Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymidylate synthase-negative mutants of cultured mouse FM3A cells were immediately committed to cell death upon thymidine deprivation especially when the cells were synchronized in the S-phase. Thymidine deprivation induced single strand breaks in parental DNA strands, as measured by alkaline sucrose gradient sedimentation, giving rise to two peaks, one with large and the other with short fragments. Increase in the short DNA fragments paralleled that of thymineless death. Thymidine deprivation also accumulated double strand DNA fragments as determined by a method of neutral filter elution, and their extent paralleled that of cell death. Double-strand DNA eluted through the filter sedimented as a single peak both in a neutral and in an alkaline sucrose gradient that coincided with that of the above short DNA fragments. Therefore, the double strand breaks seemed to occur in some defined portions of the genome and in some specific manners in contrast to those induced by X-ray, which occurred rather randomly. Cycloheximide blocked thymineless death and accumulation of the double stranded DNA fragments in parallel. The double strand breaks induced by thymidine starvation were not repaired, but instead advanced on subsequent incubation of the cells in growth medium containing thymidine. Cytogenetically, thymidine deprivation induced chromosome aberrations such as chromatid breaks, chromatid interchanges, and chromosome fragmentation. Also, 5-bromodeoxyuridine deprivation induced sister chromatid exchange. Thymidylate stress also induced loss of a stably integrated human gene in mouse cells, possibly by DNA rearrangements, under the conditions where no point mutations were induced.
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PMID:Thymineless death and genetic events in mammalian cells. 388 75

The biosynthesis of 2'-deoxyuridine monophosphate (dUMP) has been studied in a cytidine- and uracil-requiring mutant of Salmonella typhimurium (DP-55). The dUMP pool and the thymidine monophosphate (dTMP) pool of DP-55, grown in the presence of (3)H-uracil and unlabeled cytidine, are found to have the same specific activities. However, only 30% of the dUMP and the dTMP is synthesized from a uridine nucleotide. Seventy per cent is derived directly from a cytosine compound. The identification and partial purification of a Mg(2+)-dependent 2'-deoxycytidine triphosphate (dCTP) deaminase from S. typhimurium suggests that the combined action of dCTP deaminase and 2'-deoxyuridine triphosphate pyrophosphatase accounts for 70% of the dUMP, and therefore the dTMP, synthesized in vivo. The introduction of a thymine requirement (i.e., a block in thymidylate synthetase) into DP-55 results in a 100-fold increase in the size of the dUMP pool. However, the relative contribution of the uridine and cytidine pathways to dUMP synthesis is unaltered. The high dUMP pool is accompanied by extensive catabolism of dUMP to uracil. Partial thymine starvation of the cells results in a significant increase in the dUMP and dCTP pools. Moreover, an increase in the contribution of the dCTP pathway to dUMP synthesis is observed. As a result of these changes the catabolism of dUMP to uracil is augmented.
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PMID:Deoxycytidine triphosphate deaminase: identification and function in Salmonella typhimurium. 554 39

The biosynthesis of thymine nucleotides in Saccharomyces cerevisiae can be inhibited either by genetic lesions in the structural gene for thymidylate synthetase (TMP1) or by drugs that prevent the methylation of dUMP to dTMP. This methylation can be blocked by folate antagonists. We find that 5-fluoro-dUMP (FdUMP) is also an effective inhibitor in vivo. Inhibition of dTMP biosynthesis by these three different routes causes thymineless death. In addition to being cytotoxic, we find that FdUMP is highly recombinagenic in yeast but does not induce nuclear gene mutations. Provision of exogenous dTMP eliminates this induced mitotic recombination and cell killing. Similar results were obtained when a thymineless condition was provoked in cells by antifolate drugs or by dTMP deprivation in strains auxotrophic for this nucleotide. These findings show that, in contrast to the situation in prokaryotes, starvation for thymine nucleotides in yeast induces genetic recombination but is not mutagenic.
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PMID:Induction of mitotic recombination in yeast by starvation for thymine nucleotides. 644 1

Thymidylate synthase-negative mutants of cultured mouse cells were immediately committed to cell death upon thymidine deprivation, especially when the cells were synchronized in the S phase. Thymidylate deprivation induced single strand breaks in chromosome-size DNA strands, as measured by alkaline sucrose gradient sedimentation, giving rise to two peaks, one with large and the other with small fragments, the latter about the size of T4 DNA. An increase in the small DNA fragments paralleled that of thymineless death. Thymidine deprivation also produced double strand DNA fragments as determined by a method of neutral filter elution, and their extent paralleled that of cell death. Double-stranded DNA eluted through the filter sedimented as a single peak both in a neutral and in an alkaline sucrose gradient that coincided with that of the above small DNA fragments. Therefore, the strand breaks seemed to occur in some defined portions of the genome and in a specific manner compared to breaks induced by x-rays, which occurred rather randomly. Cycloheximide blocked both thymineless death and the production of the small DNA fragments. The strand breaks induced by thymidine starvation were not repaired but instead advanced on subsequent incubation of the cells in growth medium containing thymidine.
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PMID:Accumulation of DNA strand breaks during thymineless death in thymidylate synthase-negative mutants of mouse FM3A cells. 663 Jan 93

Thymidylate synthase-negative mutants of mouse FM3A cells are immediately committed to cell death upon thymidine starvation. Thymineless death can be mimicked by use of drugs that block the formation of reduced folate or dTMP. In parallel with this thymineless death, DNA double strand breaks and chromosome aberrations are induced. Thymidylate starvation does not induce mutation, whereas very mild thymidylate starvation does. Thymidylate starvation, however, induces strongly a deletion of a heterologous genetic marker at specific sites which is stably integrated in a mouse cell chromosome by means of DNA-mediated gene transfer.
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PMID:[Cell death and genetic alterations induced by thymidylate stress]. 671 62

For many years it has been known that thymine auxotrophic microorganisms undergo cell death in response to thymine starvation [thymineless death (TLD)]. This effect is unusual in that deprivation of many other nutritional requirements has a biostatic, but not lethal, effect. Studies of numerous microbes have indicated that thymine starvation has both direct and indirect effects. The direct effects involve both single- and double-strand DNA breaks. The former may be repaired effectively, but the latter lead to cell death. DNA damaged by thymine starvation is a substrate for DNA repair processes, in particular recombinational repair. Mutations in recBCD recombinational repair genes increase sensitivity to thymineless death, whereas mutations in RecF repair protein genes enhance the recovery process. This suggests that the RecF repair pathway may be critical to cell death, perhaps because it increases the occurrence of double-strand DNA breaks with unique DNA configurations at lesion sites. Indirect effects in bacteria include elimination of plasmids, loss of transforming ability, filamentation, changes in the pool sizes of various nucleotides and nucleosides and in their excretion, and phage induction. Yeast cells show effects similar to those of bacteria upon thymine starvation, although there are some unique features. The mode of action of certain anticancer drugs and antibiotics is based on the interruption of thymidylate metabolism and provides a major impetus for further studies on TLD. There are similarities between TLD of bacteria and death of eukaryotic cells. Also, bacteria have "survival" genes other than thy (thymidylate synthetase), and this raises the question of whether there is a relationship between the two. A model is presented for a molecular basis of TLD.
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PMID:Thymine metabolism and thymineless death in prokaryotes and eukaryotes. 989 9

Thymidylate synthase (TS) is the enzyme that catalyses the last step in de novo thymidylate synthesis. It is of interest clinically because it is an effective target for drugs such as 5-fluorouracil, often used in combination therapy. Despite a number of earlier reports indicating that TS is a cell cycle-dependent enzyme, this remains equivocal. Here, we show that in HCT116 cells synchronised by serum starvation, there is a clear dissociation between the expression of cyclin E (a well-characterised cell-cycle protein) and TS. Although both cyclin E and TS mRNA and protein increased during G(1), TS upregulation was delayed. Moreover, TS levels did not decrease following S-phase completion while cyclin E decreased sharply. Similarly, clear differences were seen between cyclin E and TS as asynchronously growing HCT116 cells were growth-inhibited by low-serum treatment. In contrast to previous reports using rodent cells, adenovirus-mediated over-expression of E2F1 and cyclin E in three human cell lines had no effect on TS. Cell-cycle progression was blocked by treatment of cells with pharmacological inhibitors of CDK2 and CDK4 and by ectopic expression of p16INK4A. Whereas CDK2 inhibition had no effect on TS levels, inhibition of CDK4 was associated with decreased TS protein levels. These results provide the first evidence that drugs targeting CDK4 may be useful with anti-TS drugs as combination therapy for cancer.
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PMID:Expression of thymidylate synthase in human cells is an early G(1) event regulated by CDK4 and p16INK4A but not E2F. 1792 72

Thymine deprivation results in the loss of viability in cells from bacteria to eukaryotes. Numerous studies have identified a variety of molecular processes and cellular responses associated with thymineless death (TLD). It has been observed that TLD occurs in actively growing cells, and DNA damage and DNA recombination structures have been associated with cells undergoing TLD. We measured the loss of viability in thymine-starved cells differing in the number of overlapping replication cycles (n), and we found that the magnitude of TLD correlates with the number of replication forks. By using pulsed field gel electrophoresis (PFGE), we determined the proportion of linear DNA (DSBs) and the amount of DNA remaining in the well after treatment with XbaI (nmDNA) under thymine starvation in the absence or presence of both rifampicin (suppressing TLD) and hydroxyurea (maintaining TLD). Our results indicate that DSBs and nmDNA are induced by thymine starvation, but they do not correlate with the lethality observed in the presence of the drugs. We asked whether TLD was related to chromosomal DNA initiation. DNA labeling experiments and flow cytometric analyses showed that new initiation events were induced under thymine starvation. These new DNA replication initiation events were inhibited in the presence of rifampicin but not in the presence of hydroxyurea, indicating that TLD correlates with the induction of new initiation events in Escherichia coli. In support of this finding, cells carrying a deletion of the datA site, in which DNA initiation is allowed in the presence of rifampicin, underwent TLD in the presence of rifampicin. We propose that thymineless-induced DNA initiation generates a fraction of DNA damage and/or nmDNA at origins that is critical for TLD. Our model provides new elements to be considered when testing mammalian chemotherapies that are based on the inhibition of thymidylate synthetase.
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PMID:DNA replication initiation as a key element in thymineless death. 2107 1