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MYC modulates TOP2A diffusion to promote substrate detection and activity

Donald P Cameron1,2, Kathryn Jackson1, Alessia Loffreda3

  • 1Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.

Nature Communications
|February 9, 2026
PubMed

Insights

The oncoprotein MYC accelerates the diffusion of topoisomerase TOP2A in cells. This mechanism enhances MYC-driven transcription by increasing TOP2A

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Topoisomerases resolve DNA supercoiling crucial for cellular processes.
  • The oncoprotein MYC recruits and stimulates topoisomerases during oncogenic transcription.
  • Understanding MYC-TOP2A interactions could reveal cancer therapeutic targets.

Purpose of the Study:

  • To elucidate the mechanism by which MYC stimulates TOP2A activity.
  • To investigate the dynamic regulation of TOP2A in human cells.
  • To determine how MYC influences TOP2A localization and function.

Main Methods:

  • Single molecule tracking to observe TOP2A diffusion dynamics.
  • In vitro assays to assess TOP2A self-interaction.
  • Cellular assays to measure TOP2A complex size and chromatin engagement.

Main Results:

  • TOP2A exists in a dynamic equilibrium between nucleolar sequestration, transcription hubs, and chromatin.
  • MYC accelerates TOP2A diffusion by limiting self-interaction and reducing complex size.
  • Increased TOP2A diffusion enhances substrate binding and genome-wide chromatin engagement.

Conclusions:

  • MYC's regulation of TOP2A diffusion is a key mechanism for stimulating its activity.
  • This finding provides insights into targeting MYC-driven transcription in cancer.
  • The dynamic regulation of TOP2A is responsive to DNA topology changes.

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