UC San Diego researchers have identified an enzyme that shatters chromosomes in cancer cells, driving rapid evolution and drug resistance. The finding opens a new path to potentially slow or stop some of the most aggressive tumors.
For more than a decade, scientists have known that many of the deadliest cancers evolve in sudden, catastrophic bursts, shattering a chromosome into pieces and stitching it back together in chaotic ways. What they did not know was what lit the fuse.
Researchers at the University of California San Diego now say they have found that spark: a single enzyme that can infiltrate vulnerable chromosomes and break them apart, helping tumors rapidly adapt and resist treatment.
The work, published in the journal Science, identifies an enzyme called N4BP2 as a key driver of a process known as chromothripsis. In chromothripsis, instead of accumulating DNA mutations slowly over time, a cancer cell can undergo dozens to hundreds of genetic changes in one event, dramatically accelerating its evolution.
Chromothripsis has emerged as a common and powerful engine of cancer progression. Scientists estimate that roughly a quarter of human cancers show signs of it, and in some tumor types the rate is far higher. Aggressive bone cancers such as osteosarcoma almost always carry this kind of genomic chaos, and many brain cancers do as well.
The new study finally nails down the molecular culprit behind this phenomenon, according to senior author Don Cleveland, a professor of cellular and molecular medicine at UC San Diego School of Medicine and member of UC San Diego Moores Cancer Center.
“This discovery finally reveals the molecular ‘spark’ that ignites one of the most aggressive forms of genome rearrangement in cancer,” Cleveland said in a news release. “By finding what breaks the chromosome in the first place, we now have a new and actionable point of intervention for slowing cancer evolution.”
Chromothripsis typically begins when something goes wrong during cell division. Instead of being evenly separated into two daughter cells, an individual chromosome can get stranded in a tiny, fragile bubble of membrane called a micronucleus. These micronuclei are unstable. When they rupture, the chromosome inside is left exposed to DNA-cutting enzymes, known as nucleases.
Until now, no one knew which nuclease was responsible for the massive chromosome shattering seen in chromothripsis. Without that information, it was impossible to design drugs that might block the process at its source.
To solve the mystery, the UC San Diego team turned to an imaging-based screening strategy. They systematically examined all known and predicted human nucleases in living cancer cells, watching in real time to see which enzymes entered micronuclei and damaged DNA.
One enzyme stood out. N4BP2 was uniquely able to slip into micronuclei and break apart the trapped chromosome.
Finding a suspect was only the first step. To show that N4BP2 actually causes chromothripsis, the researchers removed the enzyme from brain cancer cells. When N4BP2 was eliminated, chromosome shattering dropped sharply. When the team forced N4BP2 into the main nucleus of otherwise healthy cells, intact chromosomes began to break.
The experiments made the enzyme’s role unmistakable, according to first author Ksenia Krupina, a postdoctoral fellow at UC San Diego.
“These experiments showed us that N4BP2 isn’t just correlated with chromothripsis. It is sufficient to cause it,” Krupina said in the news release. “This is the first direct molecular explanation for how catastrophic chromosome fragmentation begins.”
The scientists then looked beyond lab dishes to see whether N4BP2’s activity showed up in real tumors. They analyzed more than 10,000 human cancer genomes from many cancer types. Tumors with high levels of N4BP2 expression had significantly more chromothripsis and structural rearrangements in their DNA.
Those same tumors also carried more extrachromosomal DNA, or ecDNA. These are circular pieces of DNA that sit outside the main chromosomes and often contain extra copies of cancer-driving genes. EcDNA has become a major focus in cancer research because it is strongly linked to treatment resistance and aggressive tumor growth.
The new findings suggest that ecDNA is part of a larger chain reaction. When N4BP2 triggers chromothripsis, the resulting DNA fragments can give rise to ecDNA, which then helps tumors survive and thrive under the pressure of chemotherapy, radiation or targeted drugs.
By placing N4BP2 at the start of this cascade, the study offers a new way to think about some of the most stubborn cancers, where standard therapies often fail and tumors quickly recur.
Understanding the trigger for chromothripsis could eventually lead to new treatment strategies, according to Cleveland.
“Understanding what triggers chromothripsis gives us a new way to think about stopping it,” he said. “By targeting N4BP2 or the pathways it activates, we may be able to limit the genomic chaos that allows tumors to adapt, recur and become drug‑resistant.”
Any future therapies aimed at N4BP2 are still years away. Researchers will need to learn more about how the enzyme works in normal cells, whether it has essential roles outside of cancer, and how best to block its activity without causing harmful side effects.
Still, the discovery marks a major step forward in decoding how cancers evolve so quickly and why some become nearly impossible to treat. By tracing the path from a single enzyme to shattered chromosomes, circular DNA and drug-resistant tumors, the UC San Diego team has opened a new front in the effort to outsmart cancer’s ability to change.