Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Type of study
Language
Publication year range
1.
PLoS Genet ; 11(12): e1005687, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26658668

ABSTRACT

Our knowledge of the variety and abundances of RNA base modifications is rapidly increasing. Modified bases have critical roles in tRNAs, rRNAs, translation, splicing, RNA interference, and other RNA processes, and are now increasingly detected in all types of transcripts. Can new biological principles associated with this diversity of RNA modifications, particularly in mRNAs and long non-coding RNAs, be identified? This review will explore this question by focusing primarily on adenosine to inosine (A-to-I) RNA editing by the adenine deaminase acting on RNA (ADAR) enzymes that have been intensively studied for the past 20 years and have a wide range of effects. Over 100 million adenosine to inosine editing sites have been identified in the human transcriptome, mostly in embedded Alu sequences that form potentially innate immune-stimulating dsRNA hairpins in transcripts. Recent research has demonstrated that inosine in the epitranscriptome and ADAR1 protein establish innate immune tolerance for host dsRNA formed by endogenous sequences. Innate immune sensors that detect viral nucleic acids are among the readers of epitranscriptome RNA modifications, though this does preclude a wide range of other modification effects.


Subject(s)
Adenosine Deaminase/genetics , Aminohydrolases/genetics , Immunity, Innate/genetics , RNA-Binding Proteins/genetics , Transcriptome/genetics , Adenosine/genetics , Humans , Inosine/genetics , RNA Editing/genetics , RNA Processing, Post-Transcriptional/genetics , RNA, Messenger/genetics
2.
Cell Rep ; 9(4): 1482-94, 2014 Nov 20.
Article in English | MEDLINE | ID: mdl-25456137

ABSTRACT

The ADAR RNA-editing enzymes deaminate adenosine bases to inosines in cellular RNAs. Aberrant interferon expression occurs in patients in whom ADAR1 mutations cause Aicardi-Goutières syndrome (AGS) or dystonia arising from striatal neurodegeneration. Adar1 mutant mouse embryos show aberrant interferon induction and die by embryonic day E12.5. We demonstrate that Adar1 embryonic lethality is rescued to live birth in Adar1; Mavs double mutants in which the antiviral interferon induction response to cytoplasmic double-stranded RNA (dsRNA) is prevented. Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs. We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions. Transfecting dsRNA oligonucleotides containing inosine-uracil base pairs into Adar1 mutant mouse embryo fibroblasts reduces the aberrant innate immune response. ADAR1 mutations causing AGS affect the activity of the interferon-inducible cytoplasmic isoform more severely than the nuclear isoform.


Subject(s)
Adenosine Deaminase/metabolism , Immunity, Innate , RNA Editing , RNA, Double-Stranded/metabolism , RNA-Binding Proteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adenosine Deaminase/genetics , Animals , Autoimmune Diseases of the Nervous System/genetics , Autoimmune Diseases of the Nervous System/immunology , Crosses, Genetic , Cytokines/metabolism , Embryo Loss/pathology , Embryo, Mammalian/pathology , Female , Fibroblasts/metabolism , Humans , Inflammation Mediators/metabolism , Inosine/metabolism , Liver/metabolism , Male , Mice, Inbred C57BL , Mutation/genetics , Nervous System Malformations/genetics , Nervous System Malformations/immunology , Phenotype , RNA-Binding Proteins/genetics , Receptors, Interferon/metabolism , Survival Analysis , Transcription, Genetic , Tumor Suppressor Protein p53/metabolism , Uracil/metabolism
3.
Nat Genet ; 44(11): 1243-8, 2012 Nov.
Article in English | MEDLINE | ID: mdl-23001123

ABSTRACT

Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.


Subject(s)
Adenosine Deaminase/genetics , Autoimmune Diseases of the Nervous System/genetics , Interferon Type I , Nervous System Malformations/genetics , RNA, Double-Stranded/metabolism , Alu Elements/genetics , Animals , Exome , Gene Expression , Humans , Interferon Type I/genetics , Interferon Type I/metabolism , Mice , Mutation , Protein Conformation , RNA, Double-Stranded/genetics , RNA-Binding Proteins , Sequence Analysis, DNA , Signal Transduction , Structure-Activity Relationship
SELECTION OF CITATIONS
SEARCH DETAIL
...