Researchers at the University of California, San Diego (UC San Diego) have discovered what triggers chromothripsis, a dramatic genetic event in which a chromosome breaks into many pieces and is stitched back together incorrectly. This process happens in about 25% of all cancers and in nearly all bone cancers. It can help tumors become resistant to treatment very quickly.
For many years, scientists knew that chromothripsis caused major genetic damage, but they did not know what started it. The new study identified an enzyme called N4BP2 as the key trigger.
The process begins when a mistake during cell division traps a chromosome inside a small, fragile structure called a micronucleus, separate from the main nucleus. When this micronucleus breaks open, the trapped chromosome becomes exposed. N4BP2 then enters and cuts the DNA into many fragments. These fragments are reassembled in a disorganized way, leading to the large-scale genetic chaos seen in chromothripsis.
This discovery is important because chromothripsis allows cancer cells to change rapidly. Instead of slowly building up mutations over time, a tumor can gain hundreds of genetic changes in a single event. The study also suggests that extrachromosomal DNA (ecDNA)—small circular DNA fragments that make tumors more aggressive—may be produced as a result of N4BP2’s activity.
In laboratory experiments, researchers found that removing N4BP2 stopped the chromosome from shattering. This makes N4BP2 a promising target for new drugs designed to prevent cancer from quickly evolving and becoming resistant to treatment.
As senior author Don Cleveland explained, identifying what breaks the chromosome provides a clear and practical new target for slowing cancer evolution.