Widespread A-to-I RNA Editing of Alu-Containing mRNAs in the Human Transcriptome

By A. Athanasiadis, A. Rich, S. Maas. PLoS Biology, 2004

750 citations recorded by the source corpus.

RNA editing by adenosine deamination generates RNA and protein diversity through the posttranscriptional modification of single nucleotides in RNA sequences. Few mammalian A-to-I edited genes have been identified despite evidence that many more should exist. Here we identify intramolecular pairs of Alu elements as a major target for editing in the human transcriptome. An experimental demonstration in 43 genes was extended by a broader computational analysis of more than 100,000 human mRNAs. We find that 1,445 human mRNAs (1.4%) are subject to RNA editing at more than 14,500 sites, and our data further suggest that the vast majority of pre-mRNAs (greater than 85%) are targeted in introns by the editing machinery. The editing levels of Alu-containing mRNAs correlate with distance and homology between inverted repeats and vary in different tissues. Alu-mediated RNA duplexes targeted by RNA editing are formed intramolecularly, whereas editing due to intermolecular base-pairing appears to be negligible. We present evidence that these editing events can lead to the posttranscriptional creation or elimination of splice signals affecting alternatively spliced Alu-derived exons. The analysis suggests that modification of repetitive elements is a predominant activity for RNA editing with significant implications for cellular gene expression.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/c0842b7997fdaf6092bbf6b6486cb64e87002b77

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Citations in the corpus

Establishing the role of ATP for the function of the RIG-I innate immune sensor (2015, background): “Endogenous RNAs, such as tRNAs, inverted repeat sequence elements, and pre-and mature miRNAs, are abundant in the cytoplasm and contain structured duplex regions to which RIG-I can readily bind (Athanasiadis et al., 2004; Wang and Carmichael, 2004; Watanabe et al., 2008; Wang and Leung, 2009; Chiang”
Short intronic repeat sequences facilitate circular RNA production (2014, positive): “Supporting this model, A-to-I editing is most commonly observed in intronic repeats that are engaged in intramolecular base-pairing (Athanasiadis et al. 2004), exactly the sort of structure that is needed for circularization.”
The impact of retrotransposons on human genome evolution (2009, neutral): “A to I editing is widespread in humans, and >90% of all A to I substitutions occur in Alu sequences embedded in mRNA transcript”
Complementary sequence-mediated exon circularization. (2014, background): “It has been reported that the capacity to form complementary pairs is dramatically decreased when it exceeds several kilobases (Athanasiadis et al., 2004).”
Regulation of circRNA biogenesis (2015, background): “3B) to induce back-splicing, resulting in upregulated circRNA formation from its own RNA.29 ADAR1 knockdown specifically up-regulates some circRNA expression, implying a role of ADAR1 in suppression of circRNA biogenesis.23 Mechanistically, it was suggested that such regulation is associated with Ad”
Editing modifies the GABAA receptor subunit α3 (2007, methodology): “Bioinformatic techniques have been used to demonstrate abundant hyperediting in Alu sequences within introns and untranslated regions of the human transcriptome (Athanasiadis et al. 2004; Blow et al. 2004; Levanon et al. 2004).”
Functions and Regulation of RNA Editing by ADAR Deaminases (2010, methodology): “The A→I editing of the Alu sequence and exonization of the noncoding sequence may be one important evolutionary means for generating a new variant protein with a novel function (102, 115, 116).”