ADAR Gene Family and A-to-I RNA Editing: Diverse Roles in Posttranscriptional Gene Regulation
Section snippets
Historical Overview
The phenomenon of RNA editing is different from splicing and polyadenylation, which are mechanisms that affect large stretches of sequence, whereas RNA editing is a site-specific alteration in order to fine-tune gene products (1). RNA editing was first discovered in trypanosome mitochondrial mRNAs, in which uridine nucleotides of its mRNA were inserted or deleted; this editing is necessary to generate functional proteins for this kinetoplastid protozoa (2). Shortly thereafter, RNA editing was
A Family of Editors
A base conversion of a ribonucleotide takes place during RNA editing. The deamination reactions of cytidine to uridine or adenosine to inosine are the best characterized examples of base modification and are the major type of RNA editing in higher eukaryotes (41). Editing via base deamination for A-to-I conversion occurs by a hydrolytic deamination reaction (Fig. 1A) (13, 42). This hydrolytic attack transpires on carbon 6 of the adenine base by removal of the exocyclic amine with oxygen serving
Requirement of Double-Stranded RNA in the A-to-I RNA Editing Mechanism
In order for the base modification reaction to occur, an ADAR protein must recognize its substrate dsRNA. Typically an mRNA forms duplex structures such as hairpins interceded by loops and bulges. This RNA topography dictates the binding and specificity of the ADAR enzymes for A-to-I editing (Fig. 5A). RNA secondary structural features consisting of hairpins containing mismatches, bulges, and loops are edited more selectively than completely base paired duplexed RNA. It appears that ADAR
In Vivo Phenotypes
The physiological consequences of ADAR A-to-I editing have been validated in various species. In a C. elegans strain containing double homozygous deletions for both c.e.ADAR1 and c.e.ADAR2 genes is viable, however, it displays defects in chemotaxis and has abnormal development of the vulva in a subset of worms lacking only c.e.ADAR1 (60). Drosophila engineered with a homozygous deletion in the lone dADAR gene are also viable but exhibit defective locomotion and behavior connected to a variety
Future Prospects
The recoding of neurotransmitter proteins by A-to-I editing appears to have a minor role for ADAR-regulating cellular events due to the low amount of editing observed as compared to other types of dsRNA substrates, although the functional consequences of neuroreceptor alterations can have a great impact on the organism as a whole. This is seen for GluR-B Q/R site editing by ADAR2, which is nearly ∼100% (97, 156). So the question arises: Why recode proteins at the RNA level? This is certainly a
Acknowledgments
This work was supported in part by grants from the National Institutes of Health, the Doris Duke Charitable Foundation, the March of Dimes, and the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health to KN. LV is supported by NIH Postdoctoral Supplement Grant HL070045.
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