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

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Science  23 Jul 2015:
DOI: 10.1126/science.aac7049

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Adenosine-to-inosine (A-to-I) editing is a highly prevalent post-transcriptional modification of RNA, mediated by ADAR 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 (Adar1E861A). Adar1E861A/E861A embryos died at ~E13.5, with activated interferon and dsRNA sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyper-editing within long dsRNA stem loops within 3′UTRs of endogenous transcripts. Finally, embryonic death and phenotypes of the Adar1E861A/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.

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