microRNA strand selection: Unwinding the rules

• Published in: Wiley interdisciplinary reviews. RNA 2021-05, Vol.12 (3), p.e1627-n/a
• Main Authors: Medley, Jeffrey C., Panzade, Ganesh, Zinovyeva, Anna Y.
• Format: Article
• Language: English
• Subjects: Advanced Review; Advanced Reviews; arm switching; Biogenesis of Effector Small RNAs; Complementarity; Gene expression; Gene regulation; MicroRNAs; miR; miRNA; passenger; Processing of Small RNAs; Regulatory RNAs; Riboswitches; RNA processing; RNA-mediated interference; strand selection; Transcription; Unwinding
• ISSN: 1757-7004; 1757-7012
• DOI: 10.1002/wrna.1627

microRNAs (miRNAs) play a central role in the regulation of gene expression by targeting specific mRNAs for degradation or translational repression. Each miRNA is post‐transcriptionally processed into a duplex comprising two strands. One of the two miRNA strands is selectively loaded into an Argonaute protein to form the miRNA‐Induced Silencing Complex (miRISC) in a process referred to as miRNA strand selection. The other strand is ejected from the complex and is subject to degradation. The target gene specificity of miRISC is determined by sequence complementarity between the Argonaute‐loaded miRNA strand and target mRNA. Each strand of the miRNA duplex has the capacity to be loaded into miRISC and possesses a unique seed sequence. Therefore, miRNA strand selection plays a defining role in dictating the specificity of miRISC toward its targets and provides a mechanism to alter gene expression in a switch‐like fashion. Aberrant strand selection can lead to altered gene regulation by miRISC and is observed in several human diseases including cancer. Previous and emerging data shape the rules governing miRNA strand selection and shed light on how these rules can be circumvented in various physiological and pathological contexts. This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs Summary of miRNA strand selection and regulatory mechanisms. Three major points of regulation for miRNA strand selection (1) altered miRNA processing by the Microprocessor complex (not shown) or Dicer, (2) remodeling of the miRNA duplex by nontemplated RNA modifications such as uridylation or A‐to‐I editing, and (3) changes in the strand preference of Argonaute. Once presented with a miRNA duplex, Argonaute makes a binary choice to load one miRNA strand and discard the other strand from miRISC. Alternate Argonaute programming leads to shifts in the target profile of miRISC based on the seed sequence of the loaded strand and is sometimes associated with human diseases.