# MYC modulates TOP2A diffusion to promote substrate detection and activity

## TL;DR

This paper shows how the MYC protein increases the activity of TOP2A topoisomerase by enhancing its movement and reducing self-interactions, helping it resolve DNA supercoiling.

## Contribution

The study reveals a novel mechanism by which MYC modulates TOP2A diffusion and activity through limiting self-interactions.

## Key findings

- MYC increases TOP2A diffusion in cells by limiting its self-interactions.
- TOP2A chromatin engagement is enhanced genome-wide due to MYC stimulation.
- TOP2A exists in a dynamic equilibrium between nucleolar sequestration and transcription hub activity.

## 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.

TOP2A resolves DNA supercoiling, but how MYC stimulates its activity was unclear. Here, the authors show that MYC increases TOP2A diffusion by limiting its self‑interaction, boosting substrate binding and chromatin engagement to enhance topoisomerase function.