Spliceosome inhibition generates Z-form RNAs to active ZBP1-mediated cell death

Numerous cellular stresses including oncogenic insults dysregulate RNA splicing, often provoking inflammatory responses and cell death. However, the generalized mechanisms by which cell sensed and respond to splicing dysregulation remain elusive.

Here we show that spliceosome inhibition induces the widespread formation of unique, left-handed nucleic acids, Z-form nucleic acids (Z-NAs) from the nucleus. These Z-NAs were double-stranded RNA (dsRNA) that were predominantly derived from transcripts of mis-spliced intronic RNA. Spliceosome inhibition induced the egress of these Z-RNA from the nucleus to the cytoplasm in an active manner.