通过无偏倚的、基于成像的小干扰RNA筛选，针对所有204种已知和推测的人类核酸酶，研究小组发现了一种以前未被表征的细胞质内切酶，NEDD4结合蛋白2 (N4BP2)，它进入破裂的微核并引发DNA损伤，导致染色体断裂。在人类高级别胶质瘤诱导模型中，N4BP2促进了基因组重排（包括染色体断裂）、药物诱导基因扩增中染色体外DNA （ecDNA）的形成、肿瘤发生和肿瘤细胞增殖。对1万多个人类癌症基因组的分析显示，N4BP2表达升高可预测染色体分裂和拷贝数扩增，包括ecDNA。
研究人员表示，基因组不稳定，包括染色体断裂，是癌症的一个标志。癌细胞通常含有微核——由染色体错分离形成的小的核样结构——易破裂，使染色质暴露于细胞质核酸酶。
附：英文原文
Title: Chromothripsis and ecDNA initiated by N4BP2 nuclease fragmentation of cytoplasm-exposed chromosomes
Author: 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
Issue&Volume: 2025-12-11
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.
DOI: ado0977
Source: https://www.science.org/doi/10.1126/science.ado0977