The importance of internal loops within RNA substrates of ADAR1

Lehmann, Katrina A.; Bass, Brenda

doi:10.1006/jmbi.1999.2914

Cited by 167 publications

(163 citation statements)

References 43 publications

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“…Many adenosine residues of a long, completely base-paired dsRNA (>100 bp) are edited non-selectively. By contrast, shorts dsRNAs (∼20-30 bp) or a long but partially dsRNA with mismatched bases, bulges and loops (imperfect dsRNAs) are edited selectively; only a few adenosines are specifically chosen, indicating that the secondary structure in ADAR substrates dictates editing-site selectivity 48 . For example, site-selective A→I RNA editing occurs on an imperfect fold-back dsRNA structure that is formed between the exon sequence around an editing site(s) and a downstream intronic complementary sequence, termed editing-site-complementary sequence (ECS), of glutamate receptor-2 (GluR2) and serotonin (5-HT) receptor-2C (5-HT 2C R) pre-mRNAs 49,50 (see FIG.…”

Section: Substrate and Editing-site Selectivitymentioning

confidence: 99%

Editor meets silencer: crosstalk between RNA editing and RNA interference

Nishikura

2006

Nat Rev Mol Cell Biol

258

263

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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: Substrate and Editing-site Selectivitymentioning

confidence: 99%

Editor meets silencer: crosstalk between RNA editing and RNA interference

Nishikura

2006

Nat Rev Mol Cell Biol

258

263

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“…38,39 In long, almost completely doublestranded RNA ADAR activity converts several if not most adenosines to inosines. 40 On the other hand, in site selective editing only a few adenosines are deaminated within an imperfect RNA stem loop structure. The prerequisites for site selective editing are still not fully understood but mismatches and bulges are involved in target identification.…”

Section: The Adar Enzyme Familymentioning

confidence: 99%

Proteome diversification by adenosine to inosine RNA-editing

Pullirsch

Jantsch²

2010

RNA Biology

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“…Those specifically modified substrates are typically formed by base pairing between edited exons and complementary sequences in flanking introns in pre-mRNA. Importantly, the structural determinants controlling this type of site-specific RNA editing are still not completely understood [5][6][7][8].…”

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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The importance of internal loops within RNA substrates of ADAR1

Cited by 167 publications

References 43 publications

Editor meets silencer: crosstalk between RNA editing and RNA interference

Editor meets silencer: crosstalk between RNA editing and RNA interference

Proteome diversification by adenosine to inosine RNA-editing

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

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