Control of RNA methylation by growth signals through the mTORC1 pathway

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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.