Cytoplasmic Serine Hydroxymethyltransferase Mediates Competition between Folate-dependent Deoxyribonucleotide andS-Adenosylmethionine Biosyntheses

Herbig, Alexander; Chiang, En‐Pei Isabel; Lee, Ling-Ru; Hills, Jessica; Shane, Barry; Stover, Patrick J.

doi:10.1074/jbc.m205000200

Cited by 247 publications

(281 citation statements)

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“…Previous studies have demonstrated that SHMT1 activity is the rate-limiting activity in thymidylate biosynthesis in MCF-7 cells. Overexpression of SHMT1 in MCF-7 cells not only favors the partitioning of folate-derived one-carbon units to thymidylate biosynthesis but also enhances the efficiency of de novo thymidylate biosynthesis relative to synthesis through the salvage pathway (11). Unlike the other enzymes involved in folate-mediated one-carbon metabolism, SHMT1 expression is not ubiquitous.…”

Section: Discussionmentioning

confidence: 96%

A UV-responsive Internal Ribosome Entry Site Enhances Serine Hydroxymethyltransferase 1 Expression for DNA Damage Repair

Fox

Shin

Caudill

2009

Journal of Biological Chemistry

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Thymidine nucleotides are required for faithful DNA synthesis and repair, and their de novo biosynthesis is regulated by serine hydroxymethyltransferase 1 (SHMT1). The SHMT1 transcript contains a heavy chain ferritin, heterogeneous nuclear ribonucleoprotein H2, and CUG-binding protein 1-responsive internal ribosome entry site (IRES) that regulates SHMT1 translation. In this study a non-lethal dose of UVC is shown to increase SHMT1 IRES activity and protein levels in four different cell lines. The mechanism for the UV-induced activation of the SHMT1 IRES involves an increase in heavy chain ferritin and heterogeneous nuclear ribonucleoprotein H2 expression and the translocation of CUG-binding protein 1 from the nucleus to the cytoplasm. The UV-induced increase in SHMT1 translation is accompanied by an increase in the small ubiquitin-like modifier-dependent nuclear localization of the de novo thymidylate biosynthesis pathway and a decrease in DNA strand breaks, indicating a role for SHMT1 and nuclear folate metabolism in DNA repair.UV radiation is mutagenic and damages cellular macromolecules, including proteins, lipids, and DNA. Thymine bases within DNA are sensitive to UV-induced damage, forming cyclobutane-type pyrimidine dimers and (6 -4)-photoproducts (1). These lesions hinder RNA polymerase processivity and, thus, inhibit transcription (2). In mammalian cells, cyclobutane-type pyrimidine dimers and (6 -4)-photoproducts are repaired by nucleotide excision repair (NER).2 NER involves the removal of ϳ30 nucleotides surrounding the damage site, resulting in a single-strand gap that requires DNA synthesis and ligation to complete the repair process (3).Thymidine triphosphate is required for faithful DNA synthesis. Insufficient pools of thymidine nucleotides during DNA replication and NER result in elevated rates of uracil misincorporation into DNA, which ultimately leads to DNA strand breaks and genome instability (4). Thymidine nucleotides can either be synthesized through a salvage pathway or can be synthesized de novo through folate-mediated one-carbon metabolism (see Fig. 1). In the de novo biosynthetic pathway, 5,10-methylenetetrahydrofolate (5,10-methylene-THF) provides the activated one-carbon units and reducing equivalents for the thymidylate synthase (TS)-catalyzed conversion of deoxyuridine monophosphate (dUMP) to thymidylate. 5,10-Methylene-THF can be generated by two alternative pathways; that is, the reduction of 10-formyl-THF or through the activity of serine hydroxymethyltransferase 1 (SHMT1), which catalyzes the conversion of THF and serine to glycine and 5,10-methylene-THF.The SHMT1 enzyme is a key regulator of de novo thymidylate biosynthesis and is poised to play a role in the repair of UVinduced DNA damage. In addition to providing 1-carbon units for the synthesis of thymidylate, SHMT1-derived 5,10-methylene-THF can be reduced by methylene-THF reductase to form 5-methyl-THF, a cofactor utilized in the remethylation of homocysteine to methionine (see Fig. 1). The concentration of free folate in ...

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Section: Discussionmentioning

confidence: 96%

A UV-responsive Internal Ribosome Entry Site Enhances Serine Hydroxymethyltransferase 1 Expression for DNA Damage Repair

Fox

Shin

Caudill

2009

Journal of Biological Chemistry

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“…To date, we have not detected significant changes in the levels of mRNA expression of several folate pathway genes in Hoxd4 transgenic chondrocytes (Kruger, Talmadge and Kappen, unpublished data) leaving the mechanistic targets for folate supplementation in transgenic chondrocytes as of yet unidentified. We show that chondrocytes need folate specifically for proliferation and differentiation, and the levels of cellular folate metabolites are known to control the balance between DNA synthesis and methylation of DNA and proteins (Herbig et al, 2002). Altered DNA methylation (Bird, 2002) or histone methylation (Lachner and Jenuwein, 2002) may affect the activity of genes regulated by Hox transcription factors, but this remains speculation until such downstream targets -of either Hox genes or folate -have been identified in skeletal cells.…”

Section: Discussion Folate Restores Skeletal Defects In Hox Transgenimentioning

confidence: 99%

Folate modulates Hox gene‐controlled skeletal phenotypes

Kappen

Mello

Finnell

2004

Genesis

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Hox genes are well known regulators of pattern formation (Capecchi, 1996;Krumlauf, 1994) and cell differentiation (Goff and Tabin, 1997;Papenbrock et al., 2000;Yueh et al., 1998) in the developing vertebrate skeleton. Although skeletal variations are not uncommon in humans (Hald et al., 1995), few mutations in human HOX genes have been described (Goodman and Scambler, 2001). If such mutations are compatible with life, there may be physiological modifiers for the manifestation of Hox gene-controlled phenotypes, masking underlying mutations. We here present evidence that the essential nutrient folate modulates genetically induced skeletal defects in Hoxd4 transgenic mice. We also show that chondrocytes require folate for growth and differentiation and that they express folate transport genes, providing evidence for a direct effect of folate on skeletal cells. To our knowledge, this is the first report of nutritional influence on Hox gene controlled phenotypes, and implicates gene-environment interactions as important modifiers of Hox gene function. Taken together, our results demonstrate a beneficial effect of folate on skeletal development that may also be relevant to disorders and variations of the human skeleton.

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“…For example, the enzymes affecting folate catabolism 37 or methylene-THF synthesis might be of importance. 38,39 Similarly, the mitochondrial counterpart of MTHFD1, the NAD-dependent methylenetetrahydrofolate dehydrogenase, can influence 10-formyl-THF generation that in turn contributes to the cytoplasmatic folate pools. 40 In order to analyze the whole range of polymorphisms underlying other enzymatic variants within the folate pathway, as well as their possible gene-gene interactions, it is necessary that much larger and more collaborative studies be undertaken, if we are to understand the role of gene polymorphisms in ALL outcome.…”

Section: Dfs But Not Os)mentioning

confidence: 99%

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

Krajinović

Lemieux-Blanchard²,

Chiasson³

et al. 2003

Pharmacogenomics J

153

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The central role of 5,10-methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia (ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability of event-free survival (EFS) in univariate analysis (hazard ratio (HR) ¼ 2.2, 95% confidence interval (CI), 1.0-4.7 and 2.8, 95% CI, 1.1-7.3, respectively). Multivariate analysis supported only the role of the MTHFR variant (HR ¼ 2.2, 95% CI, 0.9-5.6). However, the association of both genes with ALL outcome appears to be more obvious in the presence of another event-predisposing variant belonging to the same path of drug action. The combined effect of a thymidylate synthase (TS) triple repeat associated with increased TS levels, with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 allele, resulted in a highly significant reduction of EFS (multivariate HR ¼ 9.0, 95% CI, 1.9-42.8 and 8.9, 95% CI, 1.8-44.6, respectively). These results reveal the role of gene-gene interactions within a folate pathway, and how they can correlate with relapse probabilities in ALL patients.

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Cytoplasmic Serine Hydroxymethyltransferase Mediates Competition between Folate-dependent Deoxyribonucleotide andS-Adenosylmethionine Biosyntheses

Cited by 247 publications

References 33 publications

A UV-responsive Internal Ribosome Entry Site Enhances Serine Hydroxymethyltransferase 1 Expression for DNA Damage Repair

A UV-responsive Internal Ribosome Entry Site Enhances Serine Hydroxymethyltransferase 1 Expression for DNA Damage Repair

Folate modulates Hox gene‐controlled skeletal phenotypes

Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia

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