# Resolving cellular functions of arginine methylation

> **NIH NIH R35** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2024 · $396,380

## Abstract

Summary
PRMT5 is an essential enzyme and the cell’s primary enzyme capable of symmetric dimethylation of arginine
residues. PRMT5 is a therapeutic target in cancer and neurodegenerative diseases. PRMT5 methylation of
multiple protein substrates regulates a host of important cellular pathways and processes including transcription,
chromatin dynamics, mRNA splicing, and translation. While PRMT5 activity is required for cell and tissue survival,
which function(s) or substrate(s) of PRMT5 are required for general cell maintenance or involved in cancer and
neurodegenerative diseases has not been elucidated. Further, while PRMT5 substrate proteins are strongly
enriched for RNA binding and RNA regulatory pathways, the biochemical effects of arginine dimethylation have
not been resolved. Specifically, methyl-Arg increases the size, hydrophobicity, and charge distribution, and
decreases the H-bonding potential of substrate arginines but the mechanics of how the Arg-methyl groups affect
PRMT5 substrates’ structure/function and subsequent cell survival are not known. In this project, I will explore
how PRMT5 methylation of substrate proteins affect their ability to (1) bind to mRNA, (2) bind to other
proteins/form higher order protein complexes and (3) affect substrate-dependent processes such as mRNA
splicing. We will identify how substrates are recruited for methylation by PRMTs and what the downstream
biochemical function is in order to better understand PRMT5 essential functions in normal cells and disease.
Achieving a therapeutic window where select PRMT5 activities can be blocked without disrupting normal cell
function is critical for targeting this essential enzyme. Thus, understanding the mechanisms of PRMT5 biology
has the potential to inform our understanding of an important posttranslational modification on multiple
intracellular targets and to guide future efforts in developing modulators of PRMT activity in disease settings.
The discovery of novel sites on PRMT5 or on substrates may provide new therapeutic targets that would allow
for targeting select PRMT5 function in disease while preserving the normal healthy cells and overcoming issues
of toxicity observed with broad, catalytic PRMT5 inhibitors. We have previously defined the first mechanism of
substrate recruitment to PRMT5 through the conserved, colinear PRMT5 binding motif using a computational
tool to discover enriched protein motifs. We have predicted a new binding site for several additional PRMT5
substrates including ZNF326 – a substrate that is consistently methylated in all cells tested and that regulates
mRNA splicing. We will determine how substrates get recruited to PRMT5 (and other PRMT family enzymes) for
methylation and their cellular and biochemical outcomes as we establish a comprehensive research program
devoted to understanding how enzymes select their substrates and performing early validation of their
therapeutic potential. Overall, this project will dissect the cellula...

## Key facts

- **NIH application ID:** 10941619
- **Project number:** 1R35GM154987-01
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Kathleen Mulvaney
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $396,380
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941619

## Citation

> US National Institutes of Health, RePORTER application 10941619, Resolving cellular functions of arginine methylation (1R35GM154987-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10941619. Licensed CC0.

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