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.

Keywords: 3′UTR; IRES; MIRES; RNA circularization; circRNA; m6A; ribosome; translation.

Figure 1

Translation of circular RNAs (circRNAs). (A). Translation initiation on circRNAs by internal ribosome entry sites (IRESs) (left) and m⁶A-induced ribosome engagement sites (MIRESs) (right) is schematized with the main proteins involved in the complexes. Details are provided in the text (Section 4 and Section 5). (B). Mechanisms of translation elongation on circRNAs: even though 5′ end-independent initiation may be less efficient than cap-dependent initiation, translation efficiency is enhanced through ribosome recycling (1), reinitiation (2), overlapping start and stop codons (3) or rolling-circle elongation (4). Details are provided in the text (Section 9).

Figure 2

mRNA functional circularization is mediated by different mechanisms. Several mechanisms of mRNA circularization are represented, with the known proteins and RNA elements involved in the 3′–5′ interaction, allowing cap-dependent (a–d) and cap-independent (e–g) translation. Each mechanism is detailed in the text (Section 7 and Section 8). This list is not exhaustive and the mechanism d (METTL3/eIF3 interaction) may also serve cap-independent translation.