Pervasive translation of circular RNAs driven by short IRES-like elements

Circular RNAs (circRNAs) are an abundant and conserved class of RNAs with ambiguous functions. Some circRNAs have been shown to be translated through IRES driven cap-independent translation, yet the scope of circRNA translation is unclear because endogenous IRESs are rare. To determine the prevalence and importance of circRNA translation, we screened a random 10-nt library using a cell-based reporter system and identified a large number of AU-rich motifs that are capable of initiating circRNA translation. These IRES-like elements are significantly enriched in circRNAs vs. linear mRNA and are sufficient to drive robust translation of circRNAs containing solely the coding sequences. Importantly, these elements are predicted to present in thousands of circRNAs with 67% of which encode a truncated isoform of host genes, and are found to bind trans-acting factors that promote circRNA translation. Our results indicate that extensive circRNA translation can be driven by short IRES-like elements, suggesting a general function of circRNAs in cytoplasm through translation.