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Zebrafish models demonstrate that Z18 truncation accelerates melanoma onset and selectively increases ERV RNA. Human cancer cell lines and patient tumors with Z18 mutations upregulate ERV RNA, and engineered melanoma cells reveal dominant-negative–like stabilization and cytoplasmic relocalization.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/recurrent-zc3h18-mutations-stabilize-oncogenic-endogenous-retroviral-rna/352057/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/recurrent-zc3h18-mutations-stabilize-oncogenic-endogenous-retroviral-rna/352057.png","ImageObject",300,407,{"name":92,"@type":93},"PakDamar76","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does ZC3H18 (Z18) play in cells?","Question",{"text":112,"@type":113},"ZC3H18 (Z18) functions as a nuclear RNA surveillance factor that helps detect and manage aberrant or unstable nuclear RNAs.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do Z18 mutations affect melanoma in zebrafish?",{"text":117,"@type":113},"In zebrafish, Z18 truncation accelerates melanoma onset and selectively increases endogenous retroviral (ERV) RNA levels.",{"name":119,"@type":110,"acceptedAnswer":120},"What mechanism links Z18 truncating mutations to oncogenesis?",{"text":121,"@type":113},"Truncated Z18 directly stabilizes and relocalizes ERV RNA to the cytoplasm, and ERV RNA expression is required for Z18 truncation-mediated melanoma onset, supporting ERV RNA as a driver of oncogenesis.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},352057,1790688589,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962090893057,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Author Manuscr ipt Author Manuscr ipt Author Manuscr ipt Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>Cell Rep. Author manuscript; available in PMC 2026 August 15. |\n| --- | --- |\n\nPublished in final edited form as:  \nCell Rep. 2026 July 28; 45(7): 117526. doi:10.1016/j.celrep.2026.117526 .  \nRecurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral RNA  \nTanzina Tanu 1 , Anna M. Cox 1 , Jennifer A. Karlow2,10 , Priyanka Sharma 1,10 , Kaiwen Sun 1,10 , Xueyang He3,4,5 , Swathy Babu 1 , Madeline K. Roelofs 1 , Ethan Jeon 1 , Jiajia Chen 1 , Constance Wu6 , Jared Brown7 , Nelson B. Barrientos8 , Andrew S. McCallion8 , Kevin M. Brown9 , Stephen J. Chanock9 , David Liu 1 , Tongwu Zhang9 , Kathleen H. Burns2 , Paul L. Boutz3,4,5 , Megan L. Insco 1,11,*  \n1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA  \n2 Department of Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA  \n3 University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA  \n4Center for RNA Biology, University of Rochester, Rochester, NY 14642, USA  \n5Wilmot Cancer Institute, Rochester, NY 14642, USA  \n6Stem Cell Program and Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02115, USA  \n7 Department of Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA  \n8McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205-1832, USA  \n9 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20850, USA  \n10These authors contributed equally  \n11Lead contact  \nSUMMARY  \nThis is an open access article under the CC BY license ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)).  \n*[Correspondence: megan_insco@dfci.harvard.edu](Correspondence: megan_insco@dfci.harvard.edu).  \nAUTHOR CONTRIBUTIONS  \nConceptualization, T.T., A.M.C., K.H.B., P.L.B., and M.L.I.; methodology, T.T., A.M.C., P.S., K.S., X.H., C.W., P.L.B., and M.L.I.; formal analysis, J.A.K., P.S., X.H., S.B., J.C., J.B., M.K.R., T.Z., P.L.B., and M.L.I.; investigation, T.T., A.M.C., K.S., M.K.R., E.J., N.B.B., and M.L.I.; writing – original draft, T.T., A.M.C., and M.L.I.; writing – review and editing, T.T., A.M.C., J.A.K., M.K.R., P.L.B., and M.L.I.; supervision, A.S.M., K.M.B., S.J.C., D.L., K.H.B., P.L.B., and M.L.I.; funding acquisition, T.T., J.A.K., A.S.M., N.B.B., K.H.B., P.L.B., and M.L.I.  \nDECLARATION OF INTERESTS  \nThe authors declare no competing interests.  \nDECLARATION OF GENERATIVE AI AND AI-ASSISTED TECHNOLOGIES IN THE WRITING PROCESS  \nDuring the preparation of this work, the author used GPT4DFCI, in order to identify typos during final editing. The authors reviewed all suggested edits and take full responsibility for the content of the publication.  \nAuthor Manuscr ipt Author Manuscr ipt Author Manuscr ipt Author Manuscript  \nTanu et al. Page 2  \nEndogenous retroviral (ERV) RNA is highly expressed in cancer, suggesting a selective advantage.  \nWe 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.  \nIn zebrafish, Z18 truncation accelerates melanoma onset and selectively increases ERV RNA.  \nHuman cancer cell lines and patient tumors with Z18 mutations also upregulate ERV RNA.  \nIn 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, t","cbCaihhJjOSAOjF8","https://ap.wps.com/l/cbCaihhJjOSAOjF8","pdf",2423732,43,"English","# Summary\n# Introduction\n## RNA homeostasis and cancer\n## Nuclear RNA surveillance and ZC3H18","[{\"question\":\"What role does ZC3H18 (Z18) play in cells?\",\"answer\":\"ZC3H18 (Z18) functions as a nuclear RNA surveillance factor that helps detect and manage aberrant or unstable nuclear RNAs.\"},{\"question\":\"How do Z18 mutations affect melanoma in zebrafish?\",\"answer\":\"In zebrafish, Z18 truncation accelerates melanoma onset and selectively increases endogenous retroviral (ERV) RNA levels.\"},{\"question\":\"What mechanism links Z18 truncating mutations to oncogenesis?\",\"answer\":\"Truncated Z18 directly stabilizes and relocalizes ERV RNA to the cytoplasm, and ERV RNA expression is required for Z18 truncation-mediated melanoma onset, supporting ERV RNA as a driver of oncogenesis.\"}]","Recurrent ZC3H18 mutations stabilize oncogenic endogenous retroviral RNA | PDF",1790097482,108]