Circular RNAs—one of the enigmas of the brain

Abstract

Circular RNAs (circRNAs) provide a new and relatively unexplored class of noncoding RNAs that are predominantly found in mammalian cells. In this review, we present the latest data regarding the structural organization, possible mechanisms of synthesis, and functions of circRNAs. These transcripts were isolated as an RNA fraction that was resistant to RNase R treatment, which selectively destroys the linear forms of RNA molecules. circRNAs are encoded by orthologous genes in different organisms and show tissue- and organ-specific expression. Currently, the biogenesis and functional properties of circRNAs remain unclear; transcripts of this class, however, remain highly promising targets of research. Some of them have been ascribed the function of "molecular sponges" that can absorb microRNAs, RNA-binding proteins, and small nuclear RNAs. circRNAs are often formed from the RNA portions of protein-coding genes in the course of alternative splicing. Some features of the circRNAs of mammals were demonstrated using 11 circRNAs of the human sphingomyelin synthase 1 gene (SGMS1), which were discovered by us in the brain. These circRNAs consist mainly of portions of the multi-exon 5' untranslated region (5'UTR) of the SGMS1 gene and include one to five exons. The synthesis of circRNAs may be new, previously unknown, function of the multi-exon 5'UTR of genes. This feature is most clearly manifested in the brain, where the level of circRNAs is significantly higher.

Deficiency in the Ubiquitin Conjugating Enzyme UBE2A in Alzheimer’s Disease (AD) is Linked to Deficits in a Natural Circular miRNA-7 Sponge (circRNA; ciRS-7)

“…CircRNAs are generated (i) from both coding and noncoding exons, introns (including intron lariats); (ii) from 3′ and 5′ untranslated regions (UTRs) of mRNAs; (iii) from long non-coding intergenic sequences and pseudogenes; and (iv) from covalently-linked RNA ends produced in noncanonical splicing events, sometimes called “back-splicing” [19,21,22,24,25,26,27,28,29]. Perhaps the most intriguing feature of circRNAs are their lack of free ribonucleotide ends and their intrinsic circularity; their lack of free 3′ or 5′ termini have historically made circRNAs problematic to detect and quantify and, hence, their abundance, importance, and significance have only recently become appreciated [10,11,12,13,27,28,29].…”

“…Perhaps the most intriguing feature of circRNAs are their lack of free ribonucleotide ends and their intrinsic circularity; their lack of free 3′ or 5′ termini have historically made circRNAs problematic to detect and quantify and, hence, their abundance, importance, and significance have only recently become appreciated [10,11,12,13,27,28,29]. ssRNA circularity bestows upon circRNAs a number of extremely interesting, novel and unique properties including: (i) the lack of free ribonucleotide ends that allows circRNAs to avoid exonucleolytic degradation by abundant cellular or nuclear RNA exonucleases and/or RNaseR makes them considerably more stable than linear mRNAs; (ii) the lack of a standard 3′-poly-A adenylation signal that is associated with most linear mRNAs; (iii) a greatly enhanced structural stability that enables circRNAs to prolong their capability for signal and information transfer from DNA to protein (note that these more stable circRNAs would be useful as novel biomarkers in disease versus, for example, miRNAs which have a generally shorter half-life); (iv) the capability and potential of circRNAs to be used in nuclear processes, such as the evolutionary ancient “rolling circle amplification (RCA)”; often used in prokaryotes, it has been recently shown that circRNAs are efficiently translated into functional proteins by RCA-directed mechanisms in living human cells [21]; and (v) that through RCA, circRNAs provide brain and retinal cells with a means to very rapidly express highly-specific spatiotemporal and genetic information, and particularly in anatomical localizations of the brain and retina, such as at synapses, where they may be enriched [19,21,25,26,27,28,29]. …”

The Role of Noncoding RNAs in Brain Cells during Rat Cerebral Ischemia

“…To date, there is evidence that a substantial part of long ncRNA exists in a circular form [49][50][51][52][53][54]. Circular RNA (circRNA) is a newly discovered and relatively poorly studied class of long ncRNA, found predominantly in mammalian cells.…”

Noncoding RNAs in neurodegeneration

“…2). For instance, many protein-coding genes can be transcribed in the antisense orientation (bidirectional transcription) and/or into circular transcripts 98,195,196 . Similarly, lncRNAs often encompass small open-reading frames (ORFs) and are sometimes associated with ribosomes, suggesting that they might be involved in de novo protein synthesis 197,198 , although this possibility remains controversial 13,199,200 .…”

“…An appealing hypothesis is that ncRNAs may be mediators of certain behavioural and cognitive traits of higher organisms 207 , as opposed to CNS proteins, which are (apart from some limited examples of innovations in proteins) almost perfectly conserved across mammalian phyla 13,54,[221][222][223] . Illustrating these principles, the rapidly evolving, brain-and human-specific ncRNA HAR1F (human accelerated region 1F) is transcribed from a genomic region that has been subject to intense positive selection since human divergence from the great apes 224 and along with several Piwi-interacting RNAs (piRNAs), lincRNAs, miRNAs and circRNAs is associated with human-specific brain development and function 195,207,219,225,226 .…”