Researchers at the University of California San Diego have discovered the enzyme N4BP2, which triggers chromothripsis, a chaotic genetic event in cancer cells. This process allows tumors to rapidly evolve and resist treatments. The findings, published in Science, suggest blocking N4BP2 could limit cancer's genomic instability.
Chromothripsis involves a chromosome breaking into many fragments and reassembling in the wrong order, enabling quick genetic changes in cancer cells. First recognized over ten years ago, this event drives cancer progression but its trigger was unknown until now.
Scientists used imaging-based screening to test human nucleases in cancer cells. N4BP2 emerged as the enzyme that enters micronuclei—small compartments formed by cell division errors—and fragments trapped DNA. Removing N4BP2 from brain cancer cells sharply reduced chromosome shattering, while introducing it into healthy cell nuclei caused breaks.
"This discovery finally reveals the molecular 'spark' that ignites one of the most aggressive forms of genome rearrangement in cancer," said senior author Don Cleveland, Ph.D., professor of cellular and molecular medicine at UC San Diego School of Medicine and member of UC San Diego Moores Cancer Center. "By finding what breaks the chromosome in the first place, we now have a new and actionable point of intervention for slowing cancer evolution."
Analysis of over 10,000 cancer genomes showed higher N4BP2 activity linked to more chromothripsis, structural rearrangements, and extrachromosomal DNA (ecDNA), which promotes aggressive tumor growth and therapy resistance. Chromothripsis appears in about one in four cancers, nearly all osteosarcomas, and many brain cancers.
"These experiments showed us that N4BP2 isn't just correlated with chromothripsis. It is sufficient to cause it," said first author Ksenia Krupina, Ph.D., a postdoctoral fellow at UC San Diego. "This is the first direct molecular explanation for how catastrophic chromosome fragmentation begins."
The study highlights N4BP2 as a potential treatment target to curb tumors' adaptation. Additional coauthors include researchers from UC San Diego, the University of Cambridge, and the Wellcome Trust Sanger Institute. Funding came from the National Institutes of Health.
