A Singular and Widespread Group of Mobile Genetic Elements: RNA Circles with Autocatalytic Ribozymes

Abstract

Circular DNAs, such as most prokaryotic and phage genomes, are a frequent form of nucleic acids, whereas circular RNAs had been regarded as unusual macromolecules until very recently. The first reported RNA circles were the family of small infectious genomes of viroids and circular RNA (circRNA) satellites of plant viruses, some of which contain small self-cleaving RNA motifs, such as the hammerhead (HHR) and hairpin ribozymes. A similar infectious circRNA, the unique human hepatitis delta virus (HDV), is another viral satellite that also encodes self-cleaving motifs called HDV ribozymes. Very recently, different animals have been reported to contain HDV-like circRNAs with typical HDV ribozymes, but also conserved HHR motifs, as we describe here. On the other hand, eukaryotic and prokaryotic genomes encode sequences able to self-excise as circRNAs, like the autocatalytic Group I and II introns, which are widespread genomic mobile elements. In the 1990s, the first circRNAs encoded in a mammalian genome were anecdotally reported, but their abundance and importance have not been unveiled until recently. These gene-encoded circRNAs are produced by events of alternative splicing in a process generally known as backsplicing. However, we have found a second natural pathway of circRNA expression conserved in numerous plant and animal genomes, which efficiently promotes the accumulation of small non-coding RNA circles through the participation of HHRs. Most of these genome-encoded circRNAs with HHRs are the transposition intermediates of a novel family of non-autonomous retrotransposons called retrozymes, with intriguing potential as new forms of gene regulation.