# The role of small RNA derived tRNAs in gene regulation: Mechanism and Therapeutic Applications

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $489,147

## Abstract

ABSTRACT
One of the most important concepts in modern genetics is the realization that over 90% of the mammalian
genome is transcribed into RNA. These non-protein coding RNAs have been described as the dark matter
of the genome as the function of most of these RNAs has yet to be determined. Just over 5 years ago, we
stumbled onto a novel set of tRNA derived small RNAs (tsRNAs). These tRNA derived fragments are also
commonly called trfRNAs, and were originally thought to represent degradation products. However, it is now
clear there are hundreds or perhaps thousands of different RNA fragments generated in mammalian cells
and there is increasing evidence that these are functionally important. As a group, they have been proposed
to regulate genes at many different levels. We plan to study the 3’tsRNAs (derived from the 3’ end of the
mature tRNA) currently the least well studied of the various types of fragments, and for which no definitive
function has yet to be described. We have established that one specific RNA, the 22nt CAG-Leucine
3’tsRNA when down regulated by the addition of antisense oligonucleotides in rapidly dividing cells inhibits
ribosome biogenesis by first limiting the translation of at least one ribosomal protein mRNA. This results in
rapid cellular apoptosis. In contrast, the addition of a 3’tsRNA mimic increases cellular proliferation and can
complement the ribosome biogenesis defects in cells. These data bring to light a previously unknown post-
transcriptional gene regulatory pathway. We plan to further explore the mechanism of how this specific
3’tsRNA-mediates translational gene regulation as well as use new high-throughput sequencing approaches
to identify and then test other 3’tsRNAs that may participate in similar types of gene regulation. Finally, we
propose to use gene therapy and oligonucleotide antisense delivery to pursue the therapeutic potential of
manipulating 3’tsRNAs in treating medical conditions that affect the liver. We believe unraveling the
molecular mechanism of this regulatory circuit is important both to further understand how genes are
regulated and will provide novel therapeutic targets.

## Key facts

- **NIH application ID:** 9985112
- **Project number:** 5R01DK114483-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Mark A Kay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,147
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985112

## Citation

> US National Institutes of Health, RePORTER application 9985112, The role of small RNA derived tRNAs in gene regulation: Mechanism and Therapeutic Applications (5R01DK114483-04). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9985112. Licensed CC0.

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