G-Quadruplexes influence pri-microRNA processing

RNA Biol. 2018 Feb 1;15(2):198-206. doi: 10.1080/15476286.2017.1405211. Epub 2017 Dec 11.

Abstract

RNA G-Quadruplexes (G4) have been shown to possess many biological functions, including the regulation of microRNA (miRNA) biogenesis and function. However, their impact on pri-miRNA processing remains unknown. We identified G4 located near the Drosha cleavage site in three distinct pri-miRNAs: pri-mir200c, pri-mir451a, and pri-mir497. The folding of the potential G4 motifs was determined in solution. Subsequently, mutations disrupting G4 folding led to important changes in the mature miRNAs levels in cells. Moreover, using small antisense oligonucleotides binding to the pri-miRNA, it was possible to modulate, either positively or negatively, the mature miRNA levels. Together, these data demonstrate that G4 motifs could contribute to the regulation of pri-mRNA processing, a novel role for G4. Considering that bio-informatics screening indicates that between 9% and 50% of all pri-miRNAs contain a putative G4, these structures possess interesting potential as future therapeutic targets.

Keywords: Antisense Oligonucleotide; G-Quadruplex; biogenesis; miRNA; microRNA; mir200c; mir451a; mir497; pri-miRNA processing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • G-Quadruplexes
  • HEK293 Cells
  • Humans
  • MicroRNAs / chemistry*
  • MicroRNAs / genetics
  • Models, Molecular
  • Mutation*
  • RNA Folding

Substances

  • MIRN200 microRNA, human
  • MIRN451 microRNA, human
  • MIRN497 microRNA, human
  • MicroRNAs

Grants and funding

S. R. holds a predoctoral fellowship from the Natural Science and Engineering Research Council (NSERC) of Canada. This work was supported by a grant from the Chaire de recherche de l'Université de Sherbrooke en Structure et Génomique de l'ARN to J.P.P and as well as by grants from the Fonds de Recherche du Québec – Nature et Technologie (FRQ-NT) and from both the Natural Science and Engineering Research Council (NSERC) of Canada) to J.P.P. The RNA group is supported by a grant from the Université de Sherbrooke. J. P. P. and M. B. are members of the Centre de Recherche du CHUS