RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself.
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.
St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia.
Brian J
BJ
Liddicoat
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Robert
R
Piskol
St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia.
Alistair M
AM
Chalk
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Gokul
G
Ramaswami
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany.
Miyoko
M
Higuchi
Taconic Biosciences, 51063 Cologne, Germany.
Jochen C
JC
Hartner
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Jin Billy
JB
Li
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany.
Peter H
PH
Seeburg
St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia. cwalkley@svi.edu.au.
Carl R
CR
Walkley
D020413:3' Untranslated Regions; D000241:Adenosine / Q000235:genetics; D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D020964:Embryo Loss / Q000235:genetics*; D017353:Gene Deletion; D055879:Gene Knock-In Techniques; D007288:Inosine / Q000235:genetics; D000072640:Interferon-Induced Helicase, IFIH1; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009690:Nucleic Acid Conformation; D017393:RNA Editing; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic
D020413:3' Untranslated Regions; D012330:RNA, Double-Stranded; D007288:Inosine; C000599465:ADAR1 protein, mouse; D000243:Adenosine Deaminase; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D000241:Adenosine