Structural Differences between Pri-miRNA Paralogs Promote Alternative Drosha Cleavage and Expand Target Repertoires

Cell Rep. 2019 Jan 8;26(2):447-459.e4. doi: 10.1016/j.celrep.2018.12.054.


MicroRNA (miRNA) processing begins with Drosha cleavage, the fidelity of which is critical for downstream processing and mature miRNA target specificity. To understand how pri-miRNA sequence and structure influence Drosha cleavage, we studied the maturation of three pri-miR-9 paralogs, which encode the same mature miRNA but differ in the surrounding scaffold. We show that pri-miR-9-1 has a unique Drosha cleavage profile due to its distorted and flexible stem structure. Cleavage of pri-miR-9-1, but not pri-miR-9-2 or pri-miR-9-3, generates an alternative miR-9 with a shifted seed sequence that expands the scope of its target RNAs. Analyses of low-grade glioma patient samples indicate that the alternative-miR-9 has a potential role in tumor progression. Furthermore, we provide evidence that distortion of pri-miRNA stems induced by asymmetric internal loops correlates with Drosha cleavage at non-canonical sites. Our studies reveal that pri-miRNA paralogs can have distinct functions via differential Drosha processing.

Keywords: Drosha; RNA structure; isomiRs; miR-9; microprocessor; paralogs; primary miRNA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Glioma / genetics
  • Glioma / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • MicroRNAs / chemistry
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • RNA Processing, Post-Transcriptional*
  • Ribonuclease III / metabolism*


  • MIRN92 microRNA, human
  • MicroRNAs
  • DROSHA protein, human
  • Ribonuclease III