# Molecular tools to understand cellular mRNA demethylation

> **NIH NIH P20** · UNIVERSITY OF DELAWARE · 2020 · $240,700

## Abstract

PROJECT SUMMARY / ABSTRACT
Methyl modifications on mRNA are essential for mammalian cell fate decisions and have recently been shown
to play important roles in the progression of many human cancers. The demethylase FTO, which erases
abundant N6-methyladenosine modifications to dynamically regulate mRNA methylation, is linked to initiation
and progression of cancers including brain, breast, gastric, cervical, mesothelioma, and leukemia. Recent work
has shown that inhibition of FTO suppresses tumor progression in glioblastoma, the most common and deadliest
form of brain cancer, suggesting FTO and other mRNA-modifying enzymes may be promising anti-cancer drug
targets. However, we lack a mechanistic understanding of how FTO targets its modified mRNA substrates,
impacts mRNA function, and contributes to disease progression. Our long-term goal is to define the biochemical,
structural, and molecular mechanisms that regulate mRNA demethylation in the cell, and to develop the new
tools and understanding needed to characterize demethylation activity across the transcriptome and in diverse
human disease states. The work outlined in this proposal will: (1) define the structural and biochemical basis of
FTO target selectivity at the atomic level using X-ray crystallography and enzymology with synthetic modified
nucleotide analogs, (2) generate bioorthogonal chemical probes that covalently trap FTO-installed demethylation
intermediates to directly map sites of demethylation on mRNA, and (3) explore the molecular mechanisms
through which FTO-installed demethylation intermediates may directly regulate mRNA function. This work is
impactful and significant because it will advance the field’s understanding of how methyl eraser FTO is targeted
to different mRNA modifications and how unexplored, metastable intermediate modifications installed during
FTO-mediated demethylation impact mRNA function. Furthermore, the tools we develop to trap demethylation
intermediates will be critical to map sites of mRNA demethylation across the transcriptome in different cell types
and disease states, which will allow our lab and others to directly assess the role of mRNA demethylation in
human cancers linked to FTO function.

## Key facts

- **NIH application ID:** 10026274
- **Project number:** 2P20GM104316-06A1
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Jeffrey Scott Mugridge
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $240,700
- **Award type:** 2
- **Project period:** 2014-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026274

## Citation

> US National Institutes of Health, RePORTER application 10026274, Molecular tools to understand cellular mRNA demethylation (2P20GM104316-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10026274. Licensed CC0.

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