Many protein-coding genes in higher eukaryotes can produce circular RNAs (circRNAs) through back-splicing of exons. CircRNAs differ from mRNAs in their production, structure and turnover and thereby have unique cellular functions and potential biomedical applications. In this Review, I discuss recent progress in our understanding of the biogenesis of circRNAs and the regulation of their abundance and of their biological functions, including in transcription and splicing, sequestering or scaffolding of macromolecules to interfere with microRNA activities or signalling pathways, and serving as templates for translation. I further discuss the emerging roles of circRNAs in regulating immune responses and cell proliferation, and the possibilities of applying circRNA technologies in biomedical research.

The expanding regulatory mechanisms and cellular functions of circular RNAs.

Non-coding RNAs in disease: from mechanisms to therapeutics.

Structured elements drive extensive circular RNA translation

Most eukaryotic mRNAs are translated in a cap-dependent fashion; however, under stress conditions, the cap-independent translation driven by internal ribosomal entry sites (IRESs) can serve as an alternative mechanism for protein production. Many IRESs have been discovered from viral or cellular mRNAs to promote ribosome assembly and initiate translation by recruiting different trans-acting factors. Although the mechanisms of translation initiation driven by viral IRESs are relatively well understood, the existence of cellular IRESs is still under debate due to the limitations of translation reporter systems used to assay IRES activities. A recent screen identified > 1000 putative IRESs from viral and human mRNAs, expanding the scope and mechanism for cap-independent translation. Additionally, a large number of circular RNAs lacking free ends were identified in eukaryotic cells, many of which are found to be translated through IRESs. These findings suggest that IRESs may play a previously unappreciated role in driving translation of the new type of mRNA, implying a hidden proteome produced from cap-independent translation.

/pdf/ires-mediated-cap-independent-translation-a-path-leading-to-1c1r7502hf.pdf

IRES-mediated cap-independent translation, a path leading to hidden proteome

The majority of circular RNAs (circRNAs) spliced from coding genes contain open reading frames (ORFs) and thus, have protein coding potential. However, it remains unknown what regulates the biogenesis of these ORF-containing circRNAs, whether they are actually translated into proteins and what functions they play in specific physiological contexts. Here, we report that a large number of circRNAs are synthesized with increasing abundance when late pachytene spermatocytes develop into round and then elongating spermatids during murine spermatogenesis. For a subset of circRNAs, the back splicing appears to occur mostly at m6A-enriched sites, which are usually located around the start and stop codons in linear mRNAs. Consequently, approximately a half of these male germ cell circRNAs contain large ORFs with m6A-modified start codons in their junctions, features that have been recently shown to be associated with protein-coding potential. Hundreds of peptides encoded by the junction sequences of these circRNAs were detected using liquid chromatography coupled with mass spectrometry, suggesting that these circRNAs can indeed be translated into proteins in both developing (spermatocytes and spermatids) and mature (spermatozoa) male germ cells. The present study discovered not only a novel role of m6A in the biogenesis of coding circRNAs, but also a potential mechanism to ensure stable and long-lasting protein production in the absence of linear mRNAs, i.e., through production of circRNAs containing large ORFs and m6A-modified start codons in junction sequences.

/pdf/m6a-dependent-biogenesis-of-circular-rnas-in-male-germ-cells-spxkv2i3t0.pdf

m6A-dependent biogenesis of circular RNAs in male germ cells.

Circular RNAs (circRNAs) are a class of abundant RNAs with ambiguous function. Although some circRNAs can be translated through IRES driven mechanisms, the scope and functions of circRNA translation are unclear because endogenous IRESs are rare. To determine the prevalence and mechanism of circRNA translation, we developed a cell-based system to screen random sequences and identified 97 overrepresented AU-rich hexamers (>2% of all hexamers) that drive cap-independent translation of circRNAs. These IRES-like short elements are significantly enriched in circRNAs and sufficient to drive circRNA translation. We further identified multiple trans-acting factors that bind these IRES-like short elements to initiate translation. Using mass-spectrometry data, hundreds of circRNA-coded peptides were identified, most of which have low abundance due to rapid degradation. As judged by mass-spectrometry, 50% of endogenous circRNAs undergo rolling circle translation, several of which were experimentally validated by western blotting. Consistently, the mutation of the IRES-like short element in a circRNA reduced its translation. Collectively, our findings suggest a pervasive translation of circRNAs, providing profound implications in circRNA function.

/pdf/pervasive-translation-of-circular-rnas-driven-by-short-ires-2nltjsi88s.pdf

Pervasive translation of circular RNAs driven by short IRES-like elements

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Pervasive translation of circular RNAs driven by short IRES-like elements