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Review
. 2020 Dec 14;19(1):172.
doi: 10.1186/s12943-020-01286-3.

Circular RNA: metabolism, functions and interactions with proteins

Wei-Yi Zhou  1 , Ze-Rong Cai  1 , Jia Liu  1 , De-Shen Wang  1 , Huai-Qiang Ju  2   3 , Rui-Hua Xu  4   5
Affiliations
Review

Circular RNA: metabolism, functions and interactions with proteins

Wei-Yi Zhou et al. Mol Cancer. .

Abstract

Circular RNAs (CircRNAs) are single-stranded, covalently closed RNA molecules that are ubiquitous across species ranging from viruses to mammals. Important advances have been made in the biogenesis, regulation, localization, degradation and modification of circRNAs VSports手机版. CircRNAs exert biological functions by acting as transcriptional regulators, microRNA (miR) sponges and protein templates. Moreover, emerging evidence has revealed that a group of circRNAs can serve as protein decoys, scaffolds and recruiters. However, the existing research on circRNA-protein interactions is quite limited. Hence, in this review, we briefly summarize recent progress in the metabolism and functions of circRNAs and elaborately discuss the patterns of circRNA-protein interactions, including altering interactions between proteins, tethering or sequestering proteins, recruiting proteins to chromatin, forming circRNA-protein-mRNA ternary complexes and translocating or redistributing proteins. Many discoveries have revealed that circRNAs have unique expression signatures and play crucial roles in a variety of diseases, enabling them to potentially act as diagnostic biomarkers and therapeutic targets. This review systematically evaluates the roles and mechanisms of circRNAs, with the hope of advancing translational medicine involving circRNAs. .

Keywords: CircRNA; CircRNA-protein interaction; Function; Mechanism; Metabolism. V体育安卓版.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Metabolism of circRNA. Regulation of circRNA biogenesis. RBP can modulate circRNA biogenesis by dimerization, ICS stabilization or ICS impairment. ICS in flanking introns can facilitate exon circularization. Biogenesis of circRNA. a In the lariat model, back-spliced exons are skipped and extruded to form an intronic lariat that undergoes further back-splicing, while the remaining exons directly link with each other and form a mature mRNA. b In the direct model, back-splicing occurs first to form a circRNA, leaving an immature linear RNA containing introns. Localization of circRNA c| Long (> 800 nt) or short circRNAs can be translocated to the cytoplasm with the assistance of UAP56 or URH49, respectively. d CircRNAs can be translocated to the cytoplasm in m6A-dependent manner mediated by YTHDC1. e CircRNAs can be excreted to the extracellular space by exosomes. Degradation of circRNA. f Upon viral infection, RNase L activated by 2′-5′-oligoadenosine(2′-5′A) causes the global degradation of circRNAs, which relieves the suppression of PKR. g M6A-containing circRNAs can be recognized by YTHDF2, which interacts with the RNase P/MRP complex bridged by HRSP12, and then the complex endoribonucleolytically cleaves circRNAs. h UPF1 and G3BP1 can bind to imperfect base-paired regions of circRNAs and induce their degradation
Fig. 2
Fig. 2
Functions of circRNA. a CircRNAs can bind to the host genes at their synthesis locus and cause transcriptional pausing or termination through the formation of RNA-DNA hybrid (R-loop structure), upregulating the exon-skipped or truncated transcripts. b EIciRNAs can combine with U1 snRNP and then interact with Pol II to enhance parental gene expression. c CircRNAs can act as miR sponges and upregulate the miR target mRNAs. d CircRNAs can interact with proteins. e IRES-containing circRNAs can directly recruit ribosomes and be translated. f M6A-containing circRNAs can be recognized by YTHDF3, which recruits eIF4G2, thus triggering translation. This process can be enhanced by METTL3/14 and suppressed by fat mass and obesity-associated protein (FTO)
Fig. 3
Fig. 3
CircRNA-protein interactions. A (a) CircRNA binds to both proteins and strengthens their interaction. (b) CircRNA binds to protein A and reinforces its interaction with protein B, which does not directly bind to circRNA. (c) CircRNA binds to both proteins that originally combine with each other and then disrupts their interaction. B CircRNA blocks proteins from interacting with DNA, RNA or other proteins, thus compromising their original functions. C CircRNA recruits transcription factors, chromatin remodelers and DNA or histone modifying enzymes to the promoters and alters transcription (including activating and inhibiting). D CircRNA helps RBPs to combine with mRNA and stabilizes mRNA (indirectly promoting translation) or directly regulates translation (including promoting and inhibiting). E (a) Nuclear circRNA causes the nuclear retention of proteins. (b) Cytoplasmic or shuttling circRNA facilitates the nuclear import of proteins. (c) Cytoplasmic circRNA causes the cytoplasmic retention of proteins. (d) Nuclear or shuttling circRNA facilitates the nuclear export of proteins. (e-g) Furthermore, circRNAs can transport proteins to the nucleolus, mitochondria and membrane, respectively
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