Silvestris, D. A. | bioRxiv Science

bioRxiv2025

Editing-independent effects of Adar in Drosophila melanogaster

Vertebrate ADAR RNA editing enzymes prevent cellular dsRNA from aberrantly activating antiviral dsRNA sensors. ADARs inhibit antiviral sensor activation by deaminating selected adenosines to inosines in dsRNA and by engaging in inhibitory protein interactions with sensors on dsRNA. ADARs interact with Dicers and, in the Drosophila Adar5G1 null mutant Dicer 2 acts as the antiviral dsRNA sensor mediating aberrant innate immune induction. We overexpressed active Adar isoforms or a catalytically-inactive Adar E374A protein from UAS-Adar constructs under the control of a temperature-regulated Act5Cts-GAL4 driver. Overexpression of the edited AdarG isoform or AdarEA cause larval lethality with aberrant innate immune induction. Some escaper pupae are formed with head eversion defects. AdarS overexpression is also lethal with no progeny pupae. Ecdysone signaling gene and innate immune gene expression are aberrantly elevated in the AdarG overexpressing pupae. RNAi knockdown of Ecdysone Receptor A (EcR A) or increasing expression of HP1 partially rescue AdarG overexpression defects and normalize gene expression in progeny flies, indicating that aberrant epigenetic silencing is also involved. The structure of an ADAR2 dimer on dsRNA shows the the glycine in AdarG is suitably positioned for Adar contacts with other proteins on dsRNA.

developmental biology↗

bioRxiv2021

ADAR2-mediated RNA editing of DNA:RNA hybrids is required for DNA double strand break repair

The maintenance of genomic stability requires the coordination of multiple cellular tasks upon the appearance of DNA lesions. RNA editing, the post-transcriptional sequence alteration of RNA, has a profound effect on cell homeostasis, but its implication in the response to DNA damage was not previously explored. Here we show that, in response to DNA breaks, an overall change of the Adenosine-to-Inosine RNA editing is observed, a phenomenon we call the RNA Editing DAmage Response (REDAR). REDAR relies on the checkpoint kinase ATR and the recombination factor CtIP. Moreover, depletion of the RNA editing enzyme ADAR2 renders cells hypersensitive to genotoxic agents, increases genomic instability and hampers homologous recombination by impairing DNA resection. Such a role of ADAR2 in DNA repair goes beyond the recoding of specific transcripts, but depends on ADAR2 editing DNA:RNA hybrids to ease their dissolution. One sentence summaryDNA recombination requires RNA editing of DNA:RNA hybrids to ease their melting and facilitate DNA end resection

genetics↗