Breakthrough Study Identifies Enzyme Fueling Cancer DNA Changes

Scientists at the University of California San Diego have identified the enzyme that triggers chromothripsis-a catastrophic genetic event in which a chromosome shatters into pieces and is stitched back together in the wrong order, accelerating cancer evolution and drug resistance.

The findings, published in Science, reveal that an enzyme called N4BP2 acts as the molecular “spark” behind this destructive process. Chromothripsis allows cancer cells to undergo dozens or even hundreds of genetic alterations in a single event, rather than accumulating mutations gradually. This rapid burst of genome rearrangement can make tumors more aggressive and harder to treat.

Chromothripsis begins when errors during cell division trap chromosomes inside small compartments known as micronuclei. When these fragile structures rupture, the exposed DNA becomes vulnerable to enzymes that cut genetic material. Using advanced imaging-based screening, researchers examined all known human nucleases and discovered that N4BP2 uniquely enters micronuclei and fragments the DNA inside.

When the team removed N4BP2 from brain cancer cells, chromosome shattering dropped sharply. Conversely, forcing the enzyme into healthy cell nuclei caused chromosomes to break apart, confirming that N4BP2 is sufficient to trigger chromothripsis.

Analysis of more than 10,000 cancer genomes showed that tumors with higher N4BP2 activity had more chromothripsis and structural rearrangements. These cancers also contained elevated levels of extrachromosomal DNA (ecDNA) — circular DNA fragments linked to aggressive growth and therapy resistance.

The discovery positions N4BP2 as a promising therapeutic target. By blocking this enzyme or its pathways, researchers hope to reduce the genomic instability that enables tumors to evolve, recur, and resist treatment.

REFERENCE: Ksenia Krupina, Alexander Goginashvili, Michael W. Baughn, Stephen Moore, Christopher D. Steele, Amy T. Nguyen, Daniel L. Zhang, Jonas Koeppel, Prasad Trivedi, Aarti Malhotra, David Jenkins, Andrew K. Shiau, Yohei Miyake, Tomoyuki Koga, Shunichiro Miki, Frank B. Furnari, Peter J. Campbell, Ludmil B. Alexandrov, Don W. Cleveland. Chromothripsis and ecDNA initiated by N4BP2 nuclease fragmentation of cytoplasm-exposed chromosomes. Science, 2025; 390 (6778): 1156 DOI: 10.1126/science.ado0977