Abstract
Adenosine-to-inosine (A-to-I) editing is a post-transcriptional modification of RNA which changes its sequence, coding potential and secondary structure. Catalysed by the adenosine deaminase acting on RNA (ADAR) proteins, ADAR1 and ADAR2, A-to-I editing occurs at approximately 50 000–150 000 sites in mice and into the millions of sites in humans. The vast majority of A-to-I editing occurs in repetitive elements, accounting for the discrepancy in total numbers of sites between species. The species-conserved primary role of editing by ADAR1 in mammals is to suppress innate immune activation by unedited cell-derived endogenous RNA. In the absence of editing, inverted paired sequences, such as Alu elements, are thought to form stable double-stranded RNA (dsRNA) structures which trigger activation of dsRNA sensors, such as MDA5. A small subset of editing sites are within coding sequences and are evolutionarily conserved across metazoans. Editing by ADAR2 has been demonstrated to be physiologically important for recoding of neurotransmitter receptors in the brain. Furthermore, changes in RNA editing are associated with various pathological states, from the severe autoimmune disease Aicardi-Goutières syndrome, to various neurodevelopmental and psychiatric conditions and cancer. However, does detection of an editing site imply functional importance? Genetic studies in humans and genetically modified mouse models together with evolutionary genomics have begun to clarify the roles of A-to-I editing in vivo. Furthermore, recent developments suggest there may be the potential for distinct functions of editing during pathological conditions such as cancer.
Highlights
The epitranscriptome is the set of all biochemical modifications of RNA within the cell
We recently reported the first completely editing-deficient 7 animals where editing by both ADAR1 and ADAR2 were inactivated [37]
Overall these data support the notion that the essential functions of ADAR1 and ADAR2 are non-overlapping in normal mouse development, a result that was somewhat surprising given the overlap of editing substrates between the two enzymes
Summary
The epitranscriptome is the set of all biochemical modifications of RNA within the cell. New techniques and reagents have allowed the genomewide identification of modifications such as inosine, N6-methyladenosine (m6A), pseudouridylation, 5-methylcytosine (m5C) and more recently, N4-acetylcytidine (ac4C), among the more than 170 described [1,2]. Following the cataloguing of sites, the task of assessing the biological importance and functions of the modified sites in both normal physiology and pathological states remains. Any one of the epitranscriptome modifications can number into the thousands or, in the case of inosine, millions of potentially modified sites per transcriptome. We will discuss the biological role of adenosine-to-inosine (A-to-I) editing within RNA in mammals and recent efforts to address the questions of how many sites there are, the editing. Enzyme responsible, which sites are essential and which functions are conserved across species?
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