Synthetic ZFTA fusions pinpoint disordered protein domain acquisition as a mechanism of brain tumorigenesis

作者：Amir Arabzade, Hazheen K. Shirnekhi, Srinidhi Varadharajan, Siri Ippagunta, Alvah H. Phillips, Nic Laboe, David W. Baggett, Wahiduzzaman, Minjeong Jo, Tuyu Zheng, Rajesh Kumar Pathak, David Gee, Devesh Bhimsaria, Huiyun Wu, Xiaotong Gao, Jian Liu, Erik Emanus, Alison M. Bland, Alisha Kardian, Arthur A. Hancock, Blake Holcomb, Terry W. Wright, Taylor Bugbee, Hongyan Sun, M. Zhai, Emily Caesar, M. Park, Sudhakar Tripathi, Abbas Shirinifard, Karen Lowe, Ali Khalighifar, Rebecca A. Petersen, Sharon V. King, Daniel R. Stabley, Aaron Pitre, George E. Campbell, C-G Park, W. Toler Freyaldenhoven, Bappaditya Chandra, Youlin Xia, Erik Bonten, A. Achari, Suresh Kandikonda, Alexandre F. Carisey, Stanley Pounds, Jian Xu, David W. Ellison, Benjamin Deneen, Kelsey C. Bertrand, Richard W. Kriwacki, Stephen C. Mack · 发表于：Nature Cell Biology · 年份：2025 · DOI：10.1038/s41556-025-01745-3 · 被引用次数：4 · 研究领域：RNA Research and Splicing、RNA modifications and cancer、Ubiquitin and proteasome pathways

Over 95% of ependymomas that arise in the cortex are driven by a gene fusion involving the zinc finger translocation-associated (ZFTA) protein. Here, using super-resolution and lattice light-sheet microscopy, we demonstrate that the most frequent fusion variant, ZFTA-RELA (ZR), forms dynamic nuclear condensates that are required for oncogene expression and tumorigenesis. Mutagenesis studies of ZR reveal a key intrinsically disordered region (IDR) in RELA that governs condensate formation. Condensate-modulating IDR mutations introduced into ZR impaired its genomic occupancy at oncogenic loci and inhibited the recruitment of transcriptional effector proteins, such as MED1, BRD4 and RNA polymerase II. Using nuclear magnetic resonance spectroscopy, we examined the DNA-binding residues of the critical zinc finger (ZF1) found in ZR and characterized their significance for condensate formation, genomic binding and oncogene activation. We generated synthetic ZFTA fusion proteins where IDRs from known condensate-forming proteins were grafted into ZR. Synthetic ZFTA fusion oncoproteins utilizing IDRs from EWS and FUS restored condensate formation, oncogene transcription and tumour initiation in mice. These findings provide key insights into the oncogenic mechanism of ZR and the importance of IDR acquisition in fusion oncoproteins in brain cancer.