Siblings or doppelgängers? Deciphering the evolution of structured cis-regulatory RNAs beyond homology

Structured cis-regulatory RNAs have evolved across all domains of life, highlighting the utility and plasticity of RNA as a regulatory molecule. Homologous RNA sequences and structures often have similar functions, but homology may also be deceiving. The challenges that derive from trying to assign function to structure and vice versa are not trivial. Bacterial riboswitches, viral and eukaryotic IRESes, CITEs, and 3′ UTR elements employ an array of mechanisms to exert their effects. Bioinformatic searches coupled with biochemical and functional validation have elucidated some shared and many unique ways cis-regulators are employed in mRNA transcripts. As cis-regulatory RNAs are resolved in greater detail, it is increasingly apparent that shared homology can mask the full spectrum of mRNA cis-regulator functional diversity. Furthermore, similar functions may be obscured by lack of obvious sequence similarity. Thus looking beyond homology is crucial for furthering our understanding of RNA-based regulation.