Chromothripsis Driver Identified: N4BP2 Enzyme Shatters Tumour DNA

Analysis of over 10,000 human cancer genomes establishes that elevated expression of the enzyme N4BP2 is a strong predictor of chromothripsis and massive copy number amplifications. This study fundamentally alters our view of genomic instability, framing it as an enzymatically catalysed event rather than mere structural failure.

N4BP2: The Catalyst for Chromothripsis

Genomic instability defines cancer. A frequent occurrence involves the formation of micronuclei—small, aberrant structures containing chromosomes that failed to segregate correctly during cell division. These structures are unstable. They rupture. Upon rupture, the chromatin inside is exposed to the cytoplasm.

To identify what destroys this DNA, researchers performed an unbiased imaging-based screen using small interfering RNA. They systematically targeted all 204 known and putative human nucleases. The screen isolated a previously uncharacterised cytoplasmic endonuclease: NEDD4-binding protein 2 (N4BP2).

The mechanism is precise. N4BP2 enters the ruptured micronuclei. It attacks the chromatin. This enzymatic assault causes the chromosome fragmentation characteristic of chromothripsis. The fragments may then be stitched back together in random order.

Consequences for Tumour Evolution
The study links N4BP2 directly to aggressive cancer traits.

• ecDNA Formation: The fragmentation promotes the creation of extrachromosomal DNA. These are circular loops of DNA that replicate independently of chromosomes. They allow tumours to rapidly amplify oncogenes and develop resistance to therapies.
• Tumorigenesis: In models of human high-grade glioma, N4BP2 was not a bystander. It actively promoted tumour formation and proliferation.
• Clinical Correlation: The genomic analysis confirms that high N4BP2 expression correlates with the presence of ecDNA and complex rearrangements in patients.

While the study confirms N4BP2's ability to shatter DNA in lab settings and animal models, it suggests a broader clinical implication: that targeting this nuclease could arrest the rapid evolutionary capability of high-grade tumours. By preventing the shattering, we might prevent the subsequent adaptive mutations that make cancer so difficult to treat.