RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself

Science. 2015 Sep 4;349(6252):1115-20. doi: 10.1126/science.aac7049. Epub 2015 Jul 23.


Adenosine-to-inosine (A-to-I) editing is a highly prevalent posttranscriptional modification of RNA, mediated by ADAR (adenosine deaminase acting on RNA) enzymes. In addition to RNA editing, additional functions have been proposed for ADAR1. To determine the specific role of RNA editing by ADAR1, we generated mice with an editing-deficient knock-in mutation (Adar1(E861A), where E861A denotes Glu(861)→Ala(861)). Adar1(E861A/E861A) embryos died at ~E13.5 (embryonic day 13.5), with activated interferon and double-stranded RNA (dsRNA)-sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3' untranslated regions of endogenous transcripts. Finally, embryonic death and phenotypes of Adar1(E861A/E861A) were rescued by concurrent deletion of the cytosolic sensor of dsRNA, MDA5. A-to-I editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts.

Publication types

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

MeSH terms

  • 3' Untranslated Regions
  • Adenosine / genetics
  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism*
  • Animals
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Embryo Loss / genetics*
  • Gene Deletion
  • Gene Knock-In Techniques
  • Inosine / genetics
  • Interferon-Induced Helicase, IFIH1
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Nucleic Acid Conformation
  • RNA Editing*
  • RNA, Double-Stranded / chemistry
  • RNA, Double-Stranded / metabolism*
  • Transcription, Genetic


  • 3' Untranslated Regions
  • RNA, Double-Stranded
  • Inosine
  • ADAR1 protein, mouse
  • Adenosine Deaminase
  • Ifih1 protein, mouse
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • Adenosine

Associated data

  • GEO/GSE58917