# Stablization of Fragile Human Transfer RNAs

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $387,000

## Abstract

Project Summary
 This proposal is aimed at understanding enough to eventually have a therapeutic intervention
for a large group of human mitochondrial diseases associated with transfer RNAs. These diseases
arise from mutations in mitochondrial tRNAs that cause instability and susceptibility to nuclease degradation.
We focus on stabilizing these mutant tRNAs by identifying and utilizing a pan-specific mitochondrial tRNA
binding protein that stabilize the fragile tRNA structure. We have found one such natural protein from the
recently discovered ensemble of human tRNA synthetase splice variants.
 Because defects in mitochondrial (mt) protein synthesis have an immediate impact on cellular
metabolism, it is perhaps not surprising that more than 50% of all identified disease-causing mutations
in mtDNA are located within mtDNA genes for tRNAs. And yet, these genes constitute only 10% of the
mitochondrial genome. A significant number of mt disease-linked mutations, which cause myopathies,
neurodegenerative diseases, and multisystemic disorders, are located in the mt tRNAs. Our
laboratory has published extensively on aaRSs from bacteria to humans. However, we did not
previously have the insight to suggest a path to stabilize disease-causing mutant tRNAs.
 aaRSs have progressively acquired new domains in evolution. These new domains are
dispensable for the aminoacylation function and are mobilized for specific, novel functions outside of
translation. We discovered over 250 splice variants (SVs) of human aaRSs. The majority ablate the
catalytic activity but retain the novel motifs. Importantly, most are stable as recombinant proteins.
Amongst the SVs, we focus on the few that have the appearance of being chaperones for tRNAs, that
is, proteins that bind to and stabilize tRNAs, but with a structure- but not sequence-specific recognition
of the outside corner (elbow) of the L-shaped tRNA structure. The goal is to select one or more easy-
to-purify, stable, recombinant corner- binding splice variants. These will be tested for their ability, when
added in trans, to bind defective mutant mitochondrial tRNAs. Another criterion is that the chosen
domain can be applied exogenously to cells and enter the mitochondria. In preliminary work we
identified at least one SV that fulfills the criteria we established. If successful, this proposal will
suggest a new path for therapeutic intervention of the most prevalent human mitochondrial diseases.
!

## Key facts

- **NIH application ID:** 9942265
- **Project number:** 5R01GM125908-03
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** PAUL R SCHIMMEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,000
- **Award type:** 5
- **Project period:** 2018-08-23 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942265

## Citation

> US National Institutes of Health, RePORTER application 9942265, Stablization of Fragile Human Transfer RNAs (5R01GM125908-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9942265. Licensed CC0.

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