# Molecular mechanisms that regulate ADAR target recognition and RNA editing in vivo

> **NIH NIH R01** · TRUSTEES OF INDIANA UNIVERSITY · 2022 · $332,451

## Abstract

PROJECT SUMMARY/ABSTRACT
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Sequence alterations that change the genome-encoded information present in RNAs, referred to as RNA
editing, provide a powerful way to diversify the transcripts expressed in an organism’s tissues over time. Loss
of these modifications results in lethality in mice and behavioral phenotypes in worm and fly model systems.
Consistent with an important role in both normal development and proper neuronal function, aberrant RNA
editing has been linked over 35 human pathologies, including several neurological disorders, metabolic
diseases, and cancer. Despite the significance of A-to-I editing, there is a gap of knowledge in the molecular
mechanisms that regulate editing. Our long-term goal is to understand how differing modes of RNA recognition
by ADARs, the enzymes responsible for A-to-I RNA editing, result in specific effects on RNA editing to allow for
the rational development of therapeutics that can alter ADAR function, thus improving human health. Towards
this goal, we have identified cellular roles for naturally occurring editing-deficient ADAR family members in
altering RNA editing in worms and humans. The objective of this proposal is to determine the molecular
mechanisms of how these regulators influence recognition of specific transcripts by the editing enzymes. The
central hypothesis of the proposed research is that RNA recognition by editing-deficient ADAR family members
can both promote and antagonize RNA recognition by ADAR enzymes, and both of these functions are critical
for maintaining proper editing levels in vivo. This hypothesis has been formulated, in large part, on our findings
that ADR-2, the only A-to-I editing enzyme in C. elegans, functions with ADR-1, an editing-deficient ADAR
family member, to edit across the transcriptome, including a transcript required for proper neuronal function.
However, ADR-1 is not required for ADR-2 to edit all adenosines. In fact, ADR-1 inhibits editing of certain
neural mRNAs, supporting our hypothesis that editing-deficient ADARs serve as both positive and negative
regulators of editing depending upon the transcript. This regulatory function is likely evolutionarily conserved,
as we recently demonstrated that editing-deficient human ADAR3 binds a critical neuronal transcript to alter
editing in glioblastoma. In Aim 1, a RNA immunoprecipitation approach, which has been established as
feasible in the applicants’ hands, will be combined with high-throughput sequencing and genetic mutants the
applicant developed and characterized to determine how ADR-1 recruits the editing enzyme to specific targets.
In Aim 2, a cutting-edge neural isolation technique will be coupled to high-throughput sequencing to dissect the
mechanism of how certain neural transcripts are selectively edited. In Aim 3, the cellular targets of an inactive
editor, human ADAR3, will be identified and the impact of ADAR3 on the proper balance of unedited and edited
transcripts will be determined. The proposed...

## Key facts

- **NIH application ID:** 10656750
- **Project number:** 7R01GM130759-04
- **Recipient organization:** TRUSTEES OF INDIANA UNIVERSITY
- **Principal Investigator:** Heather Ann Hundley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $332,451
- **Award type:** 7
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10656750

## Citation

> US National Institutes of Health, RePORTER application 10656750, Molecular mechanisms that regulate ADAR target recognition and RNA editing in vivo (7R01GM130759-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10656750. Licensed CC0.

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