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

Xiaojuan Fan, Yun Yang, Chuyun Chen and Zefeng Wang ()
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Xiaojuan Fan: Shanghai Institute of Nutrition and Health
Yun Yang: Shanghai Institute of Nutrition and Health
Chuyun Chen: Shanghai Institute of Nutrition and Health
Zefeng Wang: Shanghai Institute of Nutrition and Health

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31327-y

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