title: S-adenosylmethionine limitation induces p38 mitogen-activated protein kinase and triggers cell cycle arrest in G1.
abstract: 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.
authors.affiliation: University of California Irvine, Department of Biological Chemistry, College of Medicine, 240D Med Sci I, Irvine, CA 92697-1700, USA.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Lin
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Chung
authors.forename: Peter
authors.initials: P
authors.lastname: Kaiser
mesh_terms: D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D016193:G1 Phase / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008715:Methionine / Q000172:deficiency; D008716:Methionine Adenosyltransferase / Q000235:genetics / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000172:deficiency*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D047908:Intracellular Signaling Peptides and Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D008715:Methionine; D008716:Methionine Adenosyltransferase; D048308:Mitogen-Activated Protein Kinase 14; D046912:Multiprotein Complexes; D017346:Protein Serine-Threonine Kinases; D012436:S-Adenosylmethionine; D058570:TOR Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C495894:CDK2 protein, human; C495900:CDK4 protein, human
keywords: Cell cycle; MAPKAPK2; MK2; One carbon cycle; S-adenosylmethionine; SAM; p38 MAPK