Topoisomerase-Mediated DNA Damage Response

Topoisomerases are essential enzymes that resolve DNA supercoiling and entanglements generated during replication, transcription and chromosomal segregation by transiently cleaving and rejoining DNA strands. When their covalent cleavage complexes become trapped—either through catalytic inhibition, transcriptional stress or chemotherapeutic poisons—persistent DNA breaks arise, challenging genome integrity. Cells deploy a coordinated damage-response network involving proteolytic processing, specialised endonucleases and phosphodiesterases to remove covalently linked topoisomerase adducts, restore DNA continuity and prevent chromosomal rearrangements. Dysregulation of these pathways underlies developmental disorders, neurodegeneration and cancer, while targeted modulation of topoisomerase-mediated lesions informs chemotherapeutic strategies and resistance mechanisms.

Research from Nature Portfolio

Recent studies have shown that catalytic inhibition of Topoisomerase II during interphase profoundly destabilises heterochromatin and clustered repetitive elements by trapping inactive Top2 complexes. This entrapment generates unresolved DNA catenates and induces double-strand breaks that rely on the structure-specific endonuclease Ercc1–XPF, recruited in a SUMO-dependent manner, to process and resolve these lesions. In parallel, investigation of an ATM kinase inhibitor revealed that interference with ATM–Top2β interactions stabilises Top2β-DNA cleavage complexes, impairs repair of poison-induced breaks and synergises with etoposide to accelerate lung cancer cell death. These findings highlight therapeutic avenues combining DNA damage-response inhibitors with topoisomerase poisons to enhance tumour selectivity and limit collateral genome damage.

Topoisomerase-Mediated DNA Damage Response publication trend

The graph below shows the total number of articles in topoisomerase-mediated dna damage response across all publications each year (not limited to Nature Index journals).

Technical terms

Topoisomerase: Enzyme that transiently cleaves and rejoins DNA strands to relieve torsional stress and inter-chromosomal entanglements.

Topoisomerase cleavage complex (TOPcc): A transient intermediate in which a topoisomerase is covalently linked to DNA, capable of generating double-strand breaks if stabilised.

DNA double-strand break (DSB): A lesion in which both strands of the DNA helix are severed, posing high risk to genomic stability if unrepaired.

Heterochromatin: Densely packed chromosomal regions, often repetitive, that are transcriptionally silent and subject to distinct topological constraints.

R-loop: A three-strand nucleic acid structure comprising an RNA–DNA hybrid and displaced single-stranded DNA, which can impede replication and transcription.

Sumoylation: A reversible post-translational modification involving covalent attachment of Small Ubiquitin-like Modifier (SUMO) proteins, modulating protein interactions and localisation.

Proteolysis: The enzymatic degradation of proteins, such as proteasome-mediated removal of topoisomerase adducts to expose underlying DNA breaks for repair.

References

1. Inhibition of topoisomerase 2 catalytic activity impacts the integrity of heterochromatin and repetitive DNA and leads to interlinks between clustered repeats. Nature Communications (2024).
2. ATM inhibitor KU60019 synergistically sensitizes lung cancer cells to topoisomerase II poisons by multiple mechanisms. Scientific Reports (2023).
3. RAD54L2 counters TOP2-DNA adducts to promote genome stability. Science Advances (2023).
4. MDM2 provides TOP2 poison resistance by promoting proteolysis of TOP2βcc in a p53-independent manner. Cell Death & Disease (2024).
5. TOP1 and R-loops facilitate transcriptional DSBs at hypertranscribed cancer driver genes. iScience (2024).