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Intriguing circles: Conflicts and controversies in circular RNA research

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Abstract Circular RNAs (circRNAs) are covalently closed RNA circles without a 5′ cap or 3′ tail. Since the landmark discovery of ciRS‐7/CDR1as functioning as a miR‐7 sponge in 2013, circRNAs have become a hot topic in RNA research. CircRNAs have been found to play active roles in cancer, cardiovascular diseases, neurological disorders, and many other diseases. They can function as microRNA (miRNA) sponges, protein scaffolds, and even translation templates. However, as circRNA research expands, many divergent views have emerged. For example, are most circRNAs competent in serving as miRNA sponges? What kinds of circRNAs are most likely to sponge miRNAs? Apart from sponging miRNAs, what could the functions of most circRNAs be? What are the features of circRNAs that are translatable? Many researchers have claimed that circRNAs are abundant, stable, conserved, and specific molecules, which hold great potential in serving as biomarkers. However, circRNA abundance is variable and some circRNAs are abundant while others are not. In addition, their stability and conservation may vary under different circumstances. Furthermore, it is unclear whether circRNA biogenesis is more likely to be regulated by RNA binding proteins or transcription factors. All of these are open questions that remain to be answered by researchers in this field. Discussing and investigating these questions will advance the understanding of this class of novel molecules and may propel inspiring new ideas for future studies. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease RNA Methods > RNA Analyses in Cells RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
The biogenesis and structure of three kinds of circRNAs. (a) Exonic circRNA (ecircRNA) produced from single exon. (b) Exonic circRNA back‐spliced with multiple exons. (c) Intronic circRNA (ciRNA) circularized by intron sequence. (d) Exon–intronic circRNA with intronic sequence retained
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Three grades of evidence proving circRNA as a competent miRNA sponge. (a) GRADE III: Luciferase reporter assay. Cloned wild‐type circRNA sequence interacts with miRNA and inhibits the luciferase activity (left) while the mutated circRNA sequence does not (right). (b) GRADE II evidence: RNA antisense purification (RAP). Labeled probes targeting circRNA pulled down the circRNA–miRNA complex, and subsequent experiment validates the interacted miRNAs. (c) GRADE III (strongest) evidence: AGO2 coupled RNA immunoprecipitation (AGO2‐RIP/CLIP). AGO2 antibody precipitates with the miRNA‐induced silencing complex for the subsequent miRNA analysis
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Schematic illustration of important prerequisites for a better ceRNA candidate. (a) To serve as a miRNA sponge, a circRNA with multiple binding sites is better than very few sites. (b) A circRNA that targets fewer miRNAs is better. (c) The affinity between a circRNA and miRNA (left arrowhead) should be higher than that of miRNA and mRNA (right arrowhead). (d) After binding to a miRNA, a better ceRNA candidate triggers the degradation process of a target miRNA, while others only inhibit the interaction of miRNA and mRNA
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Summary of major conflicts and controversies in biogenesis, characteristics, and function of circRNAs
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Methods > RNA Analyses in Cells
RNA in Disease and Development > RNA in Disease
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs

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