Circular RNA translation: novel protein isoforms and clinical significance

• Published in: Trends in molecular medicine Vol. 28; no. 5; pp. 405 - 420
• Main Authors: Wen, Shuo-yang, Qadir, Javeria, Yang, Burton B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2022
• Subjects: circRNA translation; circular RNA; disease modulation; Gene Expression Regulation; Humans; Internal Ribosome Entry Sites - genetics; Protein Biosynthesis; Protein Isoforms - genetics; Protein Isoforms - metabolism; RNA - genetics; RNA - metabolism; RNA, Circular - genetics; rolling translation; targeting translation; therapy; translational inhibition; rolling translation; targeting translation; circular RNA; therapy; translational inhibition; circRNA translation; disease modulation
• ISSN: 1471-4914; 1471-499X; 1471-499X
• DOI: 10.1016/j.molmed.2022.03.003

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. 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.