Recurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral RNA
Year: 2026
Type: article
Abstract: Endogenous retroviral (ERV) RNA is highly expressed in cancer, suggesting a selective advantage. We identify recurrent truncating mutations in ZC3H18 (Z18), a nuclear RNA surveillance factor lost in 30% of all cancers. We show that Z18 truncating mutations are oncogenic and that Z18 plays an evolutionarily conserved role in the nuclear surveillance of oncogenic ERV RNA. In zebrafish, Z18 truncation accelerates melanoma onset and selectively increases ERV RNA. Human cancer cell lines and patient tumors with Z18 mutations also upregulate ERV RNA. In engineered human melanoma cells, Z18 truncation enhances ERV RNA accumulation more than heterozygous Z18 loss, consistent with dominant-negative activity. Truncated Z18 directly stabilizes and relocalizes ERV RNA to the cytoplasm. ERV RNA expression accelerates melanoma and is required for Z18 truncation-mediated melanoma onset in zebrafish. Growth of human melanoma cells similarly depends on Z18-regulated ERV RNA. Together, these findings support Z18-regulated ERV RNA as a driver of oncogenesis.
Source: Cell Reports
Authors: Tanzina Tanu, Anna M. Cox, Jennifer A. Karlow, Priyanka Sharma, Kaiwen Sun, Xueyang He, Swathy Babu, Madeline K. Roelofs, Ethan Jeon, Jiajia Chen, Constance Wu, Jared Brown, Nelson B. Barrientos, Andrew S. McCallion, Kevin M. Brown, Stephen J. Chanock, David Liu, Tongwu Zhang, Kathleen H. Burns, Paul L. Boutz, Megan L. Insco
Institutions: Dana-Farber Cancer Institute, University of Rochester Medicine, University of Rochester, Boston Children's Hospital, Harvard University, Dana-Farber/Harvard Cancer Center, Johns Hopkins University, Johns Hopkins Medicine, National Cancer Institute, Division of Cancer Epidemiology and Genetics
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W7165744378