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 59 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.

Effect of S-adenosyl-l-methionine (SAM), an allosteric activator of cystathionine-β-synthase (CBS) on colorectal cancer cell proliferation and bioenergetics in vitro

“…This latter observation, coupled with the findings that the stimulatory effects of SAM are reduced in cells with CBS silencing or in the presence of the CBS inhibitor AOAA are consistent with the hypothesis that a significant portion of the stimulatory proliferative and bioenergetic effects of SAM seen in the current study are, in fact, related to intracellular H 2 S, and its downstream effects. In this context, it is also noteworthy that earlier studies found that intracellular SAM levels are highest during the proliferative phase of various cells [49] while recent studies demonstrated that depletion of endogenous SAM levels leads to a suppression of cell proliferation [50]. These findings are consistent with the hypothesis that SAM, at low/endogenous levels serves as a pro-proliferative, rather than antiproliferative molecule.…”

An integrated transcriptomic and comparative genomic analysis of differential gene expression in Arctic charr (Salvelinus alpinus) following seawater exposure

“…For instance, iNOS, which may play a role in hypoosmoregulation, localizes to small cells buried deep within gill filaments (Ebbesson et al, 2005). Enhanced expression of the methionine cycle, specifically methionine adenosyltransferase, is also regarded as essential in regulating cell cycle turnover rates (Lin et al, 2014), which complements the results from this study (Fig. 5).…”

Dietary betaine supplementation to gestational sows enhances hippocampal IGF2 expression in newborn piglets with modified DNA methylation of the differentially methylated regions

“…BHMT, the only known enzyme that uses betaine as substrate, converts homocysteine to methionine [25]. Then, methionine can be converted to S-adenosylmethionine (SAM), the most important methyl donor in the body, by methionine adenosyltransferase (MAT) [26]. SAM is converted to S-adenosylhomocysteine (SAH) after donating its methyl group for different methylation reactions catalyzed by various methyltransferases.…”