ArticleThe Journal of biological chemistry2014
Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 79 citations in OpenAlex.
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- Hallmarks of nuclear metabolism: implications for genome integrity, nuclear signaling, and therapeutic targeting.npj metabolic health and disease · 2026Review
- Transcriptome-informed metabolic modeling reveals astrocyte-specific vulnerabilities in mild cognitive impairment and Alzheimer's disease progression.Frontiers in bioinformatics · 2026Article
- Identifying MTHFD1 and LGALS4 as Potential Therapeutic Targets in Prostate Cancer Through Multi-Omics Mendelian Randomization Analysis.Biomedicines · 2025Article
- DTYMK is an essential gene in mice and heterozygosity does not cause neural tube defects.Archives of biochemistry and biophysics · 2024Article
- MTHFD2 in healthy and cancer cells: Canonical and non-canonical functions.npj metabolic health and disease · 2024Review
- Regulatory mechanisms of one-carbon metabolism enzymes.The Journal of biological chemistry · 2023Review
- A Simplified and Effective Approach for the Isolation of Small Pluripotent Stem Cells Derived from Human Peripheral Blood.Biomedicines · 2023Article
- Betaine Reduces Lipid Anabolism and Promotes Lipid Transport in Mice Fed a High-Fat Diet by Influencing Intestinal Protein Expression.Foods (Basel, Switzerland) · 2022Article
- A Common Polymorphism in theJournal of cardiovascular development and disease · 2022Article
- Review
- Epigenetic Reprogramming of the Glucose Metabolic Pathways by the Chromatin Effectors During Cancer.Sub-cellular biochemistry · 2022Article
- The Incoherent Fluctuation of Folate Pools and Differential Regulation of Folate Enzymes Prioritize Nucleotide Supply in the Zebrafish Model Displaying Folate Deficiency-Induced Microphthalmia and Visual Defects.Frontiers in cell and developmental biology · 2021Article
- One-Carbon Metabolism and Development of the Conceptus During Pregnancy: Lessons from Studies with Sheep and Pigs.Advances in experimental medicine and biology · 2021Article
- Extracellular serine and glycine are required for mouse and human skeletal muscle stem and progenitor cell function.Molecular metabolism · 2021Article
- The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies.Cancer discovery · 2020Article
- Effectiveness of community-based folate-oriented tertiary interventions on incidence of fetus and birth defects: a protocol for a single-blind cluster randomized controlled trial.BMC pregnancy and childbirth · 2020Article
- Article
- MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation.Nature genetics · 2019Article
- Deoxyuracil in DNA and disease: Genomic signal or managed situation?DNA repair · 2019Review
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
Folate-mediated one-carbon metabolism is a metabolic network of interconnected pathways that is required for the de novo synthesis of three of the four DNA bases and the remethylation of homocysteine to methionine. Previous studies have indicated that the thymidylate synthesis and homocysteine remethylation pathways compete for a limiting pool of methylenetetrahydrofolate cofactors and that thymidylate biosynthesis is preserved in folate deficiency at the expense of homocysteine remethylation, but the mechanisms are unknown. Recently, it was shown that thymidylate synthesis occurs in the nucleus, whereas homocysteine remethylation occurs in the cytosol. In this study we demonstrate that methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), an enzyme that generates methylenetetrahydrofolate from formate, ATP, and NADPH, functions in the nucleus to support de novo thymidylate biosynthesis. MTHFD1 translocates to the nucleus in S-phase MCF-7 and HeLa cells. During folate deficiency mouse liver MTHFD1 levels are enriched in the nucleus >2-fold at the expense of levels in the cytosol. Furthermore, nuclear folate levels are resistant to folate depletion when total cellular folate levels are reduced by >50% in mouse liver. The enrichment of folate cofactors and MTHFD1 protein in the nucleus during folate deficiency in mouse liver and human cell lines accounts for previous metabolic studies that indicated 5,10-methylenetetrahydrofolate is preferentially directed toward de novo thymidylate biosynthesis at the expense of homocysteine remethylation during folate deficiency.
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