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

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 N-6-methyladenosine (m(6)A) RNA methyltransferase complex. Through the control of MAT2A and WTAP levels, mTORC1 signaling stimulates m(6)A RNA modification to promote protein synthesis and cell growth. A decline in intracellular SAM levels upon MAT2A inhibition decreases m(6)A RNA modification, protein synthesis rate, and tumor growth. Thus, mTORC1 adjusts m(6)A RNA modification through the control of SAM and WTAP levels to prime the translation machinery for anabolic cell growth.