Importance of translation and nonnucleolytic ago proteins for on-target RNA interference

Curr Biol. 2008 Sep 9;18(17):1327-32. doi: 10.1016/j.cub.2008.07.072.


In animals, both siRNAs and miRNAs are thought to diminish protein synthesis from transcripts that are perfectly complementary by directing endonucleolytic cleavage where they anneal, thereby triggering rapid degradation of the entire message [1-4]. By contrast, partially complementary messages are downregulated by a combination of translational repression and accelerated decay caused by rapid poly(A) tail removal [3, 5-12]. Here we present evidence that translational repression can also make a substantial contribution to the downregulation of fully complementary messages by RNA interference. Unlike mRNA destabilization, this inhibitory effect on translation is greater for perfectly complementary elements located in the 3' untranslated region rather than in the protein-coding region. In addition to known disparities in their endonucleolytic activity [13, 14], the four Ago proteins with which siRNAs associate in humans differ significantly in their capacity to direct translational repression. As a result, the relative effect of siRNA on targets that are fully versus partially complementary is influenced by the comparative abundance of the three nonnucleolytic Ago proteins, causing this on-target/off-target ratio to vary in a cell-type-dependent manner because of the dissimilar tissue distribution of these proteins. These findings have important implications for the efficacy and specificity of RNA interference.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Argonaute Proteins
  • Cell Line
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism
  • Eukaryotic Initiation Factor-2 / physiology
  • Eukaryotic Initiation Factors / genetics
  • Eukaryotic Initiation Factors / metabolism
  • Eukaryotic Initiation Factors / physiology*
  • Genes, Reporter
  • Green Fluorescent Proteins / analysis
  • Humans
  • Protein Biosynthesis*
  • RNA Interference / physiology*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism*
  • Recombinant Fusion Proteins / analysis


  • AGO1 protein, human
  • AGO2 protein, human
  • AGO3 protein, human
  • AGO4 protein, human
  • Argonaute Proteins
  • Eukaryotic Initiation Factor-2
  • Eukaryotic Initiation Factors
  • RNA, Messenger
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins