- Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs characterized by their covalently closed-loop structure, which distinguishes them from the more familiar linear RNAs. This circular configuration arises from a non-canonical splicing event known as back-splicing, wherein a downstream 5′ splice donor site is joined to an upstream 3′ splice acceptor site. As a result, circRNAs lack 5′ caps and 3′ poly(A) tails, rendering them resistant to exonuclease-mediated degradation. This structural stability makes circRNAs more durable than linear RNAs, contributing to their relative abundance in various tissues and their potential utility as biomarkers.
- CircRNAs are expressed in a cell type-, tissue-, and developmental stage-specific manner. Although initially considered as splicing byproducts or transcriptional noise, emerging evidence has revealed that circRNAs serve diverse biological functions.
- One well-known function is microRNA (miRNA) sponging, where circRNAs contain multiple binding sites for specific miRNAs, thereby sequestering them and modulating the post-transcriptional regulation of target genes. For example, ciRS-7 (also known as CDR1as) harbors more than 60 conserved binding sites for miR-7, acting as a potent miRNA sponge in neuronal tissues.
- Beyond miRNA sponging, circRNAs have also been implicated in protein scaffolding, regulation of transcription, and even translation in some cases. Certain circRNAs can bind RNA-binding proteins (RBPs), influencing their localization or function. Some exon-intron circRNAs (EIciRNAs) and intronic circRNAs (ciRNAs) remain in the nucleus and regulate the transcription of their parental genes. Additionally, although circRNAs are generally considered non-coding, studies have demonstrated that some circRNAs can be translated into functional peptides through internal ribosome entry site (IRES)-mediated or m6A-driven cap-independent translation.
- In the context of disease, circRNAs are gaining attention as key regulators in cancer, neurodegenerative disorders, cardiovascular diseases, and viral infections. Their dysregulated expression is often associated with tumor progression, metastasis, or resistance to therapy. Given their stability, specificity, and detectability in body fluids such as blood and saliva, circRNAs are being explored as promising diagnostic and prognostic biomarkers, as well as potential therapeutic targets.
- The field of circRNA research is rapidly evolving, aided by advancements in high-throughput sequencing technologies and bioinformatics tools designed to detect and quantify circular transcripts. However, several challenges remain, including accurate annotation, understanding their biogenesis in detail, and functional validation of individual circRNAs. Overall, circRNAs represent a novel layer of gene regulation with far-reaching implications for molecular biology, physiology, and medicine.
