Abstract
Thymidine kinase converts 5-fluorodeoxyuridine to 5-fluorodeoxyuridine monophosphate, which causes disruption of deoxynucleotide triphosphate ratios. The fission yeast Schizosaccharomyces pombe does not express endogenous thymidine kinase but 5-fluorodeoxyuridine inhibits growth when exogenous thymidine kinase is expressed. Unexpectedly, we found that 5-fluorodeoxyuridine causes S phase arrest even without thymidine kinase expression. DNA damage checkpoint proteins such as the 9-1-1 complex were required for viability in the presence of 5-fluorodeoxyuridine. We also found that strains with circular chromosomes, due to loss of pot1+, which have higher levels of replication stress, were more sensitive to loss of the 9-1-1 complex in the presence of 5-fluorodeoxyuridine. Thus, our results suggest that strains carrying circular chromosomes exhibit a greater dependence on DNA damage checkpoints to ensure viability in the presence of 5-fluorodeoxyuridine compared to stains that have linear chromosomes.
Highlights
DNA replication relies on the availability of deoxyribonucleoside triphosphates and replication fidelity is dependent on their balanced ratios
Therapies targeting the cells with circular chromosomes may facilitate the selective killing
We generated checkpoint defective strains with circular chromosomes and found that these strains were more sensitive to HU and MMS than either strains with circular chromosomes or checkpoint defective single mutant
Summary
DNA replication relies on the availability of deoxyribonucleoside triphosphates and replication fidelity is dependent on their balanced ratios. Deoxyuridine monophosphate (dUMP) is converted to deoxythiamine monophosphate (dTMP) in the presence of thymidylate synthase (TS) [1]. 5-fluorodeoxyuridine (Fudr) is phosphorylated to FdUMP by thymidine kinase (TK) (Fig 1A). FdUMP acts as an inhibitor of TS thereby hampering the synthesis of dTMP and dTTP (Fig 1B). The imbalanced dNTP synthesis negatively impacts on DNA replication and induces DNA damage [2,3]. Fudr and 5-FU are used as a cancer chemotherapy agent to induce double stranded DNA breaks [4] (Fig 1C). DNA damage activates cell cycle checkpoint signaling pathways, which are crucial for maintaining the cellular integrity by arresting the cell cycle, inducing apoptosis, and repairing
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