New insights on circular RNAs and their potential applications as biomarkers, therapeutic agents, and preventive vaccines in viral infections: with a glance at SARS-CoV-2

Abstract

The occurrence of viral infections and approaches to handling them are very challenging and require prompt diagnosis and timely treatment. Recently, genomic medicine approaches have come up with the discovery of the competing endogenous RNA (ceRNA) network, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) on the basis of gene silencing. CircRNAs, as a group of non-encoded RNAs, make a loop-like structure by back-splicing through 3' and 5' ends. They are stable, abundant, specific, and highly conserved and can be quickly generated at large scales in vitro. CircRNAs have the potential to contribute in several cellular processes in a way that some serve as microRNA sponges, cellular transporters, protein-binding RNAs, transcriptional regulators, and immune system modulators. CircRNAs can even play an important role in modulating antiviral immune responses. In the present review, circRNAs' biogenesis, function, and biomarker and therapeutic potential as well as their prospective applications as vaccines against viral infections such as SARS-CoV-2 are explained. By considering their unique properties, their potential to be used as novel vaccines, biomarkers, and a therapeutic approach appears possible.

Graphical abstract

Figure 1

Three models of circRNA synthesis, including intron pairing driven, RBP driven, and lariat-circularization, are displayed Intron pairing driven: as mRNAs are transcribing, back-splicing may happen between the 5′ region of the downstream exon as an acceptor site and the 3′ region of the upstream exon as a donor site. RBP driven: dimerization of RNA-binding proteins (RBPs) and their binding to specific intron motifs of flanking bonds stimulate circRNA generation. Lariat-driven: partial folding of RNA during transcription helps exons far from each other be adjacent, jump, and stick together. As a result of these processes, EI-circRNAs, e-circRNAs, and i-circRNAs are formed.

Figure 2

Biological function of circRNAs. CircRNAs can contribute to multiple levels of protein expression and function, as illustrated here CircRNAs act as sponge of miRNA (A) and RNA-binding proteins (RBPs) (B) and thereby adjust their functions indirectly. They can even be used directly as a template for translation (C). Besides, circRNAs via participating in the structure of a protein complex can improve protein function (D). By binding to RNA polymerase II, circRNAs potentially regulate maternal gene expression at the both transcriptional and post-transcriptional levels (E).