
Neurosciences
Cancer and Oncology
DOI
10.1038/s41467-026-69232-3
PubMed
41663397