Z-Form Stabilization By The Zα Domain Of Adar1p150 Has Subtle Effects On A-To-I Editing

Nichols, P. J.; Riemondy, K. A.; Krall, J. B.; Ramos, J.; Goering, R.; Henen, M. A.; Taliaferro, J. M.; Vogeli, B.; Vicens, Q.

doi:10.1101/2025.06.02.657529

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bioRxiv · 10.1101/2025.06.02.657529

Z-Form Stabilization By The Zα Domain Of Adar1p150 Has Subtle Effects On A-To-I Editing

Nichols, P. J.·Riemondy, K. A.·Krall, J. B.·Ramos, J.·Goering, R.·Henen, M. A.·Taliaferro, J. M.·Vogeli, B.·Vicens, Q.

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Abstract

The role of Adenosine Deaminase Acting on RNA 1 (ADAR1)s Z-conformation stabilizing Z domain in A-to-I editing is unclear. Previous studies on Z mutations faced limitations, including variable ADAR1p150 expression, differential editing analysis challenges, and unaccounted changes in ADAR1p150 localization. To address these issues, we developed a Cre-lox system in ADAR1p150 KO cells to generate stable cell lines expressing Z mutant ADAR1p150 constructs. Using total RNA sequencing analyzing editing clusters as a proxy for dsRNAs, we found that Z mutations slightly decreased overall A-to-I editing, consistent with recent findings. These decreases correlated with mislocalization of ADAR1p150 rather than reduced editing specificity, and practically no statistically significant differentially edited sites were identified between wild-type and Z mutant ADAR1p150 constructs. These results suggest that Zs impact on editing is minor and that phenotypes in Z mutant mouse models and human patients may arise from editing-independent inhibition of Z-DNA-Binding Protein 1 (ZBP1), rather than changes in RNA editing.

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Nichols, P. J., Riemondy, K. A., Krall, J. B., Ramos, J., Goering, R., Henen, M. A., Taliaferro, J. M., Vogeli, B., Vicens, Q.. 2025-06-04. Z-Form Stabilization By The Zα Domain Of Adar1p150 Has Subtle Effects On A-To-I Editing. https://doi.org/10.1101/2025.06.02.657529

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