Circular RNA biogenesis can proceed through an exon-containing lariat precursor

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Abstract

Pervasive expression of circular RNA is a recently discovered feature of eukaryotic gene expression programs, yet its function remains largely unknown. The presumed biogenesis of these RNAs involves a non-canonical 'backsplicing' event. Recent studies in mammalian cell culture posit that backsplicing is facilitated by inverted repeats flanking the circularized exon(s). Although such sequence elements are common in mammals, they are rare in lower eukaryotes, making current models insufficient to describe circularization. Through systematic splice site mutagenesis and the identification of splicing intermediates, we show that circular RNA in S. pombe is generated through an exon-containing lariat precursor. Furthermore, we have performed high-throughput and comprehensive mutagenesis of a circle-forming exon, which enabled us to discover a systematic effect of exon length on RNA circularization. Our results uncover a mechanism for circular RNA biogenesis that may account for circularization in genes that lack noticeable flanking intronic secondary structure.

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Steven P Barrett

Department of Biochemistry, Stanford University School of Medicine, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Peter L Wang

Department of Biochemistry, Stanford University School of Medicine, Stanford, United States

Competing interests
The authors declare that no competing interests exist.
Julia Salzman

Department of Biochemistry, Stanford University School of Medicine, Stanford, United States

For correspondence
julia.salzman@stanford.edu

Competing interests
The authors declare that no competing interests exist.

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