Circular RNAs: from transcriptional noise to engineered therapeutics

Circular RNAs (circRNAs) are single stranded, closed, primarily non-coding RNA circles that have risen to the forefront of the non-coding RNA field. Studies from recent years have shown that circRNAs are produced from endogenous, non-canonical RNA splicing mechanisms, demonstrate specific cellular localizations, regulation by RNA modifications and function in many fundamental and critical cellular processes. CircRNAs can influence gene expression both pre- and post-transcriptionally, influence translation and interact with cellular RNA and proteins to enable cellular homeostasis. Aberrations in circRNA expression patterns lead to alterations in gene regulatory networks, which have been implicated in the progression of many cancer types. Unique characteristics of circRNAs, particularly their stability within cells and ability to be leveraged for protein production, have led to the engineering of artificial circRNAs to be used as an emerging therapeutic modality. Here we review how circRNAs regulate homeostasis in normal tissues, how dysregulated expression of circRNAs impacts various cancers and emerging therapeutic technologies that build upon their unique features.