# Regulation of tRNA fragment biogenesis and function by nucleotide modifications

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $489,616

## Abstract

Project Summary/Abstract
tRNAs are well-known as the physical adaptors of the genetic code, bridging codon-
based information with the appropriate amino acids required for protein translation. tRNA
function can be regulated by a wide variety of mechanisms, including the modulation of
tRNA aminoacylation by cellular amino acid levels. Two previously underappreciated
mechanisms have recently emerged as key regulators of tRNA biology – covalent
modifications of tRNA nucleotides, and cleavage of tRNAs, which generates stable and
potentially functional tRFs.
 Here, we propose to investigate the regulation of tRNA cleavage, and the
functions of resulting tRNA fragments, in budding yeast and in mammalian embryonic
stem cells. First, as tRNA nucleotide modifications have been shown to interfere with
tRNA cleavage in several model organisms, we will first survey the effects of all known
tRNA modifications on tRNA cleavage in yeast. Deep sequencing of small RNAs will be
carried out for a large collection of yeast deletion mutants – covering all nonessential
tRNA-modifying enzymes known at present – following overexpression of various tRNA
nucleases. In parallel, we will develop a comprehensive panel of conditional mutants in
tRNA modification machinery in murine ES cells to extend these studies to a mammalian
model.
 A complementary effort will focus on the roles for tRNA fragments in translational
control. Again comparing yeast and mammals, we will characterize translation by
ribosome footprinting in wild-type and in mutants lacking tRNA cleavage or various tRNA
modifications. To allow biochemical access to specific tRNA fragment activities, we will
use in vitro translation systems to directly investigate the roles for various purified or
synthetic tRNA fragments at well-defined stages of protein translation.
 Together, these experiments systematically address the roles for tRNA
modifications in tRNA cleavage and control of translation by resulting tRNA fragments,
providing important insights with relevance to diseases ranging from neurodegeneration
to cancer.

## Key facts

- **NIH application ID:** 10113702
- **Project number:** 1R01HD099816-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Elisabet Cecilia Mandon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $489,616
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113702

## Citation

> US National Institutes of Health, RePORTER application 10113702, Regulation of tRNA fragment biogenesis and function by nucleotide modifications (1R01HD099816-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10113702. Licensed CC0.

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