CircRNAs

CircRNAs are endogenous RNA molecules that form covalently closed loops, lacking 5' caps and 3' poly(A) tails. They arise mainly from back-splicing of precursor mRNA, in which a downstream splice donor is joined to an upstream splice acceptor. Their circular structure renders them resistant to exonucleases and highly stable in cells. CircRNAs are abundant across eukaryotes and exhibit tissue- and development-specific expression patterns.

Biogenesis: circRNAs can be exon-only (ecircRNAs), intron-only (ciRNAs), or exon-intron (EIciRNAs). Back-splicing is facilitated by complementary intronic sequences and RNA-binding proteins, such as QKI, FUS, and MBL. ADAR-mediated RNA editing can suppress circularization by disrupting base pairing. The process can also occur via lariat-driven circularization following exon skipping.

Functions: In the cytoplasm, many circRNAs act as microRNA sponges, modulating miRNA activity and target gene expression. They can bind RNA-binding proteins, influencing splicing, transport, or translation. Some circRNAs localize to the nucleus and regulate transcription of their host genes. Emerging evidence shows that a subset can be translated into peptides through internal ribosome entry sites or N6-methyladenosine–driven mechanisms.

Clinical and research relevance: circRNAs display remarkable stability and conservation, making them potential biomarkers for cancer and neurological diseases. They are detected by RNA sequencing with specialized circumscriptive algorithms and validated by methods such as RNase R treatment and divergent PCR. Ongoing research explores their biogenesis, functions, and therapeutic potential.