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PMID: 26275108 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Science (New York, N.Y.) ·Vol. 349 ·No. 6252 ·2015-09-04 ·Pages 1115-20

Liddicoat BJ, Piskol R, Chalk AM, Ramaswami G, Higuchi M, Hartner JC, Li JB, Seeburg PH, Walkley CR

Abstract

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.

MeSH Terms
3' Untranslated Regions Adenosine/genetics Adenosine Deaminase/genetics,metabolism Animals DEAD-box RNA Helicases/genetics,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,metabolism Transcription, Genetic
Chemicals
3' Untranslated Regions RNA, Double-Stranded Inosine ADAR1 protein, mouse Adenosine Deaminase Ifih1 protein, mouse DEAD-box RNA Helicases Interferon-Induced Helicase, IFIH1 Adenosine
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Liddicoat Brian J
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.
Piskol Robert
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Chalk Alistair M
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.
Ramaswami Gokul
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Higuchi Miyoko
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany.
Hartner Jochen C
Taconic Biosciences, 51063 Cologne, Germany.
Li Jin Billy
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
Seeburg Peter H
Department of Molecular Neurobiology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany.
Walkley Carl R
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. [email protected].
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.aac7049
Email
[email protected]
Published
2015-09-04
Epub
2015-00-23
Pages
1115-20
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC5444807
Subset
IM
Grants
NIGMS NIH HHS · R01 GM102484 · United States
NHGRI NIH HHS · T32 HG000044 · United States
NIGMS NIH HHS · R01GM102484 · United States
Databases
GEO
GSE58917
Corrections
CommentIn
PMID: 26596786
External Links
PubMed source DOI: 10.1126/science.aac7049 PMC Full Text View journal details
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