The complexity of the translation ability of circRNAs

•CircRNAs can serve as translational templates in vitro and in vivo.•IRES might allow the formation of peptides or proteins from circRNAs.•Translation of circRNAs could occur in the absence of IRES sequence, poly-A tail, or a cap structure.•Peptides and proteins produced by circRNAs could be biologically functional molecules in cells.

Circular RNAs (circRNAs) are a new class of long non-coding RNAs that play a potential role in gene expression regulation, acting as efficient microRNAs sponges. The latest surprise concerning circRNAs is that we now know that they can serve as transcriptional activators in human cells, indicating that circRNAs are involved in important regulatory tasks. Recently, new insight has been gained about the coding potential of circular viroid RNAs, as well as the presence of Internal Ribosomal Entry Sites (IRES) allowing the formation of peptides or proteins from circular RNA. Here, we discuss the current state of our knowledge regarding evidence supporting the hypothesis that circRNAs serve as protein-coding sequences in vitro and in vivo. Also, we remark on the difficulties of their identification and highlight some tools currently available for exploring the coding potential of circRNA.