ArticleThe Journal of biological chemistry2011
Nuclear localization of de novo thymidylate biosynthesis pathway is required to prevent uracil accumulation in DNA.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 75 citations in OpenAlex.
- Serine Hydroxymethyltransferase (SHMT) in biology and disease: molecular mechanisms and therapeutic targeting.Journal of translational medicine · 2026Review
- Dietary folic acid prevents peripheral neuropathy in mouse models of neural tube defects and type 2 diabetes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A non-enzymatic role of Nudix hydrolase 5 in repressing purine de novo synthesis.Science (New York, N.Y.) · 2025Article
- Multifaceted role of serine hydroxymethyltransferase in health and disease.Molecules and cells · 2025Review
- SHMT2 is essential for mammalian preimplantation embryonic development throughMolecular therapy. Nucleic acids · 2025Article
- DHFR2 RNA directly regulates dihydrofolate reductase and its expression level impacts folate one carbon metabolism.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Tracing the Diverse Paths of One-Carbon Metabolism in Cancer and Beyond.Cold Spring Harbor perspectives in medicine · 2024Review
- Regulatory mechanisms of one-carbon metabolism enzymes.The Journal of biological chemistry · 2023Review
- The novel anti-cancer fluoropyrimidine NUC-3373 is a potent inhibitor of thymidylate synthase and an effective DNA-damaging agent.Cancer chemotherapy and pharmacology · 2023Article
- Principles and functions of metabolic compartmentalization.Nature metabolism · 2022Review
- The mechanism underlying resistance to 5-fluorouracil and its reversal by the inhibition of thymidine phosphorylase in breast cancer cells.Oncology letters · 2022Article
- Cytosolic localization and in vitro assembly of human de novo thymidylate synthesis complex.The FEBS journal · 2022Article
- Strengths and Weaknesses of Cell Synchronization Protocols Based on Inhibition of DNA Synthesis.International journal of molecular sciences · 2021Review
- MTHFR Knockdown Assists Cell Defense against Folate Depletion Induced Chromosome Segregation and Uracil Misincorporation in DNA.International journal of molecular sciences · 2021Article
- The Roles of Mitochondrial Folate Metabolism in Supporting Mitochondrial DNA Synthesis, Oxidative Phosphorylation, and Cellular Function.Current developments in nutrition · 2020Article
- Formate metabolism in health and disease.Molecular metabolism · 2020Review
- The multifaceted role of vitamin BOpen biology · 2020Review
- Cellular mechanisms underlyingDisease models & mechanisms · 2019Article
- 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer.Nature communications · 2019Article
- MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation.Nature genetics · 2019Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Uracil accumulates in DNA as a result of impaired folate-dependent de novo thymidylate biosynthesis, a pathway composed of the enzymes serine hydroxymethyltransferase (SHMT), thymidylate synthase (TYMS), and dihydrofolate reductase. In G1, this pathway is present in the cytoplasm and at S phase undergoes small ubiquitin-like modifier-dependent translocation to the nucleus. It is not known whether this pathway functions in the cytoplasm, nucleus, or both in vivo. SHMT1 generates 5,10-methylenetetrahydrofolate for de novo thymidylate biosynthesis, a limiting step in the pathway, but also tightly binds 5-methyltetrahydrofolate in the cytoplasm, a required cofactor for homocysteine remethylation. Overexpression of SHMT1 in cell cultures inhibits folate-dependent homocysteine remethylation and enhances thymidylate biosynthesis. In this study, the impact of increased Shmt1 expression on folate-mediated one-carbon metabolism was determined in mice that overexpress the Shmt1 cDNA (Shmt1tg+ mice). Compared with wild type mice, Shmt1tg+ mice exhibited elevated SHMT1 and TYMS protein levels in tissues and evidence for impaired homocysteine remethylation but surprisingly exhibited depressed levels of nuclear SHMT1 and TYMS, lower rates of nuclear de novo thymidylate biosynthesis, and a nearly 10-fold increase in uracil content in hepatic nuclear DNA when fed a folate- and choline-deficient diet. These results demonstrate that SHMT1 and TYMS localization to the nucleus is essential to prevent uracil accumulation in nuclear DNA and indicate that SHMT1-mediated nuclear de novo thymidylate synthesis is critical for maintaining DNA integrity.
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