2. Academic Validation
  3. mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis

mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis

  • Mol Cell. 2021 May 20;81(10):2076-2093.e9. doi: 10.1016/j.molcel.2021.03.009.
Elodie Villa 1,  Umakant Sahu 1,  Brendan P O'Hara 1,  Eunus S Ali 1,  Kathryn A Helmin 2,  John M Asara 3,  Peng Gao 4,  Benjamin D Singer 5,  Issam Ben-Sahra 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 2 Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
  • 3 Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Metabolomics Core Facility, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 5 Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Simpson Querrey Center for Epigenetics, Northwestern University Feinberg School of Medicine, 320 East Superior Street, Chicago, IL 60611, USA.
  • 6 Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. Electronic address: issam.ben-sahra@northwestern.edu.
PMID: 33756106 DOI: 10.1016/j.molcel.2021.03.009
Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient, growth, and oncogenic signals. We found that mTORC1 stimulates the synthesis of the major methyl donor, S-adenosylmethionine (SAM), through the control of methionine adenosyltransferase 2 alpha (MAT2A) expression. The transcription factor c-Myc, downstream of mTORC1, directly binds to intron 1 of MAT2A and promotes its expression. Furthermore, mTORC1 increases the protein abundance of Wilms' tumor 1-associating protein (WTAP), the positive regulatory subunit of the human N6-methyladenosine (m6A) RNA methyltransferase complex. Through the control of MAT2A and WTAP levels, mTORC1 signaling stimulates m6A RNA modification to promote protein synthesis and cell growth. A decline in intracellular SAM levels upon MAT2A inhibition decreases m6A RNA modification, protein synthesis rate, and tumor growth. Thus, mTORC1 adjusts m6A RNA modification through the control of SAM and WTAP levels to prime the translation machinery for anabolic cell growth.

Keywords

Cell growth; MAT2A; Methionine cycle; N(6)-methyladenosine; Protein Synthesis; RNA metabolism; S-adenosylmethionine; WTAP; mTOR; mTORC1.

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