mTORC1 Induces Purine Synthesis Through Control of the Mitochondrial Tetrahydrofolate Cycle

By I. Ben-Sahra, Gerta Hoxhaj, S. Ricoult, J. Asara, B. Manning. Science, 2016

705 citations recorded by the source corpus.

Controlling supplies for DNA and RNA synthesis The mTORC1 protein kinase complex regulates anabolic metabolism and coordinates cellular signals that promote growth with availability of required precursor metabolites. Signaling through mTORC1 controls pyrimidine synthesis. Ben-Sahra et al. found that mTORC1 also functions by a different mechanism to regulate purine biosynthesis, thus generating precursors for the synthesis of RNA and DNA (see the Perspective by Ma and Jones). Signaling by mTORC1 caused accumulation of the transcription factor ATF4, which enhances production of the enzyme methylenetetrahydrofolate dehydrogenase 2, thus leading to increased production of the purine nucleotides needed for cell growth. Science, this issue p. 728; see also p. 670 Coupling cellular growth signals to synthesis of RNA and DNA. [Also see Perspective by Ma and Jones] In response to growth signals, mechanistic target of rapamycin complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. mTORC1 had transcriptional effects on multiple enzymes contributing to purine synthesis, with expression of the mitochondrial tetrahydrofolate (mTHF) cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) being closely associated with mTORC1 signaling in both normal and cancer cells. MTHFD2 expression and purine synthesis were stimulated by activating transcription factor 4 (ATF4), which was activated by mTORC1 independent of its canonical induction downstream of eukaryotic initiation factor 2α eIF2α phosphorylation. Thus, mTORC1 stimulates the mTHF cycle, which contributes one-carbon units to enhance production of purine nucleotides in response to growth signals.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1838978915b15ed22945c79833391f767ca586e8

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals (2017, background): “Although ATF4 acts as a common downstream target that integrates signals from those eIF2α kinases, it has also been reported to be activated by an independent mechanism upon mitochondrial stress (Münch and Harper, 2016) or even in an mTOR-dependent way (Ben-Sahra et al., 2016).”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “…of nucleotides required for DNA replication and ribosome biogenesis in growing and proliferating cells. mTORC1 increases the ATF4-dependent expression of MTHFD2, a key component of the mitochondrial tetrahydrofolate cycle that provides onecarbon units for purine synthesis (Ben-Sahra et al., 2016).”
mTOR Signaling in Growth, Metabolism, and Disease. (2017, background): “…of nucleotides required for DNA replication and ribosome biogenesis in growing and proliferating cells. mTORC1 increases the ATF4-dependent expression of MTHFD2, a key component of the mitochondrial tetrahydrofolate cycle that provides one-carbon units for purine synthesis (Ben-Sahra et al., 2016).”
Targeting Metabolism for Cancer Therapy (2017, background): “, 2010) and enhance flux through the pyrimidine and purine synthesis pathways (BenSahra et al., 2013; Ben-Sahra et al., 2016; Robitaille et al., 2013), suggesting that targeting nucleotide metabolism in tumor contexts with mTOR hyperactivation may be more effective.”
One-Carbon Metabolism in Health and Disease. (2017, background): “ATF4 can also be activated by mTOR, linking the PI3K signaling axis to overexpression of 1C genes (Ben-Sahra et al., 2016).”
Nutrient sensing and TOR signaling in yeast and mammals (2017, positive): “Interestingly, a recent report showed that mTORC1 stimulates purine synthesis through ATF4 activation independent of eIF2 a phosphorylation (Ben-Sahra et al , 2016).”