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Review
. 2021 Apr:220:107715.
doi: 10.1016/j.pharmthera.2020.107715. Epub 2020 Oct 24.

Circular RNAs are a novel type of non-coding RNAs in ROS regulation, cardiovascular metabolic inflammations and cancers

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Review

Circular RNAs are a novel type of non-coding RNAs in ROS regulation, cardiovascular metabolic inflammations and cancers

Fatma Saaoud et al. Pharmacol Ther. 2021 Apr.

Abstract

Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNAs characterized by a covalently closed-loop structure generated through a special type of alternative splicing termed back-splicing. Currently, an increasing body of evidence has demonstrated that 1) majority of circRNAs are evolutionarily conserved across species, stable, and resistant to RNase R degradation, and often exhibit cell-specific, and tissue-specific/developmental-stage-specific expression and can be largely independent of the expression levels of the linear host gene-encoded linear RNAs; 2) the biogenesis of circRNAs via back-splicing is different from the canonical splicing of linear RNAs; 3) circRNA biogenesis is regulated by specific cis-acting elements and trans-acting factors; 4) circRNAs regulate biological and pathological processes by sponging miRNAs, binding to RNA-binding protein (RBP), regulators of splicing and transcription, modifiers of parental gene expression, and regulators of protein translation or being translated into peptides in various diseases; 5) circRNAs have been identified for their enrichment and stability in exosomes and detected in body fluids such as human blood, saliva, and cerebrospinal fluids, suggesting that these exo-circRNAs have potential applications as disease biomarkers and novel therapeutic targets; 6) several circRNAs are regulated by oxidative stress and mediate reactive oxygen species (ROS) production as well as promote ROS-induced cellular death, cell apoptosis, and inflammation; 7) circRNAs have also emerged as important regulators in atherosclerotic cardiovascular disease, metabolic disease, and cancers; 8) the potential mechanisms of several circRNAs have been described in diseases, hinting at their potential applications as novel therapeutic targets. In this highlight, we summarized the current understandings of the biogenesis and functions of circRNAs and their roles in ROS regulation and vascular inflammation-associated with cardiovascular and metabolic disease. (Word count: 272).

Keywords: Circular RNAs (circRNAs); Exosomes; Reactive oxygen species (ROS); Vascular inflammation.

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Conflict of interest statement

Declaration of Competing Interest

The authors declare that there are no conflicts of interest.

Figures

Fig. 1.
Fig. 1.
A classification of non-coding RNA and their biological functions. Abbreviations: ncRNA: non-coding RNA; circRNA: circular RNA; lncRNA: long non-coding RNA; miRNA: microRNA; siRNA: small interfering RNA; snoRNA: small nucleolar RNA; snRNA: small nuclear RNA; piRNA: piwi-interacting RNA; rRNA: ribosomal RNA; tRNA: transfer RNA.
Fig. 2A.
Fig. 2A.
Schematic representation illustrating circRNA biogenesis. In the nucleus of eukaryotic cells, DNA is transcribed to form precursor mRNA (pre-mRNA), which contain coding exons and introns. Different from linear mRNAs, which are formed by canonical linear splicing and cutting away introns of the pre-mRNAs using small nuclear ribonucleoproteins (snRNPs), circular RNAs (circRNAs) are formed by back-splicing of the pre-mRNAs and circularization of the cut segment, where the 5’ end joins the 3’ end. (A) Single exon circRNAs: circular RNAs can be generated from a single exon; (B) Multi-exon circRNAs: circular RNAs can also be generated from two or more exons; (C) Exon-intron circRNAs: circular RNAs can contain intron(s) that have been retained between one or more circular exons; (D) Intronic circRNAs: introns can be excised from pre-mRNAs and circularize to give rise to circRNAs.
Fig. 2B.
Fig. 2B.
The proposed models of circRNA formation. i) Intron-pairing-driven circularization. Two complementary introns form a circular structure containing several introns and exons through a base-pairing connection. Finally, introns are removed to form exonic circRNAs (EcircRNAs). ii) RNA binding protein (RBP)-driven circularization. The binding of RBPs acts as a vehicle that binds two non-adjacent introns. Then circRNAs are generated after the removal of introns. iii) Exon skipping: the back-splicing process can take place because of exon skipping mechanism, which leads to lariat formation. This process can generate three different products: linear mRNA, an exonic or exonic-interonic circRNAs, and intron lariats iv) Intron lariat will generate intronic circRNAs.
Fig. 3.
Fig. 3.
Three major subclasses of circRNAs. (A) Exonic circRNAs (ecircRNAs) consist of only exon(s) (usually less than five) and represent the most important group of circRNA class. EcircRNAs have cytoplasmatic location and may regulate microRNA and protein functions.(B) Exon-intron circRNAs (EIciRNAs) are composed of exons and retained introns. EIciRNAs have nuclear localization and have been found to be able to regulate gene transcription in cis and probably also in trans.(C) Intronic circRNAs (ciRNAs) are derived from intron lariats and are accumulated in the nucleus in which regulate gene transcription in cis.
Fig. 4.
Fig. 4.
Schematic representation of circRNA functions and degradation. (A)microRNA sponges: circRNAs can act as miRNA sponges by competing for miRNA binding sites (miRNA response elements (MREs)) and prevents miRNA from interacting with their target messenger RNA (mRNA) at 3’ untranslated region (UTR) leading to reduced the effect of miRNA-mediated regulatory activities.(B) Interaction with RNA binding proteins (RBPs): circRNAs may act as protein sponges, by directly binding to RBPs, and therefore retain them in the cytoplasm. These RBPs includes: cyclin-dependent kinase inhibitor 1 (p21), cyclin-dependent protein kinase 2 (CKD2), inhibitor of DNA binding 1 (ID1), E2F1, Hypoxia-inducible factor-1α (HIF1a), and preface focal adhesion kinase (FAK). (C) CircRNA can be translated with ribosome and encode peptides or proteins. (D) CircRNAs (e.g. EIciRNAs and ciRNAs) may interact with transcription complexes and enhance the expression of their parental genes. (E) The degradation of circRNAs. CircRNAs are globally degraded by RNase L in early cellular innate immune responses. (F) The elimination of circRNAs. circRNAs can be eliminated into the extracellular space by exosomes
Fig. 5.
Fig. 5.
Generation of exosomal circRNAs (exo-circRNAs). circRNAs can be loaded into exosomes, released by donor cells into extracellular space, and enter the cells again (Autocrine effect) or targets nearby cells (Paracrine effect) or targets a distant cells (Endocrine effect) through endocytosis, thus modulating gene expression in recipient cells. Some exo-circRNAs are not bind to miRNAs in exosomes, they are able to sponge specific in target cells leading to target gene activation; or exo-circRNAs are bind to miRNAs in exosome. After entering target cells, miRNAs are released and target genes can be silenced.

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