Molecular diversity through RNA editing: a balancing act

Abstract

RNA editing by adenosine deamination fuels the generation of RNA and protein diversity in eukaryotes, particularly in higher organisms. This includes the recoding of translated exons, widespread editing of retrotransposon-derived repeat elements and sequence modification of microRNA (miRNA) transcripts. Such changes can bring about specific amino acid substitutions, alternative splicing and changes in gene expression levels. Although the overall prevalence of adenosine-to-inosine (A-to-I) editing and its specific functional impact on many of the affected genes is not yet known, the importance of balancing RNA modification levels across time and space is becoming increasingly evident. In particular, transcriptome instabilities in the form of too much or too little RNA editing activity, or misguided editing, manifest in several human disease phenotypes and can disrupt that balance.

Figure I

Mechanism of adenosine deamination

Figure II

ADAR domain structure

Figure 1

The three major types of A-to-I RNA editing targets and their fates. Panels on the left show schematic of RNA secondary structures highlighting translated exon sequence (dark blue box), untranslated exon sequence (light blue boxes) location of repetitive sequence elements (red arrows), non-coding and intronic RNA sequence (light blue lines) and location of mature miRNA sequence (light red line). (a) Pre-mRNA editing of protein-coding genes with composite RNA secondary structure leads to highly site-selective recoding if it affects a non-synonymous codon site. For example, the glutamate receptor subunit GRIA2 exon 11 Q/R site forms an experimentally validated secondary RNA structure between exon 11 (marked in yellow) and intron 11. (b) Pairs of repetitive elements, such as primate Alus located in coding or non-coding exons or introns can generate RNA secondary structures targeted by the RNA editing machinery. For example, editing of the intramolecular RNA fold between two Alu elements in human nuclear prelamin A recognition factor (NARF), causes recoding within the Alu-exon (marked in yellow) and leads to the creation of the 3′-splice consensus site upstream of the Alu-exon, thereby regulating alternative splicing of this exon. In the case of human lin28, extensive RNA editing within its non-coding, 3′-untranslated region mediated by a pair of Alu-elements, leads to the nuclear retention of the mRNA. (c) The characteristic secondary structure of pre-miRNAs is a frequent target of ADARs. For example, pri-miRNA-99b editing alters a nucleotide within the seed of the mature miRNA (marked in yellow and edited position highlighted in red) and therefore has the potential to alter the target interaction profile of this miRNA , whereas the modification of an adenosine outside of the mature miRNA region in pri-miRNA-133a2 causes a change in the processing rate by the RNAse Drosha .

Figure 2. Disruption of the RNA editing balance

Overview of RNA editing phenotypes in various genetic animal models and correlated observations regarding editing in human diseases. Direct causal relationships are indicated by arrows, correlations are shown as lines, and possible cross-connections as dotted lines. Partial or complete inactivation of editing has been linked to several neurological and neuropsychiatric disorders. Green shaded areas: Main disease groups. Blue shaded areas: General or gene-specific editing deficiency (genetic models with hypoediting are in lightblue boxes with dashed line). Red shaded areas: increased editing activity (genetic models with hyperediting are in light blue with dashed lines). Yellow shaded areas: changes in editing pattern or misediting without general increase or decrease in editing activity. In Prader-Willi syndrome (PWS) loss of imprinted sno RNA mbii-52 leads to increased editing of 5-HT_2C receptor transcripts . DSH1: Dyschromatosis Symmetrica Hereditaria is linked to haploinsufficiency of ADAR1 . Related references: Schizophrenia ; locomotion , ; depression , , ; ALS ; epilepsy , , ; glioblastoma ; pediatric astrocytoma , ; leukemia ; prostate cancer ; breast cancer ; lung, kidney, prostate, testicular cancer ; systemic inflammation ; autoimmune (lupus) , ; virus infection –; dADARr^−/−; mADAR2 ^−/− ; GRIK2 Q ; GRIA2 Q^+/− ; 5HT_2C−VGV ; mADAR2⁺⁺⁺ ; hADAR1^+/− ; mADAR1^−/− , .