Base-pair conformational switch modulates miR-34a targeting of Sirt1 mRNA

Nature. 2020 Jul;583(7814):139-144. doi: 10.1038/s41586-020-2336-3. Epub 2020 May 27.


MicroRNAs (miRNAs) regulate the levels of translation of messenger RNAs (mRNAs). At present, the major parameter that can explain the selection of the target mRNA and the efficiency of translation repression is the base pairing between the 'seed' region of the miRNA and its counterpart mRNA1. Here we use R relaxation-dispersion nuclear magnetic resonance2 and molecular simulations3 to reveal a dynamic switch-based on the rearrangement of a single base pair in the miRNA-mRNA duplex-that elongates a weak five-base-pair seed to a complete seven-base-pair seed. This switch also causes coaxial stacking of the seed and supplementary helix fitting into human Argonaute 2 protein (Ago2), reminiscent of an active state in prokaryotic Ago4,5. Stabilizing this transient state leads to enhanced repression of the target mRNA in cells, revealing the importance of this miRNA-mRNA structure. Our observations tie together previous findings regarding the stepwise miRNA targeting process from an initial 'screening' state to an 'active' state, and unveil the role of the RNA duplex beyond the seed in Ago2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Argonaute Proteins / metabolism
  • Base Pairing*
  • Binding Sites
  • HEK293 Cells
  • Humans
  • MicroRNAs / genetics*
  • Models, Molecular
  • RNA, Messenger / genetics*
  • RNA-Induced Silencing Complex / metabolism
  • Sirtuin 1 / genetics*


  • AGO2 protein, human
  • Argonaute Proteins
  • MIRN34 microRNA, human
  • MicroRNAs
  • RNA, Messenger
  • RNA-Induced Silencing Complex
  • SIRT1 protein, human
  • Sirtuin 1