Translation of Circular RNAs

Circular RNAs (circRNAs) are covalently closed RNAs that are present in all eukaryotes tested. CircRNAs are less abundantly expressed than mRNAs. Recent RNAseq analyses indicate that more than 800,000 circRNA isoforms exist in humans, which is more than twice the number of currently known mRNA isoforms. CircRNAs are generated through backsplicing that depends on pre-mRNA structures, which are influenced by intronic elements, for example primate-specific Alu elements, leading to species-specific circRNAs. CircRNAs are mostly cytosolic, stable and influence cells by sequestering miRNAs and RNA-binding proteins. We review the increasing evidence that circRNAs are translated into proteins using several cap-independent translational mechanisms, that include internal ribosomal entry sites, N6-methyladenosine RNA modification, adenosine to inosine RNA editing and interaction with the eIF4A3 component of the exon junction complex. CircRNA are translated under conditions that favor cap-independent translation, notably in cancer. CircRNA-encoded proteins are shorter than mRNA-encoded proteins and overall have a high propensity for phase separation. In summary, circRNA encoded proteins are translated under particular cellular conditions and contribute to proteome diversity and pathophysiology.