Role of Virally Encoded Circular RNAs in the Pathogenicity of Human Oncogenic Viruses

Abstract

Human oncogenic viruses are a group of important pathogens that etiologically contribute to at least 12% of total cancer cases in the world. As an emerging class of non-linear regulatory RNA molecules, circular RNAs (circRNAs) have gained increasing attention as a crucial player in the regulation of signaling pathways involved in viral infection and oncogenesis. With the assistance of current circRNA enrichment and detection technologies, numerous novel virally-encoded circRNAs (vcircRNAs) have been identified in the human oncogenic viruses, initiating an exciting new era of vcircRNA research. In this review, we discuss the current understanding of the roles of vcircRNAs in the respective viral infection cycles and in virus-associated pathogenesis.

Keywords: EBV; HBV; HPV; KSHV; MCV; circRNA; circular RNA; oncogenic virus.

FIGURE 1

Biogenesis and potential functions of circRNAs. Based on the parental gene component that’s carried by the circRNAs, circRNAs can be classified to four major types. (1) The most common type is the exonic circRNAs (ecircRNAs) which contain only one or multiple exons; (2) The exon-intron circRNAs (EIciRNAs) carry both exons and introns; (3) The circular intronic RNAs (ciRNAs) carry introns only; and (4) The tRNA intronic circRNAs (tricRNAs) are formed by circularization of the excised tRNA introns. The formation of ecircRNAs and EIciRNAs requires a special type of splicing known as backsplicing, which allows a downstream 5′ splice donor (SD) to react with an upstream 3′ splice acceptor (SA). Thus, a 3′–5′ phosphodiester bond can be established to circularize the RNA molecule. ciRNAs are generated by lariat introns removed from pre-mRNAs by canonical splicing. A consensus 7-nucleotide GU-rich sequence near the 5′ splice donor (shown as red dot in the figure) and an 11-nucleotide C-rich sequence near the branchpoint site (shown as green dot in the figure) can help prevent the lariat from debranching and exonuclease attacking. Stable ciRNAs can then be formed after trimming the 3′ tail downstream from the branchpoint. Lastly, tricRNAs are formed by directly linking the free ends of introns excised from the pre-tRNAs. circRNAs can function as molecular sponges to sequester miRNA and protein. In general, circRNAs mainly function as non-coding regulatory transcripts. However, some circRNAs can be translated through either IRES-mediated or m⁶A-mediated non-canonical cap-independent translation initiation.