A 360 degree view of circular RNAs: From biogenesis to functions

Abstract

The first circular RNA (circRNA) was identified more than 40 years ago, but it was only recently appreciated that circular RNAs are common outputs of many eukaryotic protein-coding genes. Some circular RNAs accumulate to higher levels than their associated linear mRNAs, especially in the nervous system, and have clear regulatory functions that result in organismal phenotypes. The pre-mRNA splicing machinery generates circular RNAs via backsplicing reactions, which are often facilitated by intronic repeat sequences that base pair to one another and bring the intervening splice sites into close proximity. When spliceosomal components are limiting, circular RNAs can become the preferred gene output, and backsplicing reactions are further controlled by exon skipping events and the combinatorial action of RNA binding proteins. This allows circular RNAs to be expressed in a tissue- and stage-specific manner. Once generated, circular RNAs are highly stable transcripts that often accumulate in the cytoplasm. The functions of most circular RNAs remain unknown, but some can regulate the activities of microRNAs or be translated to produce proteins. Circular RNAs can further interface with the immune system as well as control gene expression events in the nucleus, including alternative splicing decisions. Circular RNAs thus represent a large class of RNA molecules that are tightly regulated, and it is becoming increasingly clear that they likely impact many biological processes.

Graphical Abstract

Besides generating a linear mRNA, many protein-coding genes produce circular RNAs that are tightly regulated and have biological functions.