Figure 3. Editing of Alu double-stranded RNAs (dsRNAs) and its consequences.
a | Genome-wide inverted Alu repeats in introns and in 3′ untranslated regions (UTRs) form intramolecular RNA duplexes (Alu dsRNAs), which are edited by adenosine deaminases acting on RNA (ADARs). Inosines at intronic Alu dsRNAs are recognized by the splicing machinery as guanosines, thus effectively creating new splice sites, which results in the inclusion of intronic Alu sequences in the mature mRNAs (Alu exonization). b | Extensively edited Alu dsRNAs are retained in nuclear paraspeckles by a mechanism involving p54nrb and the long non-coding RNA nuclear paraspeckle assembly transcript 1(NEAT1).The formation of paraspeckles is absolutely dependent on NEAT1.p54nrb, and perhaps also NEAT1, bind specifically to inosine-containing RNAs such as extensively edited Alu dsRNA. Under certain conditions, such as stress, the paraspeckle-trapped RNA may be released into the cytoplasm for translation, as seen with the mouse Ctn RNA. Editing of short interspersed nuclear element (SINE) dsRNA within the 3′ UTR of the Ctn RNA leads to its nuclear retention. When cells are placed under stress, Ctn RNA is cleaved and polyadenylated at an alternative site, resulting in the loss of the edited SINE sequences and release of the mRNA from the nucleus as the protein-coding mCat2 (cationic amino acid transporter 2) mRNA. c | Extensively edited Alu dsRNAs may be degraded by endonuclease V (EndoV) together with Tudor-SN (TSN), thereby controlling the expression levels of genes harbouring Alu repeats. d | Extensively edited Alu dsRNA containing multiple and consecutive I·U mismatched wobble pairs (I·U-dsRNA) may suppress the interferon (IFN) signalling pathway, which would otherwise be activated by unedited Alu dsRNAs. Unedited long dsRNAs (viral and cellular) are potent inducers of IFN signalling. I·U-dsRNA may competitively inhibit the binding of dsRNA to retinoic acid-inducible gene 1(RIG1)or melanoma differentiation-associated protein 5 (MDA5), both of which are cytosolic sensors for dsRNA and upstream regulators of the mitochondrial antiviral signalling adaptor protein (MAVS)-mediated IFN activation pathway. e | Extensively edited Alu dsRNAs containing multiple inosines may contribute to heterochromatin formation and gene silencing. Vigilin binds to RNA containing multiple inosines, such as extensively edited Alu dsRNAs. Vigilin has been shown to form a complex with ADAR1, RNA helicase A (RHA), and 86 kDa subunit of Ku antigen (KU86)–KU70, which recruits the histone methyltransferase SUV39H1. SUV39H1 catalyses the methylation of H3 Lys9 (H3K9me), an epigenetic mark that is recognized by heterochromatin protein 1 (HP1), leading to the formation of heterochromatin and to gene silencing. AP1, activator protein-1; IRF3, interferon regulatory factor 3; NF-κB, nuclear factor-κB; pre-mRNA, precursor mRNA. Part a adapted from REF. 146, Nature Publishing Group.