A Mechanism for microRNA Arm Switching Regulated by Uridylation

Mol Cell. 2020 Jun 18;78(6):1224-1236.e5. doi: 10.1016/j.molcel.2020.04.030. Epub 2020 May 21.


Strand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may change depending on cellular contexts, the molecular mechanism and physiological significance of such alternative strand selection (or "arm switching") remain elusive. Here we find miR-324 to be one of the strongly regulated miRNAs by arm switching and identify the terminal uridylyl transferases TUT4 and TUT7 to be the key regulators. Uridylation of pre-miR-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus from which the 3' strand (3p) is selected instead of the 5' strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated, whereas the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential.

Keywords: DICER; TUTase; arm switching; glioblastoma; miR-324; miRNA; miRNA biogenesis; miRNA tailing; strand selection; uridylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • DEAD-box RNA Helicases / metabolism
  • DNA-Binding Proteins / metabolism
  • Female
  • Humans
  • Mice
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Primary Cell Culture
  • RNA Nucleotidyltransferases / metabolism
  • Ribonuclease III / metabolism
  • UDPglucose-Hexose-1-Phosphate Uridylyltransferase / metabolism*


  • DNA-Binding Proteins
  • MIRN324 microRNA, human
  • MicroRNAs
  • TUT4 protein, human
  • RNA Nucleotidyltransferases
  • UDPglucose-Hexose-1-Phosphate Uridylyltransferase
  • TUT7 protein, human
  • DICER1 protein, human
  • Ribonuclease III
  • DEAD-box RNA Helicases