Tumor Cells Require Thymidylate Kinase to Prevent dUTP Incorporation during DNA Repair

Hu, Chun Mei; Yeh, Ming Tyng; Tsao, Ning; Chen, Chih‐Wei; Gao, Quan Ze; Chang, Chia Yun; Lee, Ming Hsiang; Fang, Jim‐Min; Sheu, Sheh Yi; Lin, Chow Jaw; Tseng, Mei‐Chun; Chen, Yu‐Ju; Chang, Zee Fen

doi:10.1016/j.ccr.2012.04.038

Cited by 63 publications

(85 citation statements)

References 45 publications

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“…The resulting calculations revealed that genes predominantly involved in de novo nucleotide synthesis pathways are over-expressed in all four cancer types compared to the corresponding normal tissues (Table 1). This result is in agreement with the previous literature emphasizing the importance of nucleotide biosynthesis to rapidly proliferating cells (Hu et al, 2012; Wilson et al, 2012). Furthermore, consistent with a recent observation (Nilsson et al, 2014) we also observe methylenetetrahydrofolate dehydrogenase 2 (NADP+ dependent) ( MTHFD2 ) and serine hydroxymethyltransferase 2 ( SHMT2 ), two mitochondrial enzymes that contribute to nucleotide metabolism, to be consistently overexpressed in cancers compared to corresponding normal tissues (Table 1).…”

Section: Resultssupporting

confidence: 93%

Characterization of the Usage of the Serine Metabolic Network in Human Cancer

et al. 2014

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The serine, glycine, one carbon (SGOC) metabolic network is implicated in cancer pathogenesis but its general functions are unknown. We carried out a computational reconstruction of the SGOC network and then characterized its expression across thousands of cancer tissues. Pathways including methylation and redox metabolism exhibited heterogeneous expression indicating a strong context dependency of their usage in tumors. From an analysis of coexpression, simultaneous up- or down-regulation of nucleotide synthesis, NADPH and glutathione synthesis was found to be a common occurrence in all cancers. Finally, we developed a method to trace the metabolic fate of serine using stable isotopes, high-resolution mass spectrometry and a mathematical model. Although the expression of single genes didn’t appear indicative of flux, the collective expression of several genes in a given pathway allowed for successful flux prediction. Together these findings identify expansive and heterogeneous functions for the SGOC metabolic network in human cancer.

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Section: Resultssupporting

confidence: 93%

Characterization of the Usage of the Serine Metabolic Network in Human Cancer

et al. 2014

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“…It is possible that, in response to checkpoint activation, there are local increases of dNTP levels near the sites of DNA damage. For example, colocalization of RNR and dTMP kinase at the sites of DNA damage has been reported (64,65), but it is not known whether RNR and dTMP kinase colocalize at stalled replication forks. It is also not clear whether the rest of the machinery required for the production of dNTPs-including dUTPase, dCMP deaminase, dTMP synthase, dTMP kinase, and NDP kinase-colocalize at the sites of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Rentoft

Lindell

Tran

et al. 2016

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

105

155

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Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that several SAMHD1 mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.

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“…Multiple genes involved in nucleotide metabolism have been shown to be able to cause transformation by reducing the genomic integrity [195]. Also, through the transfer of methyl groups to proteins, DNA, and RNA, S -Adenosyl Methionine regulates protein activity as well as epigenetic marks on DNA and proteins in cells which are all broadly implicated in cancer.…”

Section: Epigenetics and Oncometabolitesmentioning

confidence: 99%

Dysregulated metabolism contributes to oncogenesis

Team

2015

Seminars in Cancer Biology

254

226

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Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review “Hallmarks of Cancer”, where the dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results suggest that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it.

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Tumor Cells Require Thymidylate Kinase to Prevent dUTP Incorporation during DNA Repair

Cited by 63 publications

References 45 publications

Characterization of the Usage of the Serine Metabolic Network in Human Cancer

Characterization of the Usage of the Serine Metabolic Network in Human Cancer

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Dysregulated metabolism contributes to oncogenesis

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