The catalytic efficiency of METTL16 affects cellular processes by governing the intracellular S-adenosylmethionine setpoint

  • Cell Rep. 2025 Jul 22;44(7):115966. doi: 10.1016/j.celrep.2025.115966.
Juliana N Flaherty  1 ,  Enakshi Sivasudhan  2 ,  Matthew Tegowski  2 ,  Zheng Xing  3 ,  Madeline M McGinnis  3 ,  Olga V Hunter  1 ,  Kyah M Featherston  1 ,  Komal Sethia  1 ,  Benjamin P Tu  3 ,  Kate D Meyer  4 ,  Nicholas K Conrad  5
Affiliations
  • 1. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
  • 3. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA.
  • 5. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].
PMID: 40644296 DOI: 10.1016/j.celrep.2025.115966
Abstract

The methyl donor S-adenosylmethionine (SAM) regulates many cellular processes. The N6-methyladenosine (m6A) methyltransferase METTL16 regulates the expression of the SAM synthetase MAT2A, but the consequences of this regulation are not well documented. Here, we used a degron and complementation strategy in HCT116 cells to demonstrate that disruption of MAT2A regulation by METTL16 influences SAM-dependent processes including histone methylation, translation, and RNA methylation. We also identify U6 snRNA pseudogenes as METTL16 substrates. Complementation by a catalytically hyperactive METTL16 complements its methyltransferase activities but decreases intracellular SAM concentrations by abrogating MAT2A regulation. Moreover, these cells are hypersensitive to treatment with a MAT2A inhibitor and to deletion of the MTAP gene, which is lost in ∼15% of cancers. These findings support the conclusion that the catalytic efficiency of METTL16 helps establish the SAM setpoint in cells and suggest that this function could be exploited as a treatment for MTAP-deficient cancers.

Keywords
CP: Molecular biology; MAT2A; METTL16; MTAP; SAM; intron retention; methylation.
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