Thymineless death

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Thymineless death is the phenomenon by which bacteria, yeasts and mammalian cells undergo 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]


The phenomenon was first reported in 1954 by Hazel D. Barner and Seymour S. Cohen in Escherichia coli when thymine-requiring mutants of the bacteria lost viability when grown in a medium lacking thymine but containing other essential nutrients.[4][5] Subsequently, this discovery led to the development of theories to explain 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 does not generally kill cells to the extent 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]


  1. ^ 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. 
  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. doi:10.1007/bf00254040. 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 357338Freely accessible. PMID 13183905. 
  5. ^ a b 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 528686Freely accessible. 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 534191Freely accessible. PMID 16589586. 
  8. ^ 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. 
  9. ^ 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. 
  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 3390671Freely accessible. 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 150121Freely accessible. PMID 12618443. 

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