Circular RNA: Functions, Applications and Prospects Minghon Lu

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Circular RNA: Functions, Applications and Prospects Minghon Lu Lu ExRNA (2020) 2:1 https://doi.org/10.1186/s41544-019-0046-5 ExRNA REVIEW Open Access Circular RNA: functions, applications and prospects Minghon Lu Abstract Following improvement and integration of novel genome sequencing techniques, a new stage light has been shone upon circular RNAs (circRNA) in regard to their structure and functionality. In comparison to their linear counterparts, circRNA possess a multitude of remarkable functions such as microRNA (miRNA) sponging, RNA- binding protein (RBP) regulation and translational capabilities whose research have recently gained traction. Comprehensive computational modelling and analysis have revealed the relationship between the sequence composition of circRNAs and their biogenesis and structural formation as well as spatial identification. Due to fluctuations in expressional activity in tissue-specific environments and stimulations by tumour cells, circRNAs have sparked considerable interest in being employed as plausible biomarkers in disease control and treatment as consequence of their impressive specificity and biocompatibility. Additionally, an increasing number of studies have proposed them as viable solutions to be just as competent as presently used disease markers and medicine, if not better. In this review, I briefly summarized the characteristics, biogenesis and function of circRNA and introduced the potential applications and prospects of circRNA. With vigorous research being carried out regarding their still unclear diversified roles and precise molecular structure, circRNAs are bound to become the new revolutionary perspective on cellular regulation, protein signalling and disease pathogenesis. Keywords: Circular RNA, Biogenesis, Function, Application potential, Prospects Background a responsive and accurate indicator. Exosomal cell trans- Traditional understanding of mRNA has been limited to portation, programmed signalling and enhanced func- its linear form, which is responsible for the majority of tionality and are few of many improvements for synthesised proteins in cells. Before the re-evaluation of circRNAs arising from computational biology and ana- the full functionalities of its circularised counterpart, lytical techniques and dedicated research on the topic. questions arise on certain intracellular signalling path- ways which were not facilitated by any of the known lin- ear mRNAs. Recently, circRNAs have been extensively Main Text studied for their roles in cell signalling and regulation. Introduction This review aims to explain the structural as well as Circular RNA (circRNA) was discovered in RNA viruses physiochemical properties of circular RNAs, looped as viroids in the mid 70s, initially hypothesised to be an mRNA molecules that have attracted recent interest with endogenous RNA splicing error [1]. Thanks to advance- its newly discovered potential in biomarking cancer as ment in computational analysis and RNA sequencing well as several other diseases. The limitations, mainly techniques in the same decade, these misunderstood cir- due to lack of knowledge of these molecules, prevent cir- cular structures have finally been recognized correctly cRNAs to be universally deployed in oncological and and deeply both in structure and functionality [2]. At its pathological treatments; counteracting that, increasing core, circRNA is a single stranded RNA, but it differs research has shown promising results of circRNAs being from the far better known linear RNA in that it continu- ously closed in on itself by covalently joining its 5′ and 3′ ends [3], thus presenting some fascinating properties Correspondence: [email protected] Department of Biochemical Engineering, Faculty of Chemical Engineering, which are not fully explored: protein complex scaffold- University College London, Gower Street, Bloomsbury, London WC1E6BT, UK ing, parental gene modulation, RNA-protein interactions © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lu ExRNA (2020) 2:1 Page 2 of 7 and microRNA (miRNA) sponge, just to name a few [4, segments that are reserved and eliminated in the final 5]. They are now considered to provide essential regula- post-transcriptionally modified product respectively [17]. tory function for plants and animals alike [6]. An in- Normally a mature messenger RNA is formed when a creasing number of study groups have shown and protein-RNA complex named the spliceosome catalyses verified to an extent the level of effectiveness and effi- the cleaving-out of intron segments in a precursor- cacy displayed in circular RNAs that is typically required mRNA molecule, usually by recognition of specific se- in viable medical treatments and other biotechnological quences flanking the intron segment at both ends. The applications. For instance, cases of traditional bio- exon segments fuse, while the intronic segments are markers being vastly outperformed by proposed cir- consequentially taken out and degraded. This conven- cRNA substitutes are being reported often. Backed up by tional perception does not take into consideration the growing support and evidence about the promosing cap- deviation and difference in potency across all splice sites abilities of circRNAs, more investigation and interest [18], some of which, as a result, the spliceosome may ig- ought to be brought out as such, not merely from a basic nore and inevitably lead to the synthesis of circRNA. comprehensive biological understanding of its structures Furthermore, the contribution of the spatial arrange- and mechanisms, but also on a systematic level of their ment of the 5′ and 3′ splice site is not to be ignored, for interactions with surrounding molecules and environ- if the former is positioned downstream of the latter, then ments. Applicably speaking, circRNAs are on par in the spliceosome favourably constructs a covalently terms of its potential and viability to target cancer and closed circular structure over a linear exonic molecule other malignant diseases with other novel treatments [19]. This mechanism, commonly referred to as “Exon such as personalised medicine and stem cell therapies. Scrambling” gives rise to different types of circRNAs in- cluding exonic, intronic, exon-intronic and intergenic CircRNA characteristics [20]. In cancer specific cases, the internal structure is CircRNAs generally consist of 1–5 exons and the introns even more difficult to determine due to the expansive flanking the exons are up to 3 times as long as their linear and thus invasive nature of malignant tumors [21]. We counterpart. Closer analysis has revealed the presence of briefly depicted the biogenesis and functionality of cir- many complementary inverter Alu repeats in the intron cRNAs in Fig. 1. segments [7], leading some to speculate this particular ar- rangement actually facilitates the splice sites to easily lo- CircRNA function: microRNA sponges cate each other and promote circularisation. Since they Owing to the uniqueness in structures of circRNA, they are closely-looped structures, there are effectively no 5′ do not code for proteins like the linear forms [3]. Studies and 3′ end structures such as poly-A tails and 5′ caps in have shown, with supporting empirical evidence, that circRNA, rendering them immune to exonuclease cleav- certain circRNAs act as microRNA sponges and effect- age [8–10]. Empirically, they last 2.5 times longer than ively obstruct their mechanism. MicroRNAs are 21-nt their linear counterparts in mammary cells, as illustrated long non-coding RNA sequences that aid in the post- in a study carried out by Enuka et al. [10]. Owing to these transcriptional regulation of gene expression, typically by physical properties, common laboratory screening tech- latching themselves onto mRNAs and inhibiting its niques such as RNase R degradation – an enzyme that ex- translation into protein via either competitive or non- clusively degrades linear RNA – as well as poly-A tail competitive fashion. They are classified into families by testing can accurately select close looped structures over their seed regions, depending on whether they share the linear forms. Several research groups in recent years have same sequence of nucleotides from positions 2 to 7 [8]. shifted their focus on identifying potential circRNA iso- CircRNAs possess the complementarity to counter- forms, structures which are originally expressed from the attach themselves onto microRNAs, recognising the seed same parental DNA but are slightly different from one an- regions of the miRNAs, and competitively deactivating other in its final mature form due to differentiation in spe- them. Two circRNAs in particular, respectively CDR1as cificity of spliceosomes to recognise exons and introns on and circSRY, are the spotlight for scientific research at the pre-mRNA strand [11]. Notable groups include present. It is observed that CDR1as contains 70 con- Salzman, Jeck, Memczak, Guo and Zhang [7, 12–15]. As served binding sites for miRNA-7, far significant than such the incredible diversity
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