Circular RNAs remain peculiarly unclear in biogenesis and function

Abstract

The known complexity of eukaryotic transcriptomes has been greatly expanded due to the identification of a large family of circular RNAs in recent years [13]. As a special form of RNA compared to the "common" linear form, these molecules were first described in 1976, when it was discovered that several plant viroids were single-stranded and covalently closed circular RNAs [4]. In a broad sense, the "circular" form RNAs may include viroids, genome of some RNA viruses, the loop portion of intronic lariats, as well as circular RNAs formed from back-splicing of exons. Currently in the field and also for this review, the term of circular RNA (circRNA) refers to circular molecules from back-splicing of exons unless specified.Thousands of circRNAs are now found in human cells and in model organisms such as mice, Drosophila, and C. elegans. A question coming out immediately is how these molecules are generated in cells. Biogenesis of certain circRNAs had long been linked to the relatively long introns and the complementary repeat sequences flanking the region of circularization [5][6][7]. Genome-wide bioinformatic analysis actually confirmed the association of these features to circRNA biogenesis [5][6][7]. The exonic sequences within the circRNAs might also be important in some cases [6,7]. At current stage, these associations are linked to the biogenesis of most but not all circRNAs, and are not connected with any actual molecular mechanism. There are also disputes about whether circRNAs are generated co-transcriptionally or post-transcriptionally [5,6]. A recent publication showed that the RNA-binding protein quaking I 5 (QKI5) might participate in the circularization [8], although we have to keep in mind with several points before considering QKI5 as an essential player in circRNA biogenesis. First, QKI5 is a known regulatory factor of alternative splicing for selective mRNAs. Presumably many factors participating in pre-mRNA splicing or alternative splicing may also get involved in back-splicing for the formation of circRNAs "non-specifically". One would wonder whether there is any protein "specific" for circRNA biogenesis. Secondly, circRNAs are wide-spread transcripts found essentially in all cell types examined. We would anticipate that essential factors for circRNA biogenesis are someway ubiquitously expressed, but QKI5 is not expressed in all cells. Thirdly, flanking complementary sequences are associated with more than half of the circRNAs, and QKI5 has not been tested for biogenesis of circRNAs with flanking complementary repeats [8]. Some circRNAs showed cell type or tissue specific expression between two cells under comparison, even when their parent genes might be expressed (as mRNA) in both cells [7]. The ratio of circRNAs to mRNAs for individual genes was also dynamic among different cells under different conditions. These indicate strongly that biogenesis of circRNAs must be regulated with gene and cell type specificity, and also argue against the idea that circRNAs may be unavoidable byproducts of sp...

Circular RNAs in Eukaryotic Cells

“…circMbl and its flanking introns contain MBL binding sites, and thus MBL can modulate the generation of circMbl [ 48 ]. As both QKI5 and MBL are known factors of alternative splicing for selective mRNAs, there is a concern about involuntary involvement of these proteins in backsplicing [ 49 ].…”

Identifying and Characterizing the Circular RNAs during the Lifespan of Arabidopsis Leaves

“…Furthermore, circRNAs could serve as miRNA sponges by sequestering and preventing microRNAs from binding corresponding target genes (Hansen et al, 2013; Liu Q. et al, 2016; Peng et al, 2016). Nevertheless, the biogenesis and function of circRNAs remains to be studied (Chen and Shan, 2015). …”

What happens at or after transcription: Insights into circRNA biogenesis and function

“…As the majority of circRNAs identified in animal cells are composed of exonic circRNAs, in this point-of-view we will focus on exonic circRNAs; therefore, when we use the term 'circRNAs' we are referring to exonic circRNAs, unless otherwise specified. 7,8 Cotranscriptional or Posttranscriptional Biogenesis of circRNAs…”