Adenosine deamination in human transcripts generates novel microRNA binding sites

Abstract

Animals regulate gene expression at multiple levels, contributing to the complexity of the proteome. Among these regulatory events are post-transcriptional gene silencing, mediated by small non-coding RNAs (e.g. microRNAs), and adenosine-to-inosine (A-to-I) editing, generated by adenosine deaminases that act on double-stranded RNA (ADAR). Recent data suggest that these regulatory processes are connected at a fundamental level. A-to-I editing can affect Drosha processing or directly alter the microRNA (miRNA) sequences responsible for mRNA targeting. Here, we analyzed the previously reported adenosine deaminations occurring in human cDNAs, and asked if there was a relationship between A-to-I editing events in the mRNA 3′ untranslated regions (UTRs) and mRNA:miRNA binding. We find significant correlations between A-to-I editing and changes in miRNA complementarities. In all, over 3000 of the 12 723 distinct adenosine deaminations assessed were found to form 7-mer complementarities (known as seed matches) to a subset of human miRNAs. In 200 of the ESTs, we also noted editing within a specific 13 nucleotide motif. Strikingly, deamination of this motif simultaneously creates seed matches to three (otherwise unrelated) miRNAs. Our results suggest the creation of miRNA regulatory sites as a novel function for ADAR activity. Consequently, many miRNA target sites may only be identifiable through examining expressed sequences.

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

“…There are multiple motifs and target sites in the 39 UTR that are recognized by trans-factors including RNA-binding proteins and miRNAs. In fact, A-to-I editing in the 39 UTR of DFFA mRNA creates a target site recognized by miR-513 (Borchert et al 2009). When the miRNA response elements (MREs) in the 39 UTR are edited, especially in the seed region, the changes modulate miRNA-MRE interactions.…”

“…Most A-to-I editing sites reside in Alu repeat elements in the untranslated regions and introns, and A-to-I editing is frequent and prominent in the transcriptomes of humans and other primates Paz-Yaacov et al 2010). A-to-I editing results in the modulation of gene expression, including amino acid alterations (Higuchi et al 1993;Burns et al 1997;Hoopengardner et al 2003;Levanon et al 2005), alternative splicing (Rueter et al 1999), prevention of aberrant exonization (Sakurai et al 2010), nuclear retention (Chen et al 2008), nonsense-mediated mRNA decay (NMD) (Agranat et al 2008), RNA interference (Bass 2006), variations in the 39 UTR (Osenberg et al 2009), altered translation (Hundley et al 2008), and miRNA-mediated translational repression (Borchert et al 2009). In addition, A-to-I editing also occurs in pre-miRNAs in dsRNA regions that modulate the processing and target specificity of the miRNA (Kawahara et al 2007a,b).…”

Proteome diversification by adenosine to inosine RNA-editing

“…8 A recent report additionally identified modifications in the seed regions of target sites in 3'UTRs of mRNAs. 51 …”

RNA Editing Modulates Human Hepatic Aryl Hydrocarbon Receptor Expression by Creating MicroRNA Recognition Sequence

“…In this study we sought to examine whether the editing of target mRNA, rather than miRNA, might affect mRNA:miRNA binding by altering seed matches. The possibility that miRNA target sites can be created or deleted by RNA editing has been proposed (23,28), but studies supporting this hypothesis are very limited (29,30).…”