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Circular RNA translation, a path to hidden proteome

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Abstract Functional proteins in the cell are translated from the messenger RNA (mRNA) molecules, constituting less than 5% of the cellular transcriptome. The majority of the RNA molecules in the cell are noncoding RNAs, including rRNA, tRNA, snRNA, piRNA, lncRNA, microRNA, and poorly characterized circular RNAs (circRNAs). Recent studies established that circRNAs regulate gene expression by associating with RNA‐binding proteins and microRNAs. With the growing understanding of circRNA functions, a subset of circRNAs has been reported to translate into proteins. Interestingly, the presence of Open Reading Frames (ORFs), N6‐methyladenosine (m6A) modifications, and internal ribosomal entry sites (IRES) in the circRNA sequences indicate their coding potential through the cap‐independent translation initiation mechanism. The purpose of this review is to highlight the mechanism of circRNA translation and the importance of circRNA‐encoded proteins (circ‐proteins) in cellular physiology and pathology. Here, we discuss the computational and molecular methods currently utilized to systematically identify translatable circRNAs and the functional characterization of the circ‐proteins. We foresee that the ongoing and future studies on circRNA translation will uncover the hidden proteome and their therapeutic implications in human health. This article is categorized under: RNA Methods > RNA Analyses in Cells Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Translation > Mechanisms
Protein‐coding circRNAs and their circ‐proteins in various tissues or disease models
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The mechanisms of cap‐independent translation of circRNAs. (a) CircRNAs with IRES can initiate translation by interacting with the translation initiation complex. (b) The m6A modifications on circRNA can associate with YTHD3 and recruit the translation initiation complex to initiate the translation
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Methods pipeline for systematic identification and characterization of protein‐coding circRNAs and their circ‐proteins
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Translation > Translation Mechanisms
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA Methods > RNA Analyses in Cells

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