A-to-I RNA Editing and Human Disease

Maas, Stefan; Kawahara, Yukio; Tamburro, Kristen M.; Nishikura, Kazuko

doi:10.4161/rna.3.1.2495

Cited by 246 publications

(214 citation statements)

References 106 publications

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“…Human diseases or pathophysiologies can also be caused by dysfunction of the A→I RNA editing mechanism 63,64 . Heterozygosity for the ADAR1-gene functional-null mutation results in dyschromatosis symmetrica hereditaria, a human pigmentary genodermatosis of autosomaldominant inheritance 65 .…”

Section: Rna-editing Deficienciesmentioning

confidence: 99%

“…3a). Last, the inactivation of ADAR1 leads to an embryonic lethal phenotype that is caused by defective erythropoiesis and widespread apoptosis [60][61][62] .Human diseases or pathophysiologies can also be caused by dysfunction of the A→I RNA editing mechanism 63,64 . Heterozygosity for the ADAR1-gene functional-null mutation results in dyschromatosis symmetrica hereditaria, a human pigmentary genodermatosis of autosomaldominant inheritance 65 .…”

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Editor meets silencer: crosstalk between RNA editing and RNA interference

Nishikura

2006

Nat Rev Mol Cell Biol

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257

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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.An RNA transcript is subjected to various maturation processes, such as 5′ capping, splicing, 3′ processing and polyadenylation, after it is transcribed from the gene. Post-transcriptional processing of primary transcripts is essential to generate mature messenger RNAs that are ready to be translated into proteins 1 . RNA editing is a post-transcriptional-processing mechanism that results in an RNA sequence that is different from the one encoded by the genome, and thereby contributes to the diversity of gene products. There are different types of RNA-editing mechanism that either add or delete nucleotides, or that change one nucleotide into another 2 (BOX 1).The type of RNA editing that is most prevalent in higher eukaryotes converts adenosine (A) residues into inosine (I) in double-stranded (ds)RNAs through the action of ADAR (adenosine deaminase acting on RNA) enzymes [3][4][5] . A→I RNA editing of a short dsRNA that has formed between a coding exon and nearby intron sequences can lead to a codon change and an alteration in the protein function. However, it was recently discovered that the most frequent targets of A→I RNA editing seem to be long, but partially double-stranded, RNAs that are formed from inverted Alu repeats and long interspersed element (LINE) repeats located in introns and untranslated regions (UTRs) of mRNAs [6][7][8][9] . Global editing of non-coding RNA might control the expression of genes that harbour these repeat sequences of retrotransposon origin.Post-transcriptional gene regulation can also occur through RNA interference (RNAi), an evolutionarily conserved phenomenon that involves dsRNA molecules 10,11 . Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are non-coding RNAs that are generated by a class of RNase III ribonucleases (specifically, Dicer and Drosha). These small RNAs are incorporated into the RNA-induced silencing complex (RISC), which mediates the RNAi process [12][13][14][15][16] . The idea that the RNAi and A→I RNA editing pathways might compete for a Competing interests statement: The author declares no competing financial interests. [23][24][25] . NIH Public AccessIn this review, I discuss recent findings on new functions of A→I RNA editing in the regulation of non...

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Section: Rna-editing Deficienciesmentioning

confidence: 99%

mentioning

confidence: 99%

Editor meets silencer: crosstalk between RNA editing and RNA interference

Nishikura

2006

Nat Rev Mol Cell Biol

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257

263

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“…the R/G and Q/R editing sites [9,18,19]. These two sites are edited with a high specificity and reduction of editing efficiency at these sites leads to dramatic effects on central nervous system [20,21]. They are therefore often used as model system for studies of editing by ADARs.…”

Section: Introductionmentioning

confidence: 99%

Solution structure of the N-terminal dsRBD of Drosophila ADAR and interaction studies with RNA

2012

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Adenosine deaminases that act on RNA (ADAR) catalyze adenosine to inosine (A-to-I) editing in double-stranded RNA (dsRNA) substrates. Inosine is read as guanosine by the translation machinery; therefore A-to-I editing events in coding sequences may result in recoding genetic information. Whereas vertebrates have two catalytically active enzymes, namely ADAR1 and ADAR2, Drosophila has a single ADAR protein (dADAR) related to ADAR2. The structural determinants controlling substrate recognition and editing of a specific adenosine within dsRNA substrates are only partially understood. Here, we report the solution structure of the N-terminal dsRNA binding domain (dsRBD) of dADAR and use NMR chemical shift perturbations to identify the protein surface involved in RNA binding. Additionally, we show that Drosophila ADAR edits the R/G site in the mammalian GluR-2 pre-mRNA which is naturally modified by both ADAR1 and ADAR2. We then constructed a model showing how dADAR dsRBD1 binds to the GluR-2 R/G stem-loop. This model revealed that most side chains interacting with the RNA sugar-phosphate backbone need only small displacement to adapt for dsRNA binding and are thus ready to bind to their dsRNA target. It also predicts that dADAR dsRBD1 would bind to dsRNA with less sequence specificity than dsRBDs of ADAR2. Altogether, this study gives new insights into dsRNA substrate recognition by Drosophila ADAR.

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“…A number of pathogenic mutations in ADAR (also known as ADAR1) gene are associated with dyschromatosis symmetrica hereditaria (DSH) (Tojo et al 2006;Keller et al 2008) and Aicardi-Goutieres syndrome (AGS) (Rice et al 2012). In addition, a lack of A-to-I editing has been associated with several neurological disorders (Maas et al 2006), including malignant gliomas (Maas et al 2001) and amyotrophic lateral sclerosis (ALS) (Kawahara et al 2008). The functional importance of A-to-I editing is also indicated by the fact that both ADAR and ADARB1 (also known as ADAR2) are essential enzymes in mouse (Higuchi et al 2000;Wang et al 2000).…”

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A biochemical landscape of A-to-I RNA editing in the human brain transcriptome

et al. 2014

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Inosine is an abundant RNA modification in the human transcriptome and is essential for many biological processes in modulating gene expression at the post-transcriptional level. Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosines to inosines (A-to-I editing) in double-stranded regions. We previously established a biochemical method called “inosine chemical erasing” (ICE) to directly identify inosines on RNA strands with high reliability. Here, we have applied the ICE method combined with deep sequencing (ICE-seq) to conduct an unbiased genome-wide screening of A-to-I editing sites in the transcriptome of human adult brain. Taken together with the sites identified by the conventional ICE method, we mapped 19,791 novel sites and newly found 1258 edited mRNAs, including 66 novel sites in coding regions, 41 of which cause altered amino acid assignment. ICE-seq detected novel editing sites in various repeat elements as well as in short hairpins. Gene ontology analysis revealed that these edited mRNAs are associated with transcription, energy metabolism, and neurological disorders, providing new insights into various aspects of human brain functions.

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A-to-I RNA Editing and Human Disease

Cited by 246 publications

References 106 publications

Editor meets silencer: crosstalk between RNA editing and RNA interference

Editor meets silencer: crosstalk between RNA editing and RNA interference

Solution structure of the N-terminal dsRBD of Drosophila ADAR and interaction studies with RNA

A biochemical landscape of A-to-I RNA editing in the human brain transcriptome

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