DNA’s Stress-Reliever Can Mark the Spot for Cancer Mutations

Our cells rely on intricate machinery to manage the twisting and tangling of DNA, a task largely performed by enzymes known as topoisomerases. Specifically, Topoisomerase IIb (TOP2B) resolves this 'topological stress' by creating temporary double-strand breaks in the DNA helix. While this process is vital for genomic stability, a new study reveals that these very sites of repair can become hotspots for the genetic errors that fuel cancer.

In a comprehensive analysis of 6,500 whole cancer genomes, researchers generated detailed maps of where TOP2B binds, alongside structural proteins CTCF and RAD21. The team discovered that these binding sites are significantly enriched with somatic mutations and structural variants. It appears that in the process of untangling the genome, TOP2B marks regions that are particularly susceptible to damage, especially in areas with high transcription and long-range chromatin interactions.

The implications are profound. The study found that TOP2B binds to well-known 'driver genes'—sequences like TP53, MYC, and FOXA1 that, when mutated, actively promote cancer development. Furthermore, the researchers demonstrated that a specific non-coding element bound by TOP2B at the RMRP gene creates a mechanism that drives tumour initiation and growth in vivo. Ultimately, this research highlights a biological paradox: TOP2B acts as a safeguard of genome integrity, yet its activity delineates the very vulnerabilities that can lead to disease.