Recurrent oncogenic ZC3H18 mutations stabilize endogenous retroviral RNA
Tanu, T.; Cox, A. M.; Karlow, J.; Sharma, P.; He, X.; Wu, C.; Babu, S.; Brown, J.; Brown, K. M.; Chanock, S. J.; Liu, D.; Zhang, T.; Burns, K. H.; Boutz, P. L.; Insco, M. L.
Show abstract
Endogenous retroviral (ERV) RNA is highly expressed in cancer, although the molecular causes and consequences remain unknown. We found that ZC3H18 (Z18), a component of multiple nuclear RNA surveillance complexes, has recurrent truncating mutations in cancer. We show that Z18trunc mutations are oncogenic and that Z18 plays an evolutionarily conserved role in nuclear RNA surveillance of ERV RNA. In zebrafish, Z18trunc expedited melanoma onset and promoted a specific accumulation of ERV RNA. Z18 mutant human cell lines from the Cancer Cell Line Encyclopedia also expressed higher levels of ERV RNA. In engineered human melanoma cells, Z18trunc enhanced ERV RNA accumulation more than loss of one Z18 copy, indicating dominant negative activity. Z18trunc directly bound and stabilized ERV RNA. Notably, expression of ERV RNA was sufficient to expedite oncogenesis in a zebrafish model, which is the first evidence of which we are aware that ERV transcripts can play a functional role in cancer. Our work illuminates a mechanism for elevated ERV transcripts in cancer and supports that aberrant RNA accumulation is broadly oncogenic.
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