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 cir-cRNAs 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 > MechanismsCircular RNAs (circRNAs) are a special class of covalently closed noncoding RNA molecules without the 5 0 and 3 0 ends. Initially, circular RNAs (circRNAs) were discovered to be uncoated, infectious RNA molecules pathogenic to plants (Sanger et al., 1976). Soon after their discovery, the expression of circRNA was also confirmed in eukaryotic cells (Hsu & Coca-Prados, 1979). A few subsequent studies discovered misarranged exons and circRNAs in various samples (Capel et al., 1993;Cocquerelle et al., 1993;Nigro et al., 1991). However, they were thought to be accidental byproducts arising from splicing errors until the next-generation sequencing (NGS) technologies were developed. Recent NGS and Tanvi Sinha, Chirag Panigrahi, and Debojyoti Das contributed equally to this study.

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Circular RNAs (circRNAs) are a large family of noncoding RNAs that have emerged as novel regulators of gene expression. However, little is known about the function of circRNAs in pancreatic β-cells. Here, transcriptomic analysis of mice pancreatic islet RNA-sequencing data identified 77 differentially expressed circRNAs between mice fed with a normal diet and a high-fat diet. Surprisingly, multiple circRNAs were derived from the intron 2 of the preproinsulin 2 (Ins2) gene and are termed as circular intronic (ci)-Ins2. The expression of ci-Ins2 transcripts in mouse pancreatic islets, and βTC6 cells were confirmed by reverse transcription PCR, DNA sequencing, and RNase R treatment experiments. The level of ci-Ins2 was altered in βTC6 cells upon exposure to elevated levels of palmitate and glucose. Computational analysis predicted the interaction of several RNA-binding proteins with ci-Ins2 and their flanking region, suggesting their role in the ci-Ins2 function or biogenesis. Additionally, bioinformatics analysis predicted the association of several microRNAs with ci-Ins2. Gene ontology and pathway analysis of genes targeted by miRNAs associated with ci-Ins2 suggested the regulation of several key biological processes. Together, our findings indicate that differential expression of circRNAs, especially ci-Ins2 transcripts, may regulate β-cell function and may play a critical role in the development of diabetes.