Tertiary structural elements determine the extent and specificity of messenger RNA editing

Rieder, Leila E.; Staber, Cynthia; Hoopengardner, Barry; Reenan, Robert A.

doi:10.1038/ncomms3232

Cited by 48 publications

(69 citation statements)

References 59 publications

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“…In the Drosophila editing target para, dsRNA elements, including a predicted pseudoknot, created by the intron downstream from exonic editing sites, influence editing efficiency even though these regions lack editing sites (Rieder et al 2013). Similarly, downstream dsRNA hairpins within the introns of the human Gabra-3 and Neil1 transcripts have also been shown to increase editing efficiency of adjacent editing sites in coding regions (Daniel et al 2012(Daniel et al , 2014.…”

Section: Introductionmentioning

confidence: 99%

Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

Washburn

Hundley

2016

RNA

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Adenosine-to-inosine RNA editing by ADARs affects thousands of adenosines in an organism's transcriptome. However, adenosines are not edited at equal levels nor do these editing levels correlate well with ADAR expression levels. Therefore, additional mechanisms are utilized by the cell to dictate the editing efficiency at a given adenosine. To examine cis-and transacting factors that regulate A-to-I editing levels specifically in neural cells, we utilized the model organism Caenorhabditis elegans. We demonstrate that a double-stranded RNA (dsRNA) binding protein, ADR-1, inhibits editing in neurons, which is largely masked when examining editing levels from whole animals. Furthermore, expression of ADR-1 and mRNA expression of the editing target can act synergistically to regulate editing efficiency. In addition, we identify a dsRNA region within the Y75B8A.8 3 ′ UTR that acts as a cis-regulatory element by enhancing ADR-2 editing efficiency. Together, this work identifies mechanisms that regulate editing efficiency of noncoding A-to-I editing sites, which comprise the largest class of ADAR targets.

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Section: Introductionmentioning

confidence: 99%

Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

Washburn

Hundley

2016

RNA

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“…Because ADAR proteins recognize double-stranded RNAs (dsRNAs), substitution of adenosines by inosines may alter the stability of the RNA structures and influence the accessibility of splice sites (Morse et al 2002;Blow et al 2004;Levanon et al 2004;Mazloomian and Meyer 2015). In general, ADAR and splicing machineries may act on the same dsRNA substrates, leading to the interplay between these two processes (Reenan et al 2000;Rieder et al 2013). However, structure-mediated splicing modulation by RNA editing or ADAR binding is relatively poorly understood.…”

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confidence: 99%

RNA editing in nascent RNA affects pre-mRNA splicing

et al. 2018

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In eukaryotes, nascent RNA transcripts undergo an intricate series of RNA processing steps to achieve mRNA maturation. RNA editing and alternative splicing are two major RNA processing steps that can introduce significant modifications to the final gene products. By tackling these processes in isolation, recent studies have enabled substantial progress in understanding their global RNA targets and regulatory pathways. However, the interplay between individual steps of RNA processing, an essential aspect of gene regulation, remains poorly understood. By sequencing the RNA of different subcellular fractions, we examined the timing of adenosine-to-inosine (A-to-I) RNA editing and its impact on alternative splicing. We observed that >95% A-to-I RNA editing events occurred in the chromatin-associated RNA prior to polyadenylation. We report about 500 editing sites in the 3 ′ acceptor sequences that can alter splicing of the associated exons. These exons are highly conserved during evolution and reside in genes with important cellular function. Furthermore, we identified a second class of exons whose splicing is likely modulated by RNA secondary structures that are recognized by the RNA editing machinery. The genome-wide analyses, supported by experimental validations, revealed remarkable interplay between RNA editing and splicing and expanded the repertoire of functional RNA editing sites.

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“…Consistent with this idea, recent work in Drosophila has demonstrated that editing events located in close proximity (»10 nucleotides apart) are not functionally coupled and require binding of ADARs to 2 distinct locations on the dsRNA structure. 56 Furthermore, early biochemical work supports the hypothesis of re-binding and editing by ADARs, as partially edited RNAs re-introduced to ADARs in vitro were capable of undergoing further deamination. 23 In addition to the pair-wise editing events, the correlation analysis between the overall co-occurrence of 2 adenosines, revealed that distant editing events separated by multiple helical turns, such as nucleotides 95 and 178 in syntaxin, were positively correlated (dice coefficient of 0.05).…”

Section: Discussionmentioning

confidence: 90%

Noncoding regions ofC. elegansmRNA undergo selective adenosine to inosine deamination and contain a small number of editing sites per transcript

et al. 2015

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ADARs (Adenosine deaminases that act on RNA) "edit" RNA by converting adenosines to inosines within doublestranded regions. The primary targets of ADARs are long duplexes present within noncoding regions of mRNAs, such as introns and 3 0 untranslated regions (UTRs). Because adenosine and inosine have different base-pairing properties, editing within these regions can alter splicing and recognition by small RNAs. However, despite numerous studies identifying multiple editing sites in these genomic regions, little is known about the extent to which editing sites cooccur on individual transcripts or the functional output of these combinatorial editing events. To begin to address these questions, we performed an ultra-deep sequencing analysis of 4 Caenorhabditis elegans 3 0 UTRs that are known ADAR targets. Synchronous editing events were determined for the long duplexes in vivo. Furthermore, the validity of each editing event was confirmed by sequencing the same regions of mRNA from worms that lack A-to-I editing. This analysis identified a large number of editing sites that can occur within each 3 0 UTR, but interestingly, each individual transcript contained only a small fraction of these A-to-I editing events. In addition, editing patterns were not random, indicating that an editing event can affect the efficiency of editing at subsequent adenosines. Furthermore, we identified specific sites that can be both positively and negatively correlated with additional sites leading to mutually exclusive editing patterns. These results suggest that editing in noncoding regions is selective and hyper-editing of cellular RNAs is rare.

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Tertiary structural elements determine the extent and specificity of messenger RNA editing

Cited by 48 publications

References 59 publications

Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

Trans and cis factors affecting A-to-I RNA editing efficiency of a noncoding editing target in C. elegans

RNA editing in nascent RNA affects pre-mRNA splicing

Noncoding regions ofC. elegansmRNA undergo selective adenosine to inosine deamination and contain a small number of editing sites per transcript

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