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]

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