Recurrent oncogenic ZC3H18 mutations stabilize endogenous retroviral RNA [zfmelanoma_ribominus_RNAseq]

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.