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The primary methyl group donor S-adenosylmethionine (SAM) is important for a plethora of cellular pathways including methylation of nucleic acids, proteins, and the 5' cap structure of mRNAs, as well as biosynthesis of phospholipids and polyamines. In addition, because it is the cofactor for chromatin methylation, SAM is an important metabolite for the establishment and maintenance of epigenetic marks. Here, we demonstrate that cells halt proliferation when SAM levels become low. Cell cycle arrest occurs primarily in the G1 phase of the cell cycle and is accompanied by activation of the mitogen-activated protein kinase p38 (MAPK14) and subsequent phosphorylation of MAPK-activated protein kinase-2 (MK2). Surprisingly, Cdk4 activity remains high during cell cycle arrest, whereas Cdk2 activity decreases concomitantly with cyclin E levels. Cell cycle arrest was induced by both pharmacological and genetic manipulation of SAM synthesis through inhibition or downregulation of methionine adenosyltransferase, respectively. Depletion of methionine, the precursor of SAM, from the growth medium induced a similar cell cycle arrest. Unexpectedly, neither methionine depletion nor inhibition of methionine adenosyltransferase significantly affected mTORC1 activity, suggesting that the cellular response to SAM limitation is independent from this major nutrient-sensing pathway. These results demonstrate a G1 cell cycle checkpoint that responds to limiting levels of the principal cellular methyl group donor S-adenosylmethionine. This metabolic checkpoint might play important roles in maintenance of epigenetic stability and general cellular integrity.

S-adenosylmethionine limitation induces p38 mitogen activated protein kinase and triggers cell cycle arrest in G1