Chromothripsis and ecDNA initiated by N4BP2 nuclease fragmentation of cytoplasm-exposed chromosomes

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

doi:10.1126/science.ado0977

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Chromothripsis and ecDNA initiated by N4BP2 nuclease fragmentation of cytoplasm-exposed chromosomes

Journal article

Peer reviewed

Chromothripsis and ecDNA initiated by N4BP2 nuclease fragmentation of cytoplasm-exposed chromosomes

Ksenia Krupina, Alexander Goginashvili, Michael W Baughn, Stephen Moore, Christopher D Steele, Amy T Nguyen, Daniel L Zhang, Jonas Koeppel, Prasad Trivedi, Aarti Malhotra, …

Science (American Association for the Advancement of Science), Vol.390(6778), pp.1156-1163

12/11/2025

DOI: 10.1126/science.ado0977

PMID: 41379955

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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.

Carcinogenesis - genetics

Cell Line, Tumor

Cell Proliferation

Chromothripsis

Cytoplasm - enzymology

DNA Damage

DNA Fragmentation

DNA Repair Enzymes - genetics

DNA Repair Enzymes - metabolism

Endonucleases - genetics

Endonucleases - metabolism

Gene Amplification

Genome, Human

Genomic Instability

Humans

Mice

Micronuclei, Chromosome-Defective

Details

Title: Subtitle: Chromothripsis and ecDNA initiated by N4BP2 nuclease fragmentation of cytoplasm-exposed chromosomes
Creators: Ksenia Krupina - University of California San Diego
Alexander Goginashvili - University of California San Diego
Michael W Baughn - University of California San Diego
Stephen Moore - University of California San Diego
Christopher D Steele - Moores Cancer Center
Amy T Nguyen - University of California San Diego
Daniel L Zhang - University of California San Diego
Jonas Koeppel - University of Cambridge
Prasad Trivedi - University of California San Diego
Aarti Malhotra - University of California San Diego
David Jenkins - University of California San Diego
Andrew K Shiau - University of California San Diego
Yohei Miyake - University of California San Diego
Tomoyuki Koga - University of California San Diego
Shunichiro Miki - University of California San Diego
Frank B Furnari - University of California San Diego
Peter J Campbell - University of Cambridge
Ludmil B Alexandrov - La Jolla Bioengineering Institute
Don W Cleveland - Moores Cancer Center
Resource Type: Journal article
Publication Details: Science (American Association for the Advancement of Science), Vol.390(6778), pp.1156-1163
DOI: 10.1126/science.ado0977
PMID: 41379955
NLM abbreviation: Science
ISSN: 0036-8075
eISSN: 1095-9203
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Grant note: Wellcome Trust R35 GM122476 / NIGMS NIH HHS R01 ES030993 / NIEHS NIH HHS R01 CA258248 / NCI NIH HHS R56 NS080939 / NINDS NIH HHS R01 ES032547 / NIEHS NIH HHS U01 CA290479 / NCI NIH HHS R01 CA269919 / NCI NIH HHS
Language: English
Date published: 12/11/2025
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9985134037102771

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