# MTAP, 5'-deoxy-5'-methylthioadenosine, and the dysregulation of symmetric dimethylarginine in cancer

> **NIH NIH R01** · RESEARCH INST OF FOX CHASE CAN CTR · 2021 · $427,763

## Abstract

Project Summary
Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway whose function
is to convert 5′-deoxy-5′-methylthioadenosine (MTA) into methionine. Inactivation of MTAP, often by
homozygous deletion, is found in both solid and hematologic malignancies and is one of the most frequently
observed genetic alterations in human cancer. Previous work from our lab and others has established that MTAP
can act as a tumor suppressor gene. However the precise mechanism by which MTAP loss promotes
tumorigenesis is still unclear. One possible mechanism involves the accumulation of MTA, which is secreted by
MTAP-deleted tumor cells. Structurally, MTA closely resembles adenosine and evidence indicates that it can
interact with adenosine receptors. Large-scale genetic screens using shRNA have established that MTAP-
deleted cells are especially sensitive to knockdown of a specific protein arginine methyltransferase enzyme
(PRMT5), which is responsible for the post-translational symmetric dimethylation modification of arginine
residues (sDMA). This modification is frequently observed in proteins involved in mRNA maturation. In
preliminary data, we demonstrate that loss of MTAP or addition of extracellular MTA causes a dramatic reduction
of the steady-state levels of sDMA-containing proteins. Significantly, when extracellular MTA is added, no
increase in intracellular MTA occurs, suggesting that the reduction in sDMA-ylation is due to a signal transduction
process. However, our data also suggests that enzymatically inactive MTAP protein itself, independent of MTA,
can affect mRNA levels and antagonize the effects of MTA. Thus the overall goal of this proposal is to explore
the hypothesis MTAP mediates its tumor suppressor function via two different mechanisms: one involving MTA
as an oncometabolite and the other a direct role for the MTAP protein. The specific aims of the study are: (1)
Identify specific proteins and arginine residues that are differentially methylated in response to MTAP; (2)
Determine the roles of intracellular and extracellular MTA in the mechanism of sDMA-lyation in cancer cells; and
(3) Clarification of the enzymatic vs. non-enzymatic functions of MTAP. These studies are significant because
they provide a potential mechanism for understanding the role that MTAP deletion plays in tumorigenesis and
may lead to novel therapeutic strategies for MTAP-deleted tumors. In addition, these studies will shed light on
how a “housekeeping” metabolic enzyme can have a novel role as a tumor suppressor gene.

## Key facts

- **NIH application ID:** 10170293
- **Project number:** 5R01CA245871-02
- **Recipient organization:** RESEARCH INST OF FOX CHASE CAN CTR
- **Principal Investigator:** WARREN D KRUGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $427,763
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170293

## Citation

> US National Institutes of Health, RePORTER application 10170293, MTAP, 5'-deoxy-5'-methylthioadenosine, and the dysregulation of symmetric dimethylarginine in cancer (5R01CA245871-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10170293. Licensed CC0.

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