# Mechanism and functions of DALRD3-dependent tRNA modification

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $308,000

## Abstract

PROJECT SUMMARY
Numerous genetic variants in tRNA modification enzymes have been linked to
devastating neurodevelopmental and neurological disorders. However, the molecular
mechanisms underpinning these pathologies are unknown. Why is it that perturbations to
many different tRNA modification enzymes and thus, changes to the various chemical
modifications they catalyze, seem to affect the brain more so than other organs? To
resolve this question, our lab seeks to elucidate the molecular and cellular roles of tRNA
modification enzymes in human health and disease. We have recently uncovered a novel
tRNA synthetase-like mimic, DALRD3, that is required for a specific chemical modification
in a subset of human tRNAs. Our preliminary results suggest that the DALRD3-dependent
modification impacts tRNA conformational stability and function. Notably, we have also
identified an autosomal-recessive variant in the DALRD3 gene that causes loss of
function and the neurological disorder epileptic encephalopathy. Based upon these
findings, we propose that DALRD3-mediated modification plays a critical role in the proper
function of specific tRNAs important for protein synthesis during neurodevelopment. In
our first Aim, we will define the requirements for tRNA recognition and modification
dependent in DALRD3 and its cognate tRNA substrates. For our second Aim, we will
measure the impact of DALRD3-dependent modification on tRNA structure and function.
In our final Aim, we will determine the role of DALRD3-dependent tRNA modification on
global protein translation in the brain through ribosome profiling. In total, the proposed
research will have broad implications in understanding how tRNA modifications can
impact proper neurodevelopment. Although DALRD3 was an unexpected player in tRNA
modification, we now have a new target to explore potential therapeutics for individuals
suffering from epileptic encephalopathies linked to tRNA biology.

## Key facts

- **NIH application ID:** 10895444
- **Project number:** 5R01GM143145-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Dragony Fu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $308,000
- **Award type:** 5
- **Project period:** 2022-09-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10895444

## Citation

> US National Institutes of Health, RePORTER application 10895444, Mechanism and functions of DALRD3-dependent tRNA modification (5R01GM143145-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10895444. Licensed CC0.

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