Microscopic view of RNA splicing showing circular RNA forming a loop.

Decoding Circular RNA: How Our Cells Innovate Gene Expression

Rhea Morgan in Science & Nature September 2025 • 4 min read.

"Scientists uncover a novel method of circular RNA biogenesis, revealing how cells utilize exon-containing lariat precursors to diversify gene expression and opening new doors for understanding genetic mechanisms."

In the dynamic world of molecular biology, circular RNA (circRNA) has emerged as a key player in eukaryotic gene expression. Unlike their linear counterparts, circRNAs form a closed loop, offering stability and unique functions within the cell. While their presence has been increasingly recognized, the mechanisms behind their creation have remained largely mysterious.

Traditional models suggest that circRNA biogenesis relies on a process called 'backsplicing,' where exons are joined in a non-canonical order. This process is often facilitated by inverted repeats flanking the circularized exon(s). However, this model falls short in explaining circRNA production in organisms with fewer repetitive sequences, prompting scientists to explore alternative pathways.

A recent study published in eLife sheds light on this mystery, detailing a novel mechanism for circRNA biogenesis that involves exon-containing lariat precursors. This research, conducted on Schizosaccharomyces pombe, reveals a systematic approach to RNA circularization that could revolutionize our understanding of gene expression.

Unlocking the Secrets of Circular RNA Biogenesis

Microscopic view of RNA splicing showing circular RNA forming a loop.

The central question revolves around how circular RNA is created. The conventional model proposes 'direct backsplicing,' potentially aided by complementary sequences. In contrast, the alternative lariat precursor model suggests a different path. The study undertakes a thorough examination to identify which pathway is more prominent.

Researchers initially examined the mrps16 gene in Schizosaccharomyces pombe, predicting its pre-mRNA structure to check for base-pairing interactions around the circularized exon. Discovering a lack of significant base pairing, they proposed that circular RNA production might occur via a lariat precursor generated by exon skipping.

Exon Skipping: The process where an exon is removed from the pre-mRNA molecule during splicing.
Lariat Precursor: A looped structure formed during splicing, containing an exon that may lead to circular RNA.
Direct Backsplicing: A process where the 3' end of an exon is directly joined to its 5' end to form a circular RNA.

To test their hypothesis, the scientists utilized a yeast strain (dbr1Δ) lacking the debranching enzyme, which normally breaks down lariat structures. This allowed them to detect and analyze the various byproducts of splicing more easily. Through reverse transcription-PCR (RT-PCR), they identified canonical lariat byproducts alongside the circularized form of exon 2 in both wild-type and dbr1Δ yeast.

Implications and Future Directions

This research not only provides a detailed mechanism for circRNA biogenesis but also opens new avenues for understanding gene regulation and expression. By demonstrating the role of exon-containing lariat precursors, the study challenges existing models and highlights the complexity of RNA processing. Further exploration in this area could reveal novel therapeutic targets and strategies for manipulating gene expression in various diseases. The discovery that exon length significantly impacts circularization efficiency also prompts further research into the structural determinants of RNA circularization and their functional consequences.

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Everything You Need To Know

What exactly is circular RNA, and why should we care about it?

Circular RNA, or circRNA, is a type of RNA molecule that, unlike linear RNA, forms a closed loop. This unique structure provides circRNAs with increased stability and allows them to perform distinct functions within cells, particularly in the regulation of eukaryotic gene expression. Understanding circRNA is vital because it challenges traditional views of gene expression and introduces new possibilities for genetic research.

What are the main processes involved in creating circular RNA?

The prevailing model for circRNA biogenesis involves 'direct backsplicing,' where the 3' end of an exon joins directly to its 5' end, forming a circular structure. This process is often aided by inverted repeats that flank the exon being circularized. However, a novel mechanism involves exon-containing lariat precursors, formed during splicing when an exon is skipped. These lariats can then circularize, offering an alternative pathway, particularly significant in organisms with fewer repetitive sequences.

What does 'exon skipping' mean in the context of circular RNA formation?

Exon skipping is a process during RNA splicing where a particular exon is removed from the pre-mRNA molecule. This results in the creation of a lariat precursor, which is a looped structure containing the skipped exon. This lariat precursor can then be processed into circular RNA. Exon skipping is crucial as it provides an alternative pathway for circRNA production, especially in organisms where the traditional backsplicing mechanism is less prevalent.

What is a 'lariat precursor,' and why is it important?

A lariat precursor is a looped structure formed during the splicing process, specifically when an exon is skipped. This structure contains the exon that may eventually become circular RNA. The importance of lariat precursors lies in their role as intermediates in a novel circRNA biogenesis pathway, offering an alternative to direct backsplicing. This pathway is especially significant as it helps explain circRNA production in organisms with fewer repetitive sequences, challenging traditional models of RNA circularization.

Can you explain what 'direct backsplicing' is and why it matters?

Direct backsplicing is a mechanism where the 3' end of an exon is directly joined to its 5' end to form a circular RNA molecule. This process is often facilitated by the presence of inverted repeats flanking the circularized exon. Direct backsplicing is significant because it was the originally proposed mechanism for circRNA biogenesis. However, it doesn't fully explain circRNA production in all organisms, highlighting the need for alternative mechanisms like the lariat precursor pathway.