N4BP2 Identified as the Engine of Chromothripsis in Cancer Genomes

Analysis of over 10,000 human cancer genomes reveals that elevated expression of NEDD4-binding protein 2 (N4BP2) strongly predicts copy number amplifications and the catastrophic genomic event known as chromothripsis. Researchers identified this cytoplasmic endonuclease via an unbiased siRNA screen targeting 204 human nucleases. It acts as a demolition crew, entering ruptured micronuclei to fragment exposed DNA.

Mechanisms Driving Chromothripsis

Micronuclei—small, unstable structures resulting from chromosome missegregation—are common in malignant cells. Their envelopes are fragile. When they rupture, chromatin is exposed to the cytoplasm. This study demonstrates that N4BP2 detects this exposure. It infiltrates the micronucleus. It shreds the DNA. This fragmentation is the precursor to chromothripsis, where chromosomes are shattered and stitched back together in random order. In an induced model of human high-grade glioma, the presence of N4BP2 was not passive; it actively promoted tumorigenesis and tumour cell proliferation.

The Link to ecDNA and Resistance

DNA fragmentation by N4BP2 appears to drive the formation of extrachromosomal DNA (ecDNA). These circular DNA particles often carry oncogenes and replicate independently of chromosomes. They are potent drivers of drug resistance. The data indicates that N4BP2 facilitates the gene amplification necessary for tumours to survive drug pressure. Consequently, high levels of this protein may signal a tumour capable of rapid genetic evolution.

Clinical Implications

Current understanding suggests preventing micronuclei rupture is difficult. However, neutralising the nuclease that exploits this rupture offers a new therapeutic avenue. If N4BP2 activity is inhibited, the catastrophic shattering of chromosomes might be arrested. This suggests a potential strategy to stabilise the genome and reduce the emergence of drug-resistant subclones in aggressive cancers.