Substrate specificity of the dsRNA unwinding/modifying activity.

Nishikura, Kazuko; Yoo, C J; Kim, U.; Murray, John M.; Estes, Patricia A.; Cash, F E; Liebhaber, Stephen A.

doi:10.1002/j.1460-2075.1991.tb04916.x

Cited by 167 publications

(151 citation statements)

References 34 publications

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“…Both intermolecular and intramolecular dsRNAs of >20 base pairs (bp) (two turns of the dsRNA helix) can serve as substrates for ADAR 47 . Many adenosine residues of a long, completely base-paired dsRNA (>100 bp) are edited non-selectively.…”

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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“…Any double-stranded region of at least 15-20 base pairs may potentially be a substrate for ADARs (17). However, dsRNAs for ADARs can be broadly classified into nonspecific and specific types.…”

Section: Evolution Of Adar Targetsmentioning

confidence: 99%

Origins and evolution of ADAR‐mediated RNA editing

2009

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SummaryAdenosine deaminases acting on RNA (ADARs) convert adenosines to inosines in double-stranded RNA in animals. Identification of more ADAR targets and genome sequences of diverse eukaryotes present an opportunity to elucidate the origin and evolution of ADAR-mediated RNA editing. Comparative analysis of the adenosine deaminase family indicates that the first ADAR might have evolved from adenosine deaminases acting on tRNAs after the split of protozoa and metazoa. ADAR1 and ADAR2 arose by gene duplications in early metazoan evolution, 700 million years ago, while ADAR3 and TENR might originate after Urochordata-Vertebrata divergence. More ADAR or ADAR-like genes emerged in some animals (e.g., fish). Considering the constrained structure, ADAR targets are proposed to have evolved from transposable elements and repeats, random selection, and fixation, and intermolecular pairs of sense and antisense RNA. In some degree, increased ADAR-mediated gene regulation should substantially contribute to the emergence and evolution of complex metazoans, particularly the nervous system.2009 IUBMB IUBMB Life, 61(6): 572-578, 2009

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“…While there is no discrete sequence motif common among substrates to direct the deamination of specific adenosine residues, distinct 5Ј-nearest neighbor sequence preferences have been identified for both ADAR1 (U ϭ A Ͼ C Ͼ G) and ADAR2 (U ϭ A Ͼ C ϭ G) using in vitro editing assays with artificial RNA duplexes and a 3Ј-nearest neighbor preference for ADAR2 has also been suggested (U ϭ G Ͼ C ϭ A) (7). While up to 50% of the adenosine residues within a perfect RNA duplex may be modified by ADAR1 and ADAR2 in vitro, RNA substrates whose duplex structures are interrupted by mismatches, bulges and loops are edited more selectively (20,21). Recent in vitro studies with synthetic RNA substrates have indicated that internal loops within ADAR substrates may serve to uncouple adjacent helices to convert long, promiscuously deaminated substrates into a series of short, selectively modified RNA targets (22).…”

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confidence: 99%

Structure and Sequence Determinants Required for the RNA Editing of ADAR2 Substrates

Dawson¹,

Sansam

Emeson

2004

Journal of Biological Chemistry

119

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ADAR2 is a double-stranded RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-specific conversion of adenosine to inosine. We have demonstrated previously that ADAR2 can modify its own pre-mRNA, leading to the creation of a proximal 3-splice junction containing a non-canonical adenosine-inosine (A-I) dinucleotide. Alternative splicing to this proximal acceptor shifts the reading frame of the mature mRNA transcript, resulting in the loss of functional ADAR2 expression. Both evolutionary sequence conservation and mutational analysis support the existence of an extended RNA duplex within the ADAR2 pre-mRNA formed by base-pairing interactions between regions ϳ1.3-kilobases apart in intron 4 and exon 5. Characterization of ADAR2 pre-mRNA transcripts isolated from adult rat brain identified 16 editing sites within this duplex region, and sites preferentially modified by ADAR1 and ADAR2 have been defined using both tissue culture and in vitro editing systems. Statistical analysis of nucleotide sequences surrounding edited and non-edited adenosine residues have identified a nucleotide sequence bias correlating with ADAR2 site preference and editing efficiency. Among a mixed population of ADAR substrates, ADAR2 preferentially favors its own transcript, yet mutation of a poor substrate to conform to the defined nucleotide bias increases the ability of that substrate to be modified by ADAR2. These data suggest that both sequence and structural elements are required to define adenosine moieties targeted for specific ADAR2-mediated deamination.

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Substrate specificity of the dsRNA unwinding/modifying activity.

Cited by 167 publications

References 34 publications

Editor meets silencer: crosstalk between RNA editing and RNA interference

Editor meets silencer: crosstalk between RNA editing and RNA interference

Origins and evolution of ADAR‐mediated RNA editing

Structure and Sequence Determinants Required for the RNA Editing of ADAR2 Substrates

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