Circular RNA translation: novel protein isoforms and clinical significance

Cap-independent translation of circular RNAs (circRNAs) driven by internal ribosome entry site (IRES) or N6-methyladenosine (m6A)-containing short sequence is different from the canonical cap-dependent translation of linear mRNAs. New isoforms or novel proteins with disease-inductive or -suppressive effects are generated from translatable circRNAs. Translatable circRNAs have bifunctional characteristics exerted by the circRNAs and the translated proteins, which affirm their cell/tissue-specific expression and physiological functions. circRNAs are still in preclinical stages of assessment and require validation in human subjects. In recent years, significant attention has focused on circular RNA (circRNA) translation to determine its clinical significance. Cap-independent translation of circRNAs driven by an internal ribosome entry site (IRES) or an N6-methyladenosine (m6A)-containing short sequence is different from the canonical cap-dependent translation of linear mRNAs. New proteins or isoforms possessing novel physiological roles can be generated from translatable circRNAs. The present review describes the elements involved in circRNA translation, and the functions of the translated novel protein isoforms in human diseases. Bifunctional characteristics of translatable circRNAs exerted by the circRNAs and the translated proteins are also discussed. Furthermore, various molecular strategies that could be used as appropriate therapeutic options are proposed. In recent years, significant attention has focused on circular RNA (circRNA) translation to determine its clinical significance. Cap-independent translation of circRNAs driven by an internal ribosome entry site (IRES) or an N6-methyladenosine (m6A)-containing short sequence is different from the canonical cap-dependent translation of linear mRNAs. New proteins or isoforms possessing novel physiological roles can be generated from translatable circRNAs. The present review describes the elements involved in circRNA translation, and the functions of the translated novel protein isoforms in human diseases. Bifunctional characteristics of translatable circRNAs exerted by the circRNAs and the translated proteins are also discussed. Furthermore, various molecular strategies that could be used as appropriate therapeutic options are proposed. leader sequence that is directly present upstream of the start codon and regulates translation efficiency. translation initiation codon/start codon that encodes the amino acid methionine. the joint where back-splicing occurs when a 5′-splice site is joined to an upstream 3′-splice site to form circRNAs. refers to mRNA that contains two coding regions or exonic sequences. distinct cellular proteins that can potentially interact with circRNAs. protein-coding gene that imparts specific functions in the translation initiation process. It has binding sites for eIF4A and eIF3 at its C terminus and for eIF4E at its N terminus. individual proteins or protein complexes that regulate post-transcription gene expression by facilitating the formation of ribosomal preinitiation complexes around the translation initiation codon in eukaryotes. set of proteins that have been known to regulate the balance between tumor suppression and longevity because they have significant roles in DNA repair, cell proliferation, cell cycle arrest, and apoptosis. coding sequence that does not encounter a termination/stop codon. distinct type of amino-acyl tRNA that is capable of interacting with components of the translation initiation machinery and setting the frame of translation by decoding the initiation/start codon. RNA element that facilitates recruitment of the 40S ribosomal subunit and takes part in translation initiation through 5′-cap-independent mechanisms. proteins that regulate IRES-mediated translation, specifically under cell stress conditions. enzyme that catalyzes post-transcriptional methylation of internal adenosine residues to form N6-methyladenosine in eukaryotic mRNAs. coding DNA/mRNA sequence that can be translated into a protein. regulatory protein factors that bind to the cis-acting sequences of the DNA, thus regulating gene expression at the transcription level. cytoplasmic m6A binder that stimulates protein synthesis and facilitates decay of methylated mRNA by interacting with the other two family members, YTHDF1 and YTHDF2.