Ksenia Krupina, Alexander Goginashvili, Michael W. Baughn, Stephen Moore, Christopher D. Steele, Anh Tuan Nguyen‐Huynh, Daniel L. Zhang, Jonas Koeppel, Prasad Trivedi, A. Malhotra, David Jenkins, Andrew K. Shiau, Yohei Miyake, Tomoyuki Koga, Shunichiro Miki, Frank B. Furnari, Peter J. Campbell, Ludmil B. Alexandrov, Don W. Cleveland
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.