Thymineless death

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.
  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 357338. 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 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.
  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. PMC 3965187. 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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