Degradation of circular RNA by the ribonuclease DIS3

Features of circular RNAs (circRNAs) produced by back-splicing of eukaryotic exon(s) make them resistant to degradation by linear RNA decay machineries. Thus, a general circRNA degradation pathway under normal conditions has remained largely elusive. Here, we report that the endonucleolytic enzyme DIS3 is responsible for the degradation of circRNAs. Depletion of DIS3 leads to the upregulation of more than 60% of circRNAs with little effect on their linear cognates. Such DIS3-mediated circRNA degradation is conserved, occurs in the cytoplasm, and relies on DIS3's endonucleolytic activity but is independent of the RNA exosome complex. Sequence enrichment analyses suggest that DIS3 prefers to degrade circRNAs containing U-rich motifs. Correspondingly, synthesized RNA circles with or without U-rich motifs exhibit decreased or increased stabilities, respectively. Together, these findings suggest a general regulation of circRNA turnover by DIS3.