Flaherty Juliana N, Sivasudhan Enakshi, Tegowski Matthew, Xing Zheng, McGinnis Madeline M, Hunter Olga V, Featherston Kyah M, Sethia Komal, Tu Benjamin P, Meyer Kate D, Conrad Nicholas K
Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA.
Cell Rep. 2025 Jul 22;44(7):115966. doi: 10.1016/j.celrep.2025.115966. Epub 2025 Jul 10.
The methyl donor S-adenosylmethionine (SAM) regulates many cellular processes. The N6-methyladenosine (mA) 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.
甲基供体S-腺苷甲硫氨酸（SAM）调节许多细胞过程。N6-甲基腺苷（mA）甲基转移酶METTL16调节SAM合成酶MAT2A的表达，但其调节的后果尚未得到充分记录。在这里，我们在HCT116细胞中使用了降解子和互补策略，以证明METTL16对MAT2A的调节破坏会影响包括组蛋白甲基化、翻译和RNA甲基化在内的SAM依赖性过程。我们还确定U6 snRNA假基因是METTL16的底物。催化活性过高的METTL16的互补作用补充了其甲基转移酶活性，但通过废除MAT2A调节降低了细胞内SAM浓度。此外，这些细胞对MAT2A抑制剂治疗和MTAP基因缺失高度敏感，MTAP基因在约15%的癌症中缺失。这些发现支持了METTL16的催化效率有助于在细胞中建立SAM设定点的结论，并表明该功能可作为治疗MTAP缺陷型癌症的方法。
