Key result
ADAR1 both inhibits and promotes RNA silencing via A-to-I editing and direct Dicer interaction.
Why the study?
The interactions between ADAR1-mediated RNA editing and RNA interference pathways, including their antagonistic and stimulative roles, were not fully understood.
ADAR1 has a dual role in RNA silencing, acting antagonistically through RNA editing and stimulatively by interacting with Dicer to promote miRNA processing.
ADAR1's dual RNA roles merit targeted studies in CV models; leaves open therapeutic relevance pending functional validation.
Adenosine deaminases acting on RNA (ADARs) are involved in RNA editing that converts adenosine residues to inosine specifically in double-stranded RNAs (dsRNA). This A-to-I RNA editing pathway and the RNA interference (RNAi) pathway seem to interact antagonistically by competing for their common dsRNA substrates. For instance, A-to-I editing of certain microRNA (miRNA) precursors by ADAR1 and ADAR2 inhibits their processing to mature miRNAs. Recent studies unexpectedly revealed the presence of a completely different type of interaction between the RNA editing mechanism and the RNAi machinery. ADAR1 forms a complex via direct protein-protein interaction with Dicer, an RNase III gene family member involved in the RNAi mechanism. ADAR1 in the Dicer complex promotes pre-miRNA cleavage by Dicer and facilitates loading of miRNA onto RNA-induced silencing complexes, giving rise to an unsuspected stimulative function of ADAR1 on miRNA processing and RNAi mechanisms. ADAR1 differentiates its functions in RNA editing and RNAi by formation of either ADAR1-ADAR1 homodimer or Dicer-ADAR1 heterodimer complexes. Expression of miRNAs is globally inhibited in ADAR1-null mouse embryos, which, in turn, alters expression of their target genes and may contribute to their embryonic lethal phenotype.
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Nishikura et al. (2013) reported a review. ADAR1 was evaluated. ADAR1 exhibits both antagonistic and stimulative roles in RNA silencing by either inhibiting miRNA processing through A-to-I editing or promoting it via direct interaction with Dicer.
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