Publication Date:
2015-08-15
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liddicoat, Brian J -- Piskol, Robert -- Chalk, Alistair M -- Ramaswami, Gokul -- Higuchi, Miyoko -- Hartner, Jochen C -- Li, Jin Billy -- Seeburg, Peter H -- Walkley, Carl R -- R01GM102484/GM/NIGMS NIH HHS/ -- T32 HG000044/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Sep 4;349(6252):1115-20. doi: 10.1126/science.aac7049. Epub 2015 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Department of Genetics, Stanford University, Stanford, CA 94305, USA. ; Department of Molecular Neurobiology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany. ; Taconic Biosciences, 51063 Cologne, Germany. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26275108" target="_blank"〉PubMed〈/a〉
Keywords:
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
;
Mice
;
Mice, Mutant Strains
;
Mutation
;
Nucleic Acid Conformation
;
*RNA Editing
;
RNA, Double-Stranded/chemistry/*metabolism
;
Transcription, Genetic
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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