2025-12-11 カリフォルニア大学サンディエゴ校(UCSD)
These images show the beginnings of chromothripsis in colorectal cancer cells. The N4BP2 enzyme (green) infiltrates a micronucleus (zoomed in square selections), where it induces DNA damage (red). Blue represents the main cell nucleus. Credit: UC San Diego Health Sciences
<関連情報>
- https://today.ucsd.edu/story/scientists-uncover-key-driver-of-treatment-resistant-cancer
- https://www.science.org/doi/10.1126/science.ado0977
細胞質に露出した染色体のN4BP2ヌクレアーゼによる断片化によって開始されるクロモトリプシスとecDNA Chromothripsis and ecDNA initiated by N4BP2 nuclease fragmentation of cytoplasm-exposed chromosomes
Ksenia Krupina, Alexander Goginashvili, Michael W. Baughn, Stephen Moore, […] , and Don W. Cleveland
Science Published:11 Dec 2025
DOI:https://doi.org/10.1126/science.ado0977
Editor’s summary
Massive genome rearrangements, or chromoanagenesis, are common in cancer and associated with poor prognosis. The most frequent form, chromothripsis, arises when one or more missegregated chromosomes form micronuclei that rupture, exposing their chromatin to the cytoplasm. Using an imaging-based small interfering RNA screen of human nucleases, Krupina et al. found that N4BP2, a previously uncharacterized cytoplasmic endonuclease, enters ruptured micronuclei and shatters chromosomes (see the Perspective by Clarke and Imieliński). N4BP2 was shown to promote the formation of extrachromosomal DNA and to enhance tumor growth in a human glioma model. Analysis of approximately 10,000 cancer genomes revealed that tumors with high N4BP2 expression were enriched for chromothripsis and copy number amplifications, implicating N4BP2 as a key driver of complex genome rearrangements. —Di Jiang
Abstract
Genome instability, including chromothripsis, is a hallmark of cancer. Cancer cells frequently contain micronuclei—small, nucleus-like structures formed by chromosome missegregation—that are susceptible to rupture, exposing chromatin to cytoplasmic nucleases. Through an unbiased, imaging-based small interfering RNA screen that targeted all 204 known and putative human nucleases, we identified a previously uncharacterized cytoplasmic endonuclease, NEDD4-binding protein 2 (N4BP2), that enters ruptured micronuclei and initiates DNA damage, leading to chromosome fragmentation. N4BP2 promoted genome rearrangements (including chromothripsis), formation of extrachromosomal DNA (ecDNA) in drug-induced gene amplification, tumorigenesis, and tumor cell proliferation in an induced model of human high-grade glioma. Analysis of more than 10,000 human cancer genomes revealed elevated N4BP2 expression to be predictive of chromothripsis and copy number amplifications, including ecDNA.
