# Molecular recognition by ADAR1 of Z-RNA within transcriptomes

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2024 · $288,878

## Abstract

Project Summary
RNA editing of cellular RNAs helps the cell distinguish between self and non-self RNAs. This
editing of adenosines into inosines is generally catalyzed by the `adenosine deaminase acting on
RNA-1' protein (ADAR1). A>I editing is augmented in tumors and upon infection, primarily
through the interferon-induced longer isoform of ADAR1 that comprises a Z-DNA/Z-RNA binding
domain named ‘Zα’ at its N-terminus. Misediting is implicated in neurological diseases such as
Aicardi-Goutières syndrome. Z-RNA in the form of repeats of cytosine and guanosine (CpG) in a
left-handed double-helical conformation has been proposed in cells, but the prevalence of such
structures and their exact role are unknown. In addition, many —if not most— regions proposed
to adopt a Z conformation do not resemble regular (CpG)n. How these local Z-RNA conformations
are generated within A-form helices, stabilized and regulated by Zα of ADAR1, as well as their
exact role in the function of these RNAs, remain unknown. Our hypothesis is that the binding
of Zα to Z-RNA plays an essential role during the editing process. Here, we propose to
answer the following questions: What is the mechanism for Z-RNA formation at CpG but also
non-CpG sequences? How widespread are transitions to Z-RNA across transcriptomes? Is Z-
RNA sampled in the free form or only adopted upon binding by Zα? What are the structural
features of Z-RNA recognition by Zα at non CpG sequences? We will first dynamically
characterize the propensity of various sequence contexts to adopt Z-RNA conformations.
This aim will use advanced NMR methods to characterize the sequence of events that lead an
RNA region from A-form to Z-form. Second, we will determine the unbiased 3D structure of
RNA fragments bound to Zα in solution. Finally, we will identify and localize Zα binding
sites and Zα-dependent A>I editing events. This aim will take advantage of the robust
expertise and support for next-generation sequencing on our campus and at a contracted
company. Overall, our joint work as co-PIs will provide a structural rationale for the formation of
Z-RNA and the resulting formation of A-Z junctions across a variety of RNAs. We ultimately aim
to explain how the Z-RNA binding domain of ADAR1 increases the specificity and activity of
ADAR1. Our findings will help beyond this application with proposing a comprehensive
mechanism for ADAR1 editing and its RNA-mediated transcriptome-wide regulation, and
contribute to understanding disease such as cancer or auto-immune deficiencies.

## Key facts

- **NIH application ID:** 10935993
- **Project number:** 5R01GM150642-02
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** Quentin Vicens
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $288,878
- **Award type:** 5
- **Project period:** 2023-09-26 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935993

## Citation

> US National Institutes of Health, RePORTER application 10935993, Molecular recognition by ADAR1 of Z-RNA within transcriptomes (5R01GM150642-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10935993. Licensed CC0.

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