Reprogramming, Circular Reasoning and Self versus Non-self: One-Stop Shopping with RNA Editing

Abstract

Transcription of genetic information from archival DNA into RNA molecule working copies is vital for proper cellular function and is highly accurate. In turn, RNAs serve structural, enzymatic, and regulatory roles, as well as being informational templates for the ribosomal translation of proteins. Following RNA synthesis, maturing of RNA molecules occurs through various RNA processing events. One component of the collection of processes involving RNA species, broadly defined as RNA metabolism, is the RNA-editing pathway and is found in all animals. Acting specifically on RNA substrates with double-stranded character, RNA editing has been shown to regulate a plethora of genomic outputs, including gene recoding, RNA splicing, biogenesis and targeting actions of microRNAs and small interfering RNAs, and global gene expression. Recent evidence suggests that RNA modifications mediated via RNA editing influence the biogenesis of circular RNAs and safeguard against aberrant innate immune responses generated to endogenous RNA sources. These novel roles have the potential to contribute new insights into molecular mechanisms underlying pathogenesis mediated by mishandling of double-stranded RNA. Here, we discuss recent advances in the field, which highlight novel roles associated with the RNA-editing process and emphasize their importance during cellular RNA metabolism. In addition, we highlight the relevance of these newly discovered roles in the context of neurological disorders and the more general concept of innate recognition of self versus non-self.

Keywords: RNA editing; RNA metabolism; RNA silencing; RNA splicing; autoimmune disease; circular RNAs; immune responses; neurological disorders.

FIGURE 1

General fates of edited RNAs. (A) Specific RNA editing in coding region of a pre-mRNA. ADAR-mediated hydrolytic deamination of the adenine base within the glutamic acid codon (Q) is interpreted by the ribosomal machinery as an arginine codon (R), leading to an amino acid substitution. (B) Specific RNA editing in non-coding regions can generate novel 3′ splice acceptor sites (AA → AG). In mammals, the ADAR2 RNA-editing enzyme modifies its own transcript to generate a novel splicing signal that results in the inclusion of 47 nucleotides in the mature RNA. (C) Hyper-editing of dsRNA molecules leads to inefficient Dicer processing. Hyper-editing antagonizes RNA-mediated silencing responses through the generation of fewer siRNAs. (D) Specific RNA editing near the base of miRNA precursors leads in the inhibition of Drosha cleavage, which prevents the processing of mature miRNAs. In addition, specific RNA editing within the “seed” region of the mature miRNA may result in redirection to a new target.

FIGURE 2

Novel roles for RNA editing. (A) The biogenesis of circular RNAs involves the formation of dsRNA duplexes mediated by intronic sequences flanking the exon(s) destined for circularization. These dsRNA molecules can serve as ADAR substrates. It is currently thought that hyper-editing destroys the dsRNA nature of such substrates, which promotes linear splicing and restricts exon circularization. Examples of how RNA editing antagonizes the biogenesis of circRNAs formed by single exon and two exons are depicted. (B) In the cytoplasm, RIG-I and MDA5 act as sensors for dsRNA molecules. Upon recognition, these sensors activate MAVS, which triggers the innate immune response. MAVS-mediated signals result in the translocation of interferon-regulatory factors (IRFs) and NF-κB into the nucleus, which initiates the transcription of ISG and cytokine genes. Hyper-editing of immunoreactive dsRNAs prevents detection by RIG-I and MDA5, inhibiting aberrant innate immune responses toward endogenous dsRNA sources.