Authors
Francisco Antonio Venegas Solis, Mengsi Lu, Roni Cohen-Fultheim, Felix Bender, Valeria Fedeli, Takuya Masunaga, Mikako Fujita, Thomas Zillinger, Sabine Schneider, Andreas Kaufmann, Adolfo Saiardi, Erez Y Levanon, Henning Jessen, Stefan Bauer
Published in
RNA (New York, N.Y.). Sep 03, 2026. Epub Sep 03, 2026.
Abstract
Adenosine-to-inosine (A-to-I) RNA editing by ADAR1 is a key post-transcriptional modification, and mutations in ADAR1 lead to Aicardi-Goutières syndrome (AGS), an autoimmune disorder. Despite its biological and clinical relevance, the regulation of ADAR1 activity remains incompletely understood. Using a combination of biochemical approaches, inositol-pentakisphosphate 2-kinase (IPPK)-knockout cells, molecular dynamics simulations, and a cell-permeable inositol hexakisphosphate (IP6) prodrug (Pro-IP6), we demonstrate that IP6 depletion drastically reduces global RNA editing, while supplementation with Pro-IP6 restores and even enhances editing levels. Furthermore, we identify the C6-phosphate of IP6 as a critical determinant of ADAR1 catalytic efficiency, functioning within a hydrogen-bonding network that indirectly coordinates a Zn²⁺-ion. Finally, we show that the AGS-associated ADAR1 mutation N907S impairs RNA editing activity, most likely by altering the hydrogen-bond interaction network linking IP6 to the ADAR1 catalytic center. Together, these findings identify IP6 as an essential cofactor and regulator of ADAR1 activity and highlight cofactor availability and interaction networks as strategies for therapeutically modulating RNA editing.
PMID:
42692820
Bibliographic data and abstract were imported from PubMed on 04 Sep 2026.
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