Circular RNA, the Key for Translation

Abstract

It was thought until the 1990s that the eukaryotic translation machinery was unable to translate a circular RNA. However internal ribosome entry sites (IRESs) and m6A-induced ribosome engagement sites (MIRESs) were discovered, promoting 5′ end-independent translation initiation. Today a new family of so-called “noncoding” circular RNAs (circRNAs) has emerged, revealing the pivotal role of 5′ end-independent translation. CircRNAs have a strong impact on translational control via their sponge function, and form a new mRNA family as they are translated into proteins with pathophysiological roles. While there is no more doubt about translation of covalently closed circRNA, the linearity of canonical mRNA is only theoretical: it has been shown for more than thirty years that polysomes exhibit a circular form and mRNA functional circularization has been demonstrated in the 1990s by the interaction of initiation factor eIF4G with poly(A) binding protein. More recently, additional mechanisms of 3′–5′ interaction have been reported, including m6A modification. Functional circularization enhances translation via ribosome recycling and acceleration of the translation initiation rate. This update of covalently and noncovalently closed circular mRNA translation landscape shows that RNA with circular shape might be the rule for translation with an important impact on disease development and biotechnological applications.

Long non-coding RNA Neat1 and paraspeckle components are translational regulators in hypoxia

“…Many of the genes involved in angiogenesis or cardioprotection tested here have not been described for containing an IRES in their mRNAs. We can make the hypothesis that these mRNA families either contain IRESs that have not been identified yet, or are translated by another cap-independent mechanism such as m6A-induced ribosome engagement sites (MIRES) (Prats et al, 2020).…”

Circular RNAs: Novel potential regulators in embryogenesis, female infertility, and pregnancy‐related diseases

“…It is considered conventionally that circRNAs are noncoding RNAs, but some circRNAs have been inspected to have protein‐encoding capability through the following ways: ribosome entry site (IRES) (Prats et al, 2020; Yang et al, 2018), rolling circle amplification (RCA) (Abe et al, 2015), untranslated regions (UTR) (Pamudurti et al, 2017), and N6‐methyladenosine (m 6 A) (Yang et al, 2017)—driven translation mechanisms. For the IRES‐driven translation mechanism, IRES are located in the upstream frame of some circRNA start codons where they induce circRNA translation (Prats et al, 2020). Yang et al (2018) observed that IRES induced circ‐FBXW7 to encode a 21‐kDa protein, FBXW7‐185aa.…”

Roles of circular RNAs in colorectal cancer (Review)

“…However, more recently, circRNAs have been found to encode peptides, where an Internal Ribosome Entry site and N 6 -methyladenosines mediated cap-independent translation initiation were suggested as potential mechanisms involved in the translation of circRNAs. Detailed mechanisms of circRNA translation are reviewed elsewhere (28)(29)(30). Legnini et al (31) provided an example of translatable circRNAs in eukaryotes, suggesting that circ-zinc finger protein 609 (circZNF609) was translated into protein in a splicing-dependent and cap-independent manner, and this was shown to be involved in regulating myogenesis.…”