# Molecular functions of the TRMT1 tRNA modification enzyme

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $457,335

## Abstract

PROJECT SUMMARY
Intellectual disability (ID) is a prevalent neurodevelopmental disorder affecting more than 1 in 100
individuals worldwide. Recent genetic studies have linked numerous cases of ID to variants in
proteins that modify the chemical structure of RNA. However, the mechanisms by which tRNA
modification enzymes influence brain development are enigmatic. Here, we focus on deciphering
the biological role of tRNA methyltransferase 1 (TRMT1), a tRNA modification enzyme important
for human neurodevelopment. Individuals with TRMT1 mutations exhibit cognitive deficits, growth
delay and brain abnormalities early in age. We have discovered that TRMT1 modifies more than
half of all tRNAs in mammalian cells and is required for the stability of certain tRNAs. Moreover,
loss of TRMT1 in human cells causes proliferation defects and up-regulation of pathways involved
in protein folding. To understand the function of TRMT1 in neurodevelopment, we have generated
a novel TRMT1-deficient mouse strain which exhibits brain and developmental abnormalities.
Based upon these findings, we propose that TRMT1-catalyzed modifications play a critical role in
the biogenesis and function of tRNAs to ensure proper levels of protein synthesis during
mammalian growth and development. In our first Aim, we will use new tRNA sequencing
technologies to determine the role of TRMT1-catalyzed modifications in tRNA stability and
function. In our second Aim, we will use ribosome profiling approaches to decipher the role of
TRMT1-catalyzed tRNA modification in translation. For our final Aim, we will define the
spatiotemporal requirement for TRMT1 in mouse brain development. Altogether, the proposed
research will forge new connections between RNA modification, protein synthesis and
neurodevelopment.

## Key facts

- **NIH application ID:** 10178481
- **Project number:** 1R01GM141038-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Dragony Fu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $457,335
- **Award type:** 1
- **Project period:** 2021-06-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10178481

## Citation

> US National Institutes of Health, RePORTER application 10178481, Molecular functions of the TRMT1 tRNA modification enzyme (1R01GM141038-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10178481. Licensed CC0.

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