Circular RNAs are a class of single stranded RNAs with unique covalently closed topology. The concept of a 3`-5` covalently closed structure was first proposed in 1976 and the discovery of the first mammalian circRNA followed in 1991. Initially considered as by-products of RNA splicing due to their low expression levels, the interest in circRNAs resurged in 2012 with the advent of high-throughput sequencing technology, revealing them as a general feature of gene expression in human cells.
Natural circular RNAs were considered incapable of translation as natural circRNAs were non-coding RNAs. However, circRNAs containing internal ribosome entry sites (IRES) were found to be translated in vivo and in vitro. This finding led to the synthesis of proteins with circRNAs. This newfound translational potential prompted increased efforts in circRNA synthesis, utilizing methods such as chemical, enzymatic, and ribozyme-based approaches, all of which have been demonstrated to ligate the ends of RNA precursors.
Covalently closed topology of circRNAs render them ineffective in cap-dependent translation; however, with the help of internal ribosome entry sites, circRNAs can act as a translation template. Also, N6-methyladenosine was depicted as a promoter of translation in circRNAs. On the other hand, covalently closed topology comes with greater stability compared to linear RNAs, to an extent of a half-life of 48 hours. Lack of exonuclease-mediated degradation, which cleaves nucleotides from free ends, is associated with higher stability.
Circular RNAs with higher stability and translatable nature are now a potential design in vaccines and therapeutics. The ever-growing interest in and research efforts on circRNA will push the boundaries further.
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