Fission yeast strains with circular chromosomes require the 9-1-1 checkpoint complex for the viability in response to the anti-cancer drug 5-fluorodeoxyuridine

PLoS One. 2017 Nov 9;12(11):e0187775. doi: 10.1371/journal.pone.0187775. eCollection 2017.

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.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Chromosome Segregation / drug effects
  • Chromosomes, Fungal / genetics*
  • DNA Damage
  • DNA Replication / drug effects
  • DNA, Fungal / genetics*
  • Floxuridine / pharmacology*
  • Microbial Viability / drug effects*
  • Mutation
  • Mycoses
  • S Phase Cell Cycle Checkpoints / drug effects
  • S Phase Cell Cycle Checkpoints / genetics
  • Schizosaccharomyces / cytology
  • Schizosaccharomyces / drug effects
  • Schizosaccharomyces / genetics*
  • Schizosaccharomyces / physiology*
  • Schizosaccharomyces pombe Proteins / genetics
  • Species Specificity
  • Telomere / genetics

Substances

  • Antineoplastic Agents
  • DNA, Fungal
  • Schizosaccharomyces pombe Proteins
  • Floxuridine