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. 2015 May 21;5(3):1-7.
doi: 10.1080/2159256X.2015.1045682. eCollection 2015 May-Jun.

Repetitive elements regulate circular RNA biogenesis

Jeremy E Wilusz  1
Affiliations

Repetitive elements regulate circular RNA biogenesis

Jeremy E Wilusz. Mob Genet Elements. .

Abstract

It was long assumed that eukaryotic precursor mRNAs (pre-mRNAs) are almost always spliced to generate a linear mRNA that is subsequently translated to produce a protein. However, it is now clear that thousands of protein-coding genes can be non-canonically spliced to produce circular noncoding RNAs, some of which are expressed at much higher levels than their associated linear mRNAs. How then does the splicing machinery decide whether to generate a linear mRNA or a circular RNA? Recent work has revealed that intronic repetitive elements, including sequences derived from transposons, are critical regulators of this decision. In most cases, circular RNA biogenesis appears to be initiated when complementary sequences from 2 different introns base pair to one another. This brings the splice sites from the intervening exon(s) into close proximity and facilitates the backsplicing event that generates the circular RNA. As many pre-mRNAs contain multiple intronic repeats, distinct circular transcripts can be produced depending on which repeats base pair to one another. Intronic repeats are thus critical regulatory sequences that control the functional output of their host genes, and potentially cause the functions of protein-coding genes to be highly divergent across species.

Keywords: ADAR; Alu; LINE1; backsplicing; base pairing; circRNA; circular RNA; noncoding RNA; pre-mRNA splicing; retrotransposition.

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Figures

Figure 1.
Figure 1.
Pre-mRNA splicing can generate linear or circular RNAs. If the pre-mRNA splice sites (ss) are joined in the canonical order, a mature linear mRNA is generated that is subsequently polyadenylated (top). Alternatively, the splicing machinery can backsplice and join a splice donor to an upstream splice acceptor, generating a circular RNA whose ends are covalently linked (bottom). Here, a circular RNA composed of 2 exons is generated, although backsplicing can result in the production of circular RNAs that comprise one or many exons.
Figure 2.
Figure 2.
Minimal intronic elements that are sufficient for ZKSCAN1 circular RNA production. Using extensive mutagenesis, minimal sequences that are sufficient for generating the circular RNA from exons 2 and 3 of human ZKSCAN1 were defined. In the upstream intron, 87 nt are sufficient, which include 40 nt of an Alu element as well as the 3′ splice site (comprised of a polypyrimidine (Py) tract followed by AG) and branch point sequences. In the downstream intron, 59 nt are sufficient, which include the 5′ splice site and 36 nt of an Alu element. As the 2 Alu elements are highly complementary to one another, the repeats can base pair and form a hairpin, which promotes backsplicing.
Figure 3.
Figure 3.
The presence of multiple intronic repeats allows a variety of mature RNAs to be generated from a single gene. (A) Schematic of a 4-exon gene, with intronic repeat elements depicted as red arrows. Depending on which repeats base pair to one another (denoted by blue arcs), distinct mature RNAs are produced. (B) If the repeats flanking exon 2 base pair to one another, backsplicing (denoted in purple) is induced and a circular RNA composed of exon 2 is generated. (C) If, however, the repeats in the second intron base pair to one another, canonical splicing occurs and a linear mRNA is produced. (D) If the repeats flanking exon 3 base pair to one another, a circular RNA composed of exon 3 is generated. Finally, base pairing between the first and last repeats would yield a circular RNA composed of exons 2 and 3 (not shown).
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