Chromothripsis and ecDNA initiated by N4BP2 nuclease fragmentation of cytoplasm-exposed chromosomes
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.
Authors
- Alexander Goginashvili (ORCID: https://orcid.org/0000-0002-3305-5898)
- Tomoyuki Koga (ORCID: https://orcid.org/0000-0002-8330-117X)
- A. Malhotra
- Peter J. Campbell (ORCID: https://orcid.org/0000-0002-3921-0510)
- Daniel L. Zhang (ORCID: https://orcid.org/0009-0005-8505-2831)
- Don W. Cleveland (ORCID: https://orcid.org/0000-0002-1934-3682)
- Prasad Trivedi (ORCID: https://orcid.org/0000-0002-7150-4324)
- Frank B. Furnari (ORCID: https://orcid.org/0000-0003-1909-4361)
- Michael W. Baughn (ORCID: https://orcid.org/0000-0001-8525-8024)
- Christopher D. Steele (ORCID: https://orcid.org/0000-0002-6110-0086)
- Jonas Koeppel (ORCID: https://orcid.org/0000-0003-1306-3994)
- Ksenia Krupina (ORCID: https://orcid.org/0009-0003-7864-8069)
- Yohei Miyake (ORCID: https://orcid.org/0009-0000-7713-4419)
- Ludmil B. Alexandrov (ORCID: https://orcid.org/0000-0003-3596-4515)
- Anh Tuan Nguyen‐Huynh (ORCID: https://orcid.org/0000-0002-9628-580X)
- Andrew K. Shiau (ORCID: https://orcid.org/0000-0002-3993-4842)
- Stephen Moore (ORCID: https://orcid.org/0009-0004-3908-3920)
- David Jenkins (ORCID: https://orcid.org/0009-0000-3001-0996)
- Shunichiro Miki (ORCID: https://orcid.org/0000-0002-9625-8668)
Institutions
- University of Cambridge (GB)
- Wellcome Sanger Institute (GB)
- University of California San Diego (US)
- La Jolla Bioengineering Institute (US)
- Moores Cancer Center
Publication Details
- Journal
- Science
- Published
- 2025-12-11
- DOI
- https://doi.org/10.1126/science.ado0977
- Citations
- 4
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.22