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

Sonia Jimeno,Pablo Huertas,Amador Romero-Franco,Valeriana Cesarini,Judit Domingo-Prim,Silvia Jimeno-González,Guillermo Rodríguez-Real,Sonia Silva,Neus Visa,Rosario Prados-Carvajal,Sonia Barroso,Fernando Mejías-Navarro,Andrés Aguilera,María Jesús Fernández-Ávila,Angela Gallo,Martín Endara-Coll,Domenico Alessandro Silvestris

doi:10.1038/s41467-021-25790-2

Sonia Jimeno, Pablo Huertas + Show 15 more

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https://doi.org/10.1038/s41467-021-25790-2

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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.

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The maintenance of genomic stability requires the coordination of multiple cellular tasks upon the appearance of DNA lesions
In U2OS cells stably transfected with the reporter, we observed that DNA damage induced by ionizing radiation increased GFP expression by 50% in the RNAG reporter and not in the RNWG control, in agreement with a DNA damage stimulation of RNA A-to-I editing in this system (Fig. 1B)
One possibility is that DNA damage induces the accumulation of the A-to-I editing machinery, namely ADAR1 and ADAR2 enzymes, increasing this process

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The maintenance of genomic stability requires the coordination of multiple cellular tasks upon the appearance of DNA lesions. 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. Several labs have shown the formation of DNA:RNA hybrids around DSBs in different eukaryotes, either dependent on previous transcription[13,14] or upon de novo transcription of the broken chromatin[15,16] The relevance of such RNA molecules is still under debate, with both pro- and anti-repair effects ascribed to them[9]

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