Nuclear Enrichment of Folate Cofactors and Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) Protect de Novo Thymidylate Biosynthesis during Folate Deficiency

Field, Martha S.; Kamynina, Elena; Agunloye, Olufunmilayo C.; Liebenthal, Rebecca P.; Lamarre, Simon G.; Brosnan, Margaret E.; Brosnan, John T.; Stover, Patrick J.

doi:10.1074/jbc.m114.599589

Cited by 66 publications

(87 citation statements)

References 31 publications

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“…Nuclear folate-dependent de novo dTMP biosynthesis limits misincorporation of uracil into DNA and provides a means of cell cycle-dependent regulation of dTMP production (2,5,14,18,32). Here we show that As 2 O 3 concentrations in the range of documented environmental exposures impair folate-dependent de novo dTMP biosynthesis and specifically target SHMT1 and MTHFD1, the two sources of folate-activated one-carbon units in the form of 5,10-methylenetetrahydrofolate.…”

Section: Discussionmentioning

confidence: 99%

“…MTHFD1 has also been shown to localize to the nucleus during S-phase of the cell cycle (14). In this study, the presence of MTHFD1 in nuclei of cells undergoing DNA synthesis was investigated by culturing cells in the presence of 5-ethynyl-2′-deoxyuridine (EdU), a thymidine analog that is incorporated into DNA during synthesis.…”

Section: Mthfd1mentioning

confidence: 99%

“…The MTHFD1-GFP construct was generated as previously described (14). The MTHFD1-K223R-GFP construct was generated with the following primers: 5′-CAGCCTGAAATGGTTAGAGGGGAGTGGATCAAAC-3′ and 5′-GTTTG-ATCCACTCCCCTCTAACCATTTCAGGCTG-3′, and MTHFD1-GFP plasmid was used as template with the QuikChange II Site-directed Mutagenesis Kit (Agilent Technologies), according to the manufacturer's protocol.…”

Section: Mouse Embryonic Fibroblast Isolation For the Isolation Of Smentioning

confidence: 99%

“…Formate translocates to the cytosol and nucleus, where it is conjugated to THF by MTHFD1 (14,17). SHMT is also a source of cytosolic and nuclear one-carbon units, but makes minor catalytic contributions to dTMP synthesis ( Fig.…”

mentioning

confidence: 99%

“…5,10-methyleneTHF can be regenerated either from serine and THF through the activity of serine hydroxymethyltransferase (SHMT1 or SHMT2α) or from formate, ATP, NADPH, and THF by the activity of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) (4)(5)(6). SHMT1, DHFR, and TYMS are small ubiquitin-like modifier (SUMO)-ylated and translocate to the nucleus at the G1/S boundary (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). During S-phase of the cell cycle, the nuclear de novo dTMP synthesis pathway assembles as a lamin-associated multienzyme complex that consists of SHMT, MTHFD1, TYMS, DHFR, and other components of the replication machinery (12,13).…”

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confidence: 99%

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Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Kamynina

Lachenauer

DiRisio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Arsenic exposure increases risk for cancers and is teratogenic in animal models. Here we demonstrate that small ubiquitin-like modifier (SUMO)-and folate-dependent nuclear de novo thymidylate (dTMP) biosynthesis is a sensitive target of arsenic trioxide (As 2 O 3 ), leading to uracil misincorporation into DNA and genome instability. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and serine hydroxymethyltransferase (SHMT) generate 5,10-methylenetetrahydrofolate for de novo dTMP biosynthesis and translocate to the nucleus during S-phase, where they form a multienzyme complex with thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR), as well as the components of the DNA replication machinery. As 2 O 3 exposure increased MTHFD1 SUMOylation in cultured cells and in in vitro SUMOylation reactions, and increased MTHFD1 ubiquitination and MTHFD1 and SHMT1 degradation. As 2 O 3 inhibited de novo dTMP biosynthesis in a dose-dependent manner, increased uracil levels in nuclear DNA, and increased genome instability. These results demonstrate that MTHFD1 and SHMT1, which are key enzymes providing one-carbon units for dTMP biosynthesis in the form of 5,10-methylenetetrahydrofolate, are direct targets of As 2 O 3 -induced proteolytic degradation, providing a mechanism for arsenic in the etiology of cancer and developmental anomalies.MTHFD1 | arsenic trioxide | one-carbon metabolism | SUMO-1

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Section: Discussionmentioning

confidence: 99%

Section: Mthfd1mentioning

confidence: 99%

Section: Mouse Embryonic Fibroblast Isolation For the Isolation Of Smentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Kamynina

Lachenauer

DiRisio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Thymidylate Synthesis

Field

Kisliuk

2016

Encyclopedia of Life Sciences

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Thymidylate is a component of DNA (deoxyribonucleic acid), and is synthesised from the de novo or nucleotide salvage pathways. Many cell types rely on the salvage pathway, but often this is insufficient. Thymidylate is synthesised de novo from deoxyuridylate and methylenetetrahydrofolate by thymidylate synthase (TYMS), with the enzymes dihydrofolate reductase (DHFR) and serine hydroxymethyltransferase (SHMT) or methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) which are required to regenerate methylenetetrahydrofolate. The de novo synthesis pathway forms a nuclear complex at the nuclear lamina at sites of DNA replication. DNA polymerases do not distinguish between deoxyuridylate and thymidylate, and when thymidylate synthesis is insufficient, uracil is misincorporated into DNA. This can lead to futile cycles of DNA repair and subsequent DNA single‐ and double‐strand breaks. Impaired de novo thymidylate synthesis can result in neural tube defects, megaloblastic anaemia and severe combined immunodeficiency (SCID). Inhibitors of TYMS and DHFR impair cell replication and have been used in the treatment of cancer. Key Concepts Thymidylate (deoxythymidine 5′‐monophosphate, 5‐methyluracil‐2′‐deoxyriboside‐5′‐phosphate, dTMP) ( Figure 1) is an essential metabolite required for deoxyribonucleic acid (DNA) synthesis and repair. Thymidylate can be synthesised through a salvage pathway or de novo through a folate‐dependent pathway. Thymidylate synthesis through both the salvage and de novo pathways occurs in the nucleus and mitochondria. Thymidylate biosynthesis in the nucleus functions during DNA replication and repair. Thymidylate synthesis occurs at a greater rate during DNA replication when cells are in S‐phase of the cell cycle. De novo thymidylate biosynthesis is impaired by folate or vitamin B12 deficiency. Impaired de novo thymidylate biosynthesis causes uracil misincorporation into DNA and DNA instability. Thymidylate synthesis enzymes have been successfully targeted by chemotherapeutic agents for treatment of several types of cancers. Common polymorphisms in the TYMS gene are associated with cancer risk. Inhibition of thymidylate biosynthesis can cause a class of common birth defect known as neural tube defects, as well as severe combined immune deficiency (SCID) and megaloblastic anaemia.

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Folate Protects Hepatocytes of Hyperhomocysteinemia Mice From Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Activated Endoplasmic Reticulum Stress

Sun

Mao

et al. 2017

J. Cell. Biochem.

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Nuclear Enrichment of Folate Cofactors and Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) Protect de Novo Thymidylate Biosynthesis during Folate Deficiency

Cited by 66 publications

References 31 publications

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Thymidylate Synthesis

Folate Protects Hepatocytes of Hyperhomocysteinemia Mice From Apoptosis via Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Activated Endoplasmic Reticulum Stress

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