# SnoRNA-guided modifications of mRNA

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $61,128

## Abstract

ABSTRACT
Post-transcriptional modification of RNA is a fundamental and essential aspect of gene expression, with
important consequences for many aspects of human health and disease. One pathway for RNA modification is
guided by small nucleolar RNAs (snoRNAs). SnoRNAs are non-coding and primarily direct site-specific
modifications on ribosomal RNA (rRNA). However, some snoRNAs have “non-canonical” biological effects that
are independent of rRNA modification. These non-canonical snoRNA effects contribute to cancer, neurobiology,
metabolism, and oxidative stress, via diverse mechanisms such as direct protein binding, generation of
microRNAs, and regulation of messenger RNA (mRNA) splicing. Our work has shown that four snoRNAs
encoded by the Rpl13a genetic locus are non-canonical regulators of reactive oxygen species (ROS) and
oxidative stress. Loss of these snoRNAs protects cells and animals from many kinds of insults, including
metabolic stress, sepsis, and diabetes. However, the precise molecular mechanism has been elusive. Our
preliminary data suggest that a mechanism for this effect is snoRNA-guided methylation of mRNA, affecting both
mRNA stability and protein production. This would be a novel function for snoRNAs. The objective of this
application is therefore to determine whether snoRNA-guided methylation of mRNA links the Rpl13a snoRNAs
to ROS and oxidative stress. Our central hypothesis is that the Rpl13a snoRNAs guide the enzyme fibrillarin to
catalyze 2’-O-methylation of select mRNA targets, and that these methylations alter mRNA stability and
translation. Aim 1 will verify a putative mRNA target of Rpl13a snoRNA-guided methylation. Aim 2 will define the
role of this mRNA modification in cellular physiology, including ROS production and oxidative stress. Aim 3 will
identify novel targets of snoRNA-guided methylation, using methods to capture snoRNA-mRNA interactions, and
by mapping these modifications transcriptome-wide. The overall impact of this project will be to define a
molecular mechanism linking the Rpl13a snoRNAs to ROS and oxidative stress, while at the same time
expanding the known functions of snoRNAs to include 2’OMe modification of mRNA.

## Key facts

- **NIH application ID:** 10135253
- **Project number:** 3R01GM135383-01S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Christopher Lee Holley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $61,128
- **Award type:** 3
- **Project period:** 2019-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135253

## Citation

> US National Institutes of Health, RePORTER application 10135253, SnoRNA-guided modifications of mRNA (3R01GM135383-01S1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10135253. Licensed CC0.

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