# Control of RNA methylation by growth signals through the mTORC1 pathway

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $320,000

## Abstract

SUMMARY
The mechanistic target of rapamycin complex 1 (mTORC1) senses and integrates diverse environmental signals
to control energy and nutrient-consuming biosynthetic processes, such as protein, lipid, and nucleotide
synthesis. mTORC1 stimulates anabolic cell growth through posttranslational and transcriptional mechanisms
leading to increased macromolecule synthesis a prerequisite to augment cellular biomass priming cells for
growth and division. In many diseases, the prominence of mTORC1 signaling reinforces the importance of
considering targeting mTORC1 signaling in several diseases including neurodegenerative disorders, diabetes,
tumor syndromes, and aging. However, direct mTORC1 targeted therapies, being conceptually and preclinically
a promising target, displayed only limited efficacy in human patients. Therefore, a better understanding of the
biology downstream of mTORC1 and the development of more effective and specific therapeutic strategies in
the treatment of mTORC1-driven diseases are needed. To achieve the biosynthetic demands accompanying
proliferation, cells must increase the transport of nutrients from the environment. Glucose, lactate, and glutamine
are the principal nutrients that promote biosynthesis and survival in mammalian cells. An emerging aspect of
nutrient utilization in aging and proliferative diseases includes the role of dietary methionine restriction, which
was recently explored in the context of obesity, metabolic syndrome, and cancer. Methionine is an essential
amino acid that is catabolized and recycled in a sequence of metabolic reactions designated as the methionine
cycle. Methionine and ATP are converted into the universal methyl donor S-adenosylmethionine (SAM) via the
methionine adenosyltransferase 2 alpha (MAT2A) enzyme. Under this proposal, we propose to study the
influence of mTORC1 signaling on S-adenosylmethionine (SAM) synthesis and the subsequent methylation
processes supporting anabolic metabolism. We have identified that mTORC1 stimulates SAM synthesis in
various cell settings through direct transcriptional control of MAT2A expression by c-MYC. We propose to
evaluate the influence of mTORC1 signaling on SAM synthesis in a variety of human cells (Specific Aim1). Will
identify the mechanisms by which mTORC1 signaling promotes RNA methylation, particularly the N6-
methyladenosine (m6A) mark. We will determine the role of m6A on RNA downstream of mTORC1 in the control
of cell growth (Specific Aim2). Furthermore, we will determine the implication of the mTORC1-MAT2A axis on
tumor growth and the potential therapeutic strategy derived from this mechanism (Specific Aim3). Thus, the
overall goal of this proposal is to decipher the molecular mechanisms by which mTORC1 controls RNA
methylation in normal and pathological settings. We anticipate that the proposed studies will yield new insights
into how SAM levels alter anabolic metabolism and will uncover therapeutic targets to perturb mTORC1-driven
diseases.

## Key facts

- **NIH application ID:** 10873014
- **Project number:** 5R01GM143334-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Issam Ben-Sahra
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $320,000
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873014

## Citation

> US National Institutes of Health, RePORTER application 10873014, Control of RNA methylation by growth signals through the mTORC1 pathway (5R01GM143334-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10873014. Licensed CC0.

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