A Slow Dynamic RNA Switch Regulates Processing of MicroRNA-21

Overview

Journal J Mol Biol

Publisher Elsevier

Specialties Microbiology
Molecular Biology

Date 2022 Jun 25

PMID 35752213

Authors

Matthew D Shortridge

Greg L Olsen

Wen Yang

Matthew J Walker

Gabriele Varani

Affiliations

Soon will be listed here.

Abstract

The microRNAs are non-coding RNAs which post-transcriptionally regulate the expression of many eukaryotic genes, and whose dysregulation is a driver of human disease. Here we report the discovery of a very slow (0.1 s) conformational rearrangement at the Dicer cleavage site of pre-miR-21, which regulates the relative concentration of readily- and inefficiently-processed RNA structural states. We show that this dynamic switch is affected by single nucleotide mutations and can be biased by small molecule and peptide ligands, which can direct the microRNA to occupy the inefficiently processed state and reduce processing efficiency. This result reveals a new mechanism of RNA regulation and suggests a chemical approach to suppressing or activating pathogenic microRNAs by selective stabilization of their unprocessed or processed states.

Citing Articles

Investigating Ligand-Mediated Conformational Dynamics of Pre-miR21: A Machine-Learning-Aided Enhanced Sampling Study.

Aureli S, Bellina F, Rizzi V, Gervasio F J Chem Inf Model. 2024; 64(22):8595-8603.

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Use of steric blocking antisense oligonucleotides for the targeted inhibition of junction containing precursor microRNAs.

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Structure of pre-miR-31 reveals an active role in Dicer-TRBP complex processing.

Ma S, Kotar A, Hall I, Grote S, Rouskin S, Keane S Proc Natl Acad Sci U S A. 2023; 120(39):e2300527120.

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Drug-Like Small Molecules That Inhibit Expression of the Oncogenic MicroRNA-21.

Shortridge M, Chaubey B, Zhang H, Pavelitz T, Vidadala V, Tang C ACS Chem Biol. 2023; 18(2):237-250.

PMID: 36727622 PMC: 10593481. DOI: 10.1021/acschembio.2c00502.

Structure of pre-miR-31 reveals an active role in Dicer processing.

Ma S, Kotar A, Grote S, Rouskin S, Keane S bioRxiv. 2023; .

PMID: 36711709 PMC: 9881868. DOI: 10.1101/2023.01.03.519659.

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