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Review
. 2014 Dec;20(12):1829-42.
doi: 10.1261/rna.047126.114.

Circular RNAs: diversity of form and function

Erika Lasda  1 , Roy Parker  2
Affiliations
Review

Circular RNAs: diversity of form and function

Erika Lasda et al. RNA. 2014 Dec.

Abstract

It is now clear that there is a diversity of circular RNAs in biological systems. Circular RNAs can be produced by the direct ligation of 5' and 3' ends of linear RNAs, as intermediates in RNA processing reactions, or by "backsplicing," wherein a downstream 5' splice site (splice donor) is joined to an upstream 3' splice site (splice acceptor). Circular RNAs have unique properties including the potential for rolling circle amplification of RNA, the ability to rearrange the order of genomic information, protection from exonucleases, and constraints on RNA folding. Circular RNAs can function as templates for viroid and viral replication, as intermediates in RNA processing reactions, as regulators of transcription in cis, as snoRNAs, and as miRNA sponges. Herein, we review the breadth of circular RNAs, their biogenesis and metabolism, and their known and anticipated functions.

Keywords: backsplicing; circRNA; circular RNA; intermediates; intron; nonlinear; splicing.

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Figures

FIGURE 1.
FIGURE 1.
Properties of circles. Circular RNAs can serve as a template for rolling circle amplification (A), provide a means to rearrange sequences (B), evade exonucleolytic degradation (C), and constrain the RNA folding and structural stability (D).
FIGURE 2.
FIGURE 2.
Production of ciRNAs. Circular intronic RNAs are produced by eukaryotic spliceosome-mediated splicing. The lariat intron generated from the splicing reaction evades normal debranching and degradation, and instead the 3′ “tail” downstream from the branchpoint is trimmed resulting in a stable ciRNA.
FIGURE 3.
FIGURE 3.
In some archaea, circular RNA is formed as an intermediate in ribosomal RNA processing. Ribosomal RNA precursors containing the bulge–helix–bulge motif are cleaved and ligated, forming circular intermediates which are further processed to release the 16S and 23S rRNA. rRNA regions are indicated by light blue; upstream and downstream regions contained within the circular intermediate are yellow and green, respectively.
FIGURE 4.
FIGURE 4.
A circRNA is formed by a backsplice event. Spliceosome-mediated splicing joins a 5′ splice site (splice donor) of a downstream exon with a 3′ splice site (splice acceptor) of an upstream exon to yield a circular RNA with a “scrambled exon” junction between exon 4 and exon 2. (Red line) Backsplice and (arrowheads) 5′–3′ direction.
FIGURE 5.
FIGURE 5.
Scrambled exon junctions can be formed from different mechanisms. Outward-facing primers in exons 2 and 4 (green arrows) will not yield an RT-PCR product if the exons are ordered linearly (A), but will yield a product, indicated by orange line above primers, if the exons are scrambled in the mRNA. Scrambled exons could occur through trans-splicing (B), genomic rearrangements (C), including tandem duplication within the DNA (D), or backsplicing (E). (Red lines) Unusual (nonsequential) splicing, (arrowheads) 5′–3′ direction, (green arrows) outward-facing PCR primers, and (orange line) RT-PCR product.
FIGURE 6.
FIGURE 6.
Possible mechanisms for promoting circularization by bringing backsplice sites into close proximity. (A) An intron lariat resulting from exon skipping. (B) Flanking inverted repeats or ALU elements forms an extended base-paired structure. (C) Interactions between RNA-binding proteins form a bridge between the flanking introns. (Red line) backsplice and (arrowheads) 5′–3′ direction.
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