WordNet

the time when something ends; "it was the death of all his plans"; "a dying of old hopes" (同)dying, demise
the time at which life ends; continuing until dead; "she stayed until his death"; "a struggle to the last" (同)last
the absence of life or state of being dead; "he seemed more content in death than he had ever been in life"
the permanent end of all life functions in an organism or part of an organism; "the animal died a painful death"
the act of killing; "he had two deaths on his conscience"
the event of dying or departure from life; "her death came as a terrible shock"; "upon your decease the capital will pass to your grandchildren" (同)decease, expiry
the personification of death; "Death walked the streets of the plague-bound city"

PrepTutorEJDIC

〈U〉〈C〉『死』,死亡;死に方,死にざま / 〈U〉死んだ[ような]状体 / 《the~》(…の)絶滅,破滅《+『of』+『名』》 / 《the~》(…の)死の原因,命取り《+『of』+『名』》 / 《通例『D-』》死神(手に鎌(かマ)を持った黒装束の骸骨(がいこつ)で表される)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/10 13:16:36」(JST)

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Thymineless death is the phenomenon by which bacteria, yeasts and mammalian cells undergo irreversible cell death when they are starved of thymidine triphosphate (dTTP), an essential precursor for DNA replication.^[1] This phenomenon underlies the mechanism of action of several antibacterial, antimalarial and anticancer agents, such as Trimethoprim, Sulfamethoxazole, Methotrexate and Fluorouracil.^[1]^[2]^[3]

History

The phenomenon was first reported in 1954 by Hazel D. Barner and Seymour S. Cohen in Escherichia coli when thymine requiring mutants of the bacterium lost viability when grown in a medium lacking thymine but containing other essential nutrients.^[4]^[5] Subsequently, this discovery led to the development of or explained the mechanism of action of several pyrimidine analogs that targeted thymine metabolism in bacteria and tumor cells.^[5]^[6] The phenomenon was commonly attributed to "unbalanced growth" wherein cells continued fundamental processes of RNA transcription, protein synthesis and metabolism in the absence of DNA replication.^[7] However, nutrient starvation generally do not kill cells to the extent as observed in cells that lack thymine. The molecular mechanism of thymineless death remains unknown;^[1] DNA breaks were observed during thymineless death, which could explain the killing.^[8]^[9] Possible pathways involved with the killing mechanism include: replication initiation,^[8]^[10] breakage of ongoing replication forks,^[11] futile DNA repair,^[9] replication origin destruction,^[12] and an addiction module.^[13]

References

^ ^a ^b ^c Ahmad, S. I.; Kirk, S. H.; Eisenstark, A. (October 1998). "Thymine Metabolism and Thymineless Death in Prokaryotes and Eukaryotes". Annual Review of Microbiology 52: 591–625. doi:10.1146/annurev.micro.52.1.591. PMID 9891809. Retrieved 3 October 2011.
^ Longley, D. B.; Harkin, D. P.; Johnston, P. G. (2003). "5-Fluorouracil: Mechanisms of action and clinical strategies". Nature Reviews Cancer 3 (5): 330–338. doi:10.1038/nrc1074. PMID 12724731.
^ Friedman, M. A.; Sadée, W. (1978). "The fluoropyrimidines: Biochemical mechanisms and design of clinical trials". Cancer chemotherapy and pharmacology 1 (2): 77–82. PMID 373913.
^ Barner, H. D.; Cohen, S. S. (1954). "The Induction of Thymine Synthesis by T2 Infection of a Thymine Requiring Mutant of Escherichia Coli". Journal of bacteriology 68 (1): 80–88. PMC 357338. PMID 13183905.
^ ^a ^b 50 years ago in cell biology - A virologist recalls his work on cell growth inhibition
^ Cohen, S. S.; Flaks, J. G.; Barner, H. D.; Loeb, M. R.; Lichtenstein, J. (1958). "The Mode of Action of 5-Fluorouracil and Its Derivatives". Proceedings of the National Academy of Sciences of the United States of America 44 (10): 1004–1012. doi:10.1073/pnas.44.10.1004. PMC 528686. PMID 16590300.
^ Cohen, S. S.; Barner, H. D. (1954). "Studies on Unbalanced Growth in Escherichia Coli". Proceedings of the National Academy of Sciences of the United States of America 40 (10): 885–893. doi:10.1073/pnas.40.10.885. PMC 534191. PMID 16589586.
^ ^a ^b Martín, C. M.; Guzmán, E. C. (2011). "DNA replication initiation as a key element in thymineless death". DNA Repair 10 (1): 94–101. doi:10.1016/j.dnarep.2010.10.005. PMID 21074501.
^ ^a ^b Nakayama, K.; Kusano, K.; Irino, N.; Nakayama, H. (1994). "Thymine starvation-induced structural changes in Escherichia coli DNA. Detection by pulsed field gel electrophoresis and evidence for involvement of homologous recombination". Journal of molecular biology 243 (4): 611–620. doi:10.1016/0022-2836(94)90036-1. PMID 7966286.
^ Sangurdekar, D. P.; Hamann, B. L.; Smirnov, D.; Srienc, F.; Hanawalt, P. C.; Khodursky, A. B. (2010). "Thymineless death is associated with loss of essential genetic information from the replication origin". Molecular Microbiology 75 (6): 1455–1467. doi:10.1111/j.1365-2958.2010.07072.x. PMID 20132444.
^ Kuong, K. J.; Kuzminov, A. (2010). "Stalled replication fork repair and misrepair during thymineless death in Escherichia coli". Genes to Cells 15 (6): 619–634. doi:10.1111/j.1365-2443.2010.01405.x. PMID 20465561.
^ Kuong, K. J.; Kuzminov, A (2012). "Disintegration of nascent replication bubbles during thymine starvation triggers RecA- and RecBCD-dependent replication origin destruction". The Journal of biological chemistry 287 (28): 23958–70. doi:10.1074/jbc.M112.359687. PMC 3390671. PMID 22621921.
^ Sat, B.; Reches, M.; Engelberg-Kulka, H. (2003). "The Escherichia coli mazEF Suicide Module Mediates Thymineless Death". Journal of bacteriology 185 (6): 1803–1807. doi:10.1128/jb.185.6.1803-1807.2003. PMC 150121. PMID 12618443.

External links

UpToDate Contents

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English Journal

Quartz crystal microbalance with dissipation and microscale thermophoresis as tools for investigation of protein complex formation between thymidylate synthesis cycle enzymes.

Antosiewicz A1, Senkara E2, Cieśla J3.
Biosensors & bioelectronics.Biosens Bioelectron.2015 Feb 15;64:36-42. doi: 10.1016/j.bios.2014.08.031. Epub 2014 Aug 22.
Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) play essential role in DNA synthesis, repair and cell division by catalyzing two subsequent reactions in thymidylate biosynthesis cycle. The lack of either enzyme leads to thymineless death of the cell, therefore inhibition of the enzyme a
PMID 25189098

Thymineless death in F10-treated AML cells occurs via lipid raft depletion and Fas/FasL co-localization in the plasma membrane with activation of the extrinsic apoptotic pathway.

Gmeiner WH1, Jennings-Gee J2, Stuart CH3, Pardee TS4.
Leukemia research.Leuk Res.2015 Feb;39(2):229-35. doi: 10.1016/j.leukres.2014.11.006. Epub 2014 Nov 29.
The polymeric fluoropyrimidine F10 displays excellent anti-leukemia activity in pre-clinical models of acute myelogenous leukemia (AML) through dual targeting of thymidylate synthase and DNA topoisomerase 1. Here we report that F10 activates the extrinsic apoptotic pathway in AML cells by enhancing
PMID 25510486

A balanced perspective on unbalanced growth and thymineless death.

Hanawalt PC1.
Frontiers in microbiology.Front Microbiol.2015 Jun 5;6:504. doi: 10.3389/fmicb.2015.00504. eCollection 2015.
The early history of the esoteric phenomenon of thymineless death (TLD) is recounted, from the pioneering discovery by Seymour Cohen and Hazel Barner, through my graduate studies at Yale and postdoctoral research in Copenhagen. My principal contribution was the discovery that restricted synthesis of
PMID 26097468

Japanese Journal

Thymine metabolism and thymineless death in prokaryotes and eukaryotes

Ann Rev Microbiol 52, 591-625, 1998
NAID 80010727829

Induction of apoptosis in androgen-independent human prostate cancer cells undergoing thymineless death

Prostate 25, 66-75, 1994
NAID 30025840157

'Thymineless' death in androgen-independent prostatic cancer cells

Biochem. Biophys. Res. Commun. 165, 73-81, 1989
NAID 80004898515

「チミン欠乏死」

　　[★]

英: thymineless death
同: チミン飢餓死
関: チミン

「death」

　　[★]

n.

死

[Ahmad-1] Ahmad, S. I.; Kirk, S. H.; Eisenstark, A. (October 1998). "Thymine Metabolism and Thymineless Death in Prokaryotes and Eukaryotes". Annual Review of Microbiology 52: 591–625. doi:10.1146/annurev.micro.52.1.591. PMID 9891809. Retrieved 3 October 2011.

[2] Longley, D. B.; Harkin, D. P.; Johnston, P. G. (2003). "5-Fluorouracil: Mechanisms of action and clinical strategies". Nature Reviews Cancer 3 (5): 330–338. doi:10.1038/nrc1074. PMID 12724731.

[3] Friedman, M. A.; Sadée, W. (1978). "The fluoropyrimidines: Biochemical mechanisms and design of clinical trials". Cancer chemotherapy and pharmacology 1 (2): 77–82. PMID 373913.

[4] Barner, H. D.; Cohen, S. S. (1954). "The Induction of Thymine Synthesis by T2 Infection of a Thymine Requiring Mutant of Escherichia Coli". Journal of bacteriology 68 (1): 80–88. PMC 357338. PMID 13183905.

[scientist-5] 50 years ago in cell biology - A virologist recalls his work on cell growth inhibition

[6] Cohen, S. S.; Flaks, J. G.; Barner, H. D.; Loeb, M. R.; Lichtenstein, J. (1958). "The Mode of Action of 5-Fluorouracil and Its Derivatives". Proceedings of the National Academy of Sciences of the United States of America 44 (10): 1004–1012. doi:10.1073/pnas.44.10.1004. PMC 528686. PMID 16590300.

[7] Cohen, S. S.; Barner, H. D. (1954). "Studies on Unbalanced Growth in Escherichia Coli". Proceedings of the National Academy of Sciences of the United States of America 40 (10): 885–893. doi:10.1073/pnas.40.10.885. PMC 534191. PMID 16589586.

[pmid21074501-8] Martín, C. M.; Guzmán, E. C. (2011). "DNA replication initiation as a key element in thymineless death". DNA Repair 10 (1): 94–101. doi:10.1016/j.dnarep.2010.10.005. PMID 21074501.

[pmid7966286-9] Nakayama, K.; Kusano, K.; Irino, N.; Nakayama, H. (1994). "Thymine starvation-induced structural changes in Escherichia coli DNA. Detection by pulsed field gel electrophoresis and evidence for involvement of homologous recombination". Journal of molecular biology 243 (4): 611–620. doi:10.1016/0022-2836(94)90036-1. PMID 7966286.

[10] Sangurdekar, D. P.; Hamann, B. L.; Smirnov, D.; Srienc, F.; Hanawalt, P. C.; Khodursky, A. B. (2010). "Thymineless death is associated with loss of essential genetic information from the replication origin". Molecular Microbiology 75 (6): 1455–1467. doi:10.1111/j.1365-2958.2010.07072.x. PMID 20132444.

[11] Kuong, K. J.; Kuzminov, A. (2010). "Stalled replication fork repair and misrepair during thymineless death in Escherichia coli". Genes to Cells 15 (6): 619–634. doi:10.1111/j.1365-2443.2010.01405.x. PMID 20465561.

[12] Kuong, K. J.; Kuzminov, A (2012). "Disintegration of nascent replication bubbles during thymine starvation triggers RecA- and RecBCD-dependent replication origin destruction". The Journal of biological chemistry 287 (28): 23958–70. doi:10.1074/jbc.M112.359687. PMC 3390671. PMID 22621921.

[13] Sat, B.; Reches, M.; Engelberg-Kulka, H. (2003). "The Escherichia coli mazEF Suicide Module Mediates Thymineless Death". Journal of bacteriology 185 (6): 1803–1807. doi:10.1128/jb.185.6.1803-1807.2003. PMC 150121. PMID 12618443.

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thymineless death