Beyond Back Splicing, a Still Poorly Explored World: Non-Canonical Circular RNAs

Most of the circRNAs reported to date originate from back splicing of a pre-mRNA, and these exonic circRNAs are termed canonical circRNAs. Our objective was to provide an overview of all other (non-canonical) circRNAs that do not originate from the junction of two exons and to characterize their common properties. Those generated through a failure of intron lariat debranching are the best known, even though studies on them are rare. These circRNAs retain the 2′–5′ bond derived from the intron lariat, and this feature probably explains the difficulties in obtaining efficient reverse transcription through the circular junction. Here, we provide an unprecedented overview of non-canonical circRNAs (lariat-derived intronic circRNAs, sub-exonic circRNAs, intron circles, tricRNAs), which all derive from non-coding sequences. As there are few data suggesting their involvement in cellular regulatory processes, we believe that it is early to propose a general function for circRNAs, even for lariat-derived circRNAs. We suggest that their small size and probably strong secondary structures could be major obstacles to their reliable detection. Nevertheless, we believe there are still several possible ways to advance our knowledge of this class of non-coding RNA.