Recurrent oncogenic ZC3H18 mutations stabilize endogenous retroviral RNA [hs_pAselected_RNAseq]

ZC3H18 (Z18) is a component of multiple nuclear RNA surveillance complexes which detect and degrade aberrant nuclear RNAs. We found recurrent truncating mutations in Z18 (Z18trunc) enriched in many cancer types, and as these truncating forms lack the distal domain required for recruitment of RNA degradation machinery, we predicted that Z18’s target transcripts would be stabilized. Expression of Z18trunc expedited melanoma onset in a zebrafish melanoma model and caused a specific accumulation of endogenous retroviral (ERV) RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia also had increased ERV expression. In engineered human melanoma cells, Z18trunc caused a more severe accumulation of ERV RNA than loss of one Z18 copy, showing dominant negative activity. Z18trunc was exported to the cytoplasm and failed to recruit RNA degradation machinery, while maintaining binding to two RNA stabilizing proteins. Z18trunc bound ERV RNA via aromatic amino acids in the zinc finger domain but failed to recruit the degradation machinery, so in lieu of destruction, ERV messages were stabilized. We find that Z18 normally specifically identifies ERV messages for destruction, while Z18trunc protects ERV RNA, contributing to oncogenesis. This work demonstrates that mutations in a second nuclear RNA surveillance component are oncogenic, supporting that deficient nuclear RNA surveillance is a broad tumor suppressive mechanism. Our work provides a specific mechanism that results in elevated ERV transcripts in cancer and reveals that nuclear RNA surveillance complexes play a complementary role in suppressing ERV expression.