Circular exonic RNAs: When RNA structure meets topology

Area of Science:

• Molecular Biology
• Genetics
• RNA Biology

Background:

• Circular RNAs (circRNAs) were first observed decades ago, but their prevalence and roles were unclear until high-throughput sequencing enabled their widespread identification.
• Despite advances, fundamental aspects of circRNA biogenesis, structure, and function remain poorly understood.
• This review specifically examines circular exonic RNAs, a subset of circRNAs formed via backsplicing.

Purpose of the Study:

• To hypothesize that RNA secondary structure is a key factor promoting both exon skipping and spliceosomal RNA circularization.
• To propose that backsplicing within double-stranded RNA regions can generate topologically linked circRNA molecules.
• To re-evaluate the interpretation of tail-to-head exon junctions as definitive evidence of circRNA formation.

Main Methods:

• Review of existing literature on RNA circularization, backsplicing, and high-throughput sequencing data.
• Theoretical analysis of RNA secondary structure's role in exon skipping and circularization.
• Revisiting and reinterpreting observations of tail-to-head exon junctions in RNA transcripts.

Main Results:

• RNA secondary structures are proposed as a common mechanism facilitating both exon skipping and the formation of circular RNAs via backsplicing.
• Backsplicing of double-stranded RNA regions may lead to the creation of complex, topologically linked circRNA structures.
• Tail-to-head exon junctions, while indicative of backsplicing, are insufficient on their own to confirm a circular RNA topology.

Conclusions:

• RNA secondary structure plays a crucial, unifying role in the biogenesis of circular RNAs and potentially influences alternative splicing events like exon skipping.
• The formation of circular RNAs via backsplicing of double-stranded regions results in unique molecular topologies.
• Distinguishing true circular RNAs from other transcript structures requires more than just identifying tail-to-head exon junctions.