Language

English

Publication Date

9-1-2025

Journal

Nature Cell Biology

DOI

10.1038/s41556-025-01745-3

PMID

40866513

PMCID

PMC12431856

PubMedCentral® Posted Date

8-27-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Animals, Humans, Mice, Oncogene Proteins, Fusion, Brain Neoplasms, Carcinogenesis, RNA-Binding Protein EWS, Transcription Factor RelA, Intrinsically Disordered Proteins, Zinc Fingers, Transcription Factors, RNA-Binding Protein FUS, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Protein Domains, CNS cancer, CNS cancer, NMR spectroscopy, Protein folding

Published Open-Access

yes

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