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

Some circular RNAs (circRNAs) were found to be translated through IRES-driven mechanism, however the scope and functions of circRNA translation are unclear because endogenous IRESs are rare. To determine the prevalence and mechanism of circRNA translation, we develop a cell-based system to screen random sequences and identify 97 overrepresented hexamers that drive cap-independent circRNA translation. These IRES-like short elements are significantly enriched in endogenous circRNAs and sufficient to drive circRNA translation. We further identify multiple trans-acting factors that bind these IRES-like elements to initiate translation. Using mass-spectrometry data, hundreds of circRNA-coded peptides are identified, most of which have low abundance due to rapid degradation. As judged by mass-spectrometry, 50% of translatable endogenous circRNAs undergo rolling circle translation, several of which are experimentally validated. Consistently, mutations of the IRES-like element in one circRNA reduce its translation. Collectively, our findings suggest a pervasive translation of circRNAs, providing profound implications in translation control. Unbiased screen of random sequences identified many short IRES-like elements to drive circular RNA translation and hundreds of rolling circle translation events, suggesting a pervasive cap-independent translation in human transcriptome.

Automated summary

Circular RNAs (circRNAs) have been found to be translated through IRES-driven mechanism. Short elements that drive circRNA translation have been identified, suggesting a pervasive cap-independent translation in the human transcriptome.