Key Points
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Adenosine to inosine (A→I) RNA editing is catalysed by ADAR (adenosine deaminases acting on RNA) proteins.
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Three mammalian ADAR genes (ADAR1–3), the products of which have common functional domains, have been identified.
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Protein-coding sequences of a limited number of genes, such as the glutamate receptor GluR2 and serotonin receptor 2C, are edited, which results in dramatic alterations of protein functions.
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Deficiencies in the A→I RNA editing mechanism cause human diseases and pathophysiologies.
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Recent bioinformatics studies identified numerous A→I RNA editing sites genome wide in Alu and long interspersed element (LINE) repetitive RNA sequences located in introns and untranslated regions, but identified only a few sites in protein-coding exons.
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The biogenesis of certain microRNAs is regulated by the editing of their precursors.
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A→I RNA editing and RNA-interference mechanisms seem to interact and compete for common substrate double-stranded RNAs.
Abstract
The most prevalent type of RNA editing is mediated by ADAR (adenosine deaminase acting on RNA) enzymes, which convert adenosines to inosines (a process known as A→I RNA editing) in double-stranded (ds)RNA substrates. A→I RNA editing was long thought to affect only selected transcripts by altering the proteins they encode. However, genome-wide screening has revealed numerous editing sites within inverted Alu repeats in introns and untranslated regions. Also, recent evidence indicates that A→I RNA editing crosstalks with RNA-interference pathways, which, like A→I RNA editing, involve dsRNAs. A→I RNA editing therefore seems to have additional functions, including the regulation of retrotransposons and gene silencing, which adds a new urgency to the challenges of fully understanding ADAR functions.
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Acknowledgements
I am grateful to J. M. Gott, H. H. Kazazian, J. M. Murray and also members of my laboratory, especially L. Valente and Y. Kawahara, for their comments and suggestions. This work was supported in part by grants from the US National Institutes of Health, Juvenile Diabetes Research Foundation and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.
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Glossary
- ADAR
-
An adenosine deaminase that catalyses an RNA-editing reaction whereby an adenosine is converted to an inosine.
- Alu repeat
-
A dispersed, moderately repetitive DNA sequence found in the human genome with ∼1.4 million copies. The sequence is ∼300 base pairs long. The name Alu comes from the restriction endonuclease (AluI) that cleaves the sequence.
- LINE
-
A long interspersed element (LINE) sequence that is typically used for non-long terminal repeat retrotransposons.
- Non-coding RNA
-
RNA that is transcribed from DNA, but that is not translated into protein. Introns, 5′ and 3′ untranslated regions of mRNA, antisense transcripts (RNAs transcribed from the antisense strand of DNA), siRNA, miRNA, RNAs transcribed from repetitive sequences, tRNA, rRNA, small nuclear (sn)RNA and small nucleolar (sno)RNA are all non-coding RNAs.
- Retrotransposon
-
A mobile genetic element; its DNA is transcribed into RNA, which is reverse-transcribed into DNA and then is inserted into a new location in the genome.
- RNA interference
-
(RNAi). A post-transcriptional gene-silencing process in which double-stranded (ds)RNA triggers the degradation of homologous mRNA. Degradation of the target mRNA is induced by siRNAs that are derived from long dsRNA.
- Small interfering RNA
-
(siRNA). A small (19–23 base pair) non-coding double-stranded (ds)RNA that is processed from a longer dsRNA. Such non-coding RNAs hybridize with mRNA targets, and confer target specificity to the silencing complexes in which they reside.
- microRNA
-
(miRNA). A small (19–23 nucleotide) single-stranded RNA that is processed from a precursor that consists of a short double-stranded (ds)RNA region, internal loops or bulges, and a loop. miRNAs have an essential role in suppressing translation or in the degradation of a target mRNA by the miRNA-mediated RNA-interference mechanism.
- RNase III family
-
A group of double-stranded (ds)RNA-specific endonucleases that cleave dsRNA into short fragments with a 3′ overhang and a recessed 5′ phosphate on each strand. Drosha and Dicer, which are essential for RNA interference, belong to this family.
- RNA-induced silencing complex
-
(RISC). This complex, which contains siRNAs and protein factors, such as AGO2, mediates the degradation of target mRNAs with high sequence complementarity to the siRNA. A similar complex that contains miRNA instead of siRNA (miRISC) suppresses the translation of target mRNAs with partial complementarity to the miRNA.
- Deamination
-
The chemical process that replaces a primary amino group by a hydroxyl group, resulting in the conversion of one nucleoside to another.
- Double-stranded RNA-binding domain
-
(dsRBD). This compact (∼65 amino acids) domain with an α–β–β–β–α structure makes direct contact with the dsRNA. Proteins that function on dsRNAs contain a single or multiple dsRBDs.
- Inositol hexakisphosphate
-
(IP6). A phospholipid that is widely distributed throughout the animal kingdom and is affiliated with a wide-ranging array of important physiological activities.
- Z-DNA
-
A left-handed DNA form that is different from the A and B forms and that is believed to be involved in specific biological functions.
- Expressed sequence tag
-
(EST). A single-pass, short read of complementary DNA that is generated from a transcribed region of the genome.
- Single nucleotide polymorphism
-
(SNP). Typically a bi-allelic base-pair substitution, which is the most common form of genetic polymorphism.
- SINE
-
Short interspersed, repetitive sequences, such as Alu elements, generated by retrotransposition.
- Nuclear speckle
-
An irregularly shaped nuclear organelle that can be visualized by immunofluorescence microscopy using anti-splicing-factor antibodies. Usually, ∼25–50 speckles are present in the interphase mammalian nucleus, and they are thought to constitute storage and/or assembly sites for certain splicing factors.
- rasiRNA
-
(repeat-associated siRNA). siRNA derived from repetitive sequences such as Alu or LINE retrotransposon elements or centromeric repeat sequences.
- Wobble base pair
-
Non-G·C, A·U pairing, such as the thermodynamically less stable G·U, I·U pairing. Wobble base pairs, like Watson–Crick pairs, participate in forming helical regions in RNA folding.
- piRNA
-
An siRNA-like, small non-coding RNA (26–30 nucleotides) that was identified as an RNA component that is complexed with Piwi-family proteins in testes.
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Nishikura, K. Editor meets silencer: crosstalk between RNA editing and RNA interference. Nat Rev Mol Cell Biol 7, 919–931 (2006). https://doi.org/10.1038/nrm2061
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DOI: https://doi.org/10.1038/nrm2061
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