An Overview of Circular RNAs and Their Implications in Myotonic Dystrophy

Abstract

Circular RNAs (circRNAs) are a class of single-stranded covalently closed RNA rings. Biogenesis of circRNAs, which may occur co-transcriptionally and post-transcriptionally via a back-splicing mechanism, requires the presence of complementary and/or inverted repeat sequences in introns flanking back-spliced exons and is facilitated by RNA-binding proteins. CircRNAs are abundant across eukaryotes; however, their biological functions remain largely speculative. Recently, they have been emerging as new members of a gene regulatory network and contributing factors in various human diseases including cancer, neurological, muscular and cardiovascular disorders. In this review, we present an overview of the current knowledge about circRNAs biogenesis and their aberrant expression in various human disorders. In particular, we focus on the latest discovery of circRNAs global upregulation in myotonic dystrophy type 1 (DM1) skeletal muscles and the role these prospective biomarkers might have for prognosis and therapeutic response in DM1.

<p>The Biogenesis, Functions, and Roles of circRNAs in Bladder Cancer</p>

“…26 Because of the lack of 5ʹ-cap and 3ʹ-poly(A) structures, RNA circularization normally involves a back-splicing process, wherein the 3ʹ downstream splice donor (SD) is connected to the 5ʹ upstream splice acceptor (SA). 27 There are two widely accepted mechanisms that can explain the backsplicing process, known as lariat-driven circularization and intron pairing-driven circularization. 12 In the former model, circularization usually happens in exon-skipping events 28 and needs the downstream SD to attach to the upstream SA covalently to form a lariat which also contains the skipped exons.…”

“…12 In the former model, circularization usually happens in exon-skipping events 28 and needs the downstream SD to attach to the upstream SA covalently to form a lariat which also contains the skipped exons. 27 If the back-splicing event takes place in the lariat before this lariat is disintegrated, a steady and covalent circRNA including the skipped exons will be produced. 12 If the lariat possesses only one exon, the downstream SD of the exon attaches to its own upstream SA through a transesterification reaction, resulting in a circular RNA containing one exon without introns.…”

Regulatory Potential of Competing Endogenous RNAs in Myotonic Dystrophies

“…An understanding of the role and importance of ncRNAs in numerous human diseases, including DM1 and DM2, is increasingly growing. Several types of ncRNAs, such as miRNA, lncRNA or circRNA, are affected in both DMs, suggesting that they are implicated in multiple disease mechanisms at the molecular level [ 44 , 62 , 66 , 93 , 94 , 95 , 96 , 97 ] ( Table 2 ). Moreover, changes in ncRNA expression profiles were reported mostly in muscle cells, the primary cell type affected in DMs, which additionally implies their involvement in the pathophysiology of the disease.…”

“…The importance of other ncRNAs, with a particular focus on lncRNAs and circRNAs, in the context of DM pathology has also been highlighted in the literature [ 44 , 93 , 96 , 105 , 109 ] ( Table 2 ). In the last years, lncRNAs are emerging as critical regulators of muscle differentiation, growth, and regeneration, as well as important factors contributing to muscle disease [ 96 , 109 , 110 , 111 , 112 , 113 ].…”

Protein-Related Circular RNAs in Human Pathologies

“…The presence of ADAR (adenosine deaminase acting on RNA)-theRNA-binding protein (RBP), which have the ability to deaminate adenosine to inosine in double-stranded RNA, leads to the destabilization of inverted repeats and hinders the circularization of the transcript [20]. Quaking (QKI) belongs to a group of RNA-binding proteins that enhance circRNA production during the epithelial-mesenchymal transition [21]. The mechanism of action includes binding to its target single-stranded RNA (ssRNA) motif in intron-flanking sequences, causing these ssRNAs to be circularized and dimerized, which brings two ends of the sequence into close proximity, thus resulting in circRNA formation [22,23].…”