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Wistar Team Finds New Role for ADAR1 in RNA-Induced Gene Silencing

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While adenosine deaminases acting on RNA are known to be involved in the RNA editing that converts adenosine residues into inosine in double-stranded RNA, new research from the Wistar Institute shows that one member of this family of enzymes plays a key role in microRNA processing and RNA-induced gene silencing.

The findings, which appeared in Cell, support previous research indicating that miRNA regulation is essential to life, and show that ADAR1 is tightly involved in that regulation.

Previous research has found that the A-to-I editing controlled by ADARs primarily occurs in non-coding regions containing repetitive elements such as Alu and LINE, yet the biological significance of repetitive RNA editing is “largely unknown,” according to the Wistar team. It has also been demonstrated that inactivation of one of ADAR1 triggers widespread apoptosis and results in an embryonic lethal phenotype in mice.

The exact mechanism behind that phenotype, however, is unclear.

Meanwhile, data show that RNAi-dependent endogenous siRNAs derived from loci enriched for inverted repeats and transposons are “dramatically upregulated in ADAR-null mutant worms,” which suggests that A-to-I RNA editing of dsRNA regions of transcripts derived from these loci prevents their entry into the RNAi silencing pathway, the team wrote in Cell.

As such, the A-to-I RNA editing mechanism “appears to compete for shared dsRNA substrates with the RNAi machinery and inhibit synthesis of endo-siRNAs,” and because certain pri-miRNAs are subject to A-to-I editing, such editing could inhibit their processing, suppress RISC loading, or cause off-target silencing, they noted.

In light of the apparent antagonistic interaction between A-to-I RNA editing and RNAi pathways, the Wistar scientists began exploring the interplay between ADAR1 and RISC proteins.

They found that ADAR1 interacts directly with Dicer in an RNA-binding-independent manner, while promoting processing of siRNAs and miRNAs, RISC loading of miRNAs, and silencing of target RNAs — all of which “reveals a stimulative, instead of antagnonistic, role of ADAR1 in RNAi,” the researchers wrote.

Specifically, ADAR1 forms a complex with Dicer through direct protein-protein interaction, and increases the maximum rate of pre-miRNA cleavage by Dicer while facilitating miRNA RISC loading.

“In contrast to the requirement of homodimerization for the A-to-I RNA editing activities of ADAR1, one monomer of ADAR1 binds to one molecule of Dicer,” they added. “ADAR1 thus acts as an RNA editing enzyme or as a modulator of the RNAi machinery by choosing its complex partner.”

In terms of the lethal phenotype observed in ADAR1-/- mouse embryos, the investigators determined that normal upregulation of miRNA production in the animal is unable to occur due to the lack of formation of the Dicer/ADAR1 complex, which appears to cause dysregulation of many genes that are ordinarily repressed by the miRNAs during proper development.

“It is tempting to speculate that a deficiency in the RNAi function rather than the RNA editing function of ADAR1 underlies the ADAR1-/- mouse phenotype,” the Wistar team concluded.

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