Monday, December 15, 2025 12/15/2025

Molecular recognition by ADAR1 of Z-RNA within transcriptomes

Award Number: R01GM150642
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/26/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Molecular recognition by ADAR1 of Z-RNA within transcriptomes - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	001	3	12/5/2025	NON-COMPETING CONTINUATION	$0
2026	2025	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	3	11/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $288,878 )
2025	2025	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	002	3	8/1/2025	NON-COMPETING CONTINUATION	$288,878
2025	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	2	7/11/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	001	2	7/14/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $288,878

Issue Date FY: 2024 ( Subtotal = $309,352 )
2024	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	001	2	9/20/2024	SUPPLEMENT FOR EXPANSION	$20,474
2024	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	2	9/19/2024	NON-COMPETING CONTINUATION	$288,878
														Subtotal = $309,352

Issue Date FY: 2023 ( Subtotal = $302,628 )
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Biomedical Research and Research Training	000	1	9/25/2023	NEW	$302,628
														Subtotal = $302,628

Grand Total All Awards = $900,858

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Molecular recognition by ADAR1 of Z-RNA within transcriptomes

Award Number: R01GM150642

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/26/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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