Checkpoint-dependent sensitivities to nucleoside analogues uncover specific patterns of genomic instability

Abstract

Nucleoside analogues are used as drugs and as labels in lab-based research. However, the effect of different nucleoside analogue mechanism(s) on cell sensitivity or mutagenesis is unclear. This is particularly important in cancer treatments where checkpoint proteins and DNA damage factors are often mutated. We tested 6 nucleoside analogues in the fission yeast, Schizosaccharomyces pombe. We found that the mutations in the DNA replication checkpoint cause unique sensitivity profiles towards chemotherapeutic nucleoside analogues (gemcitabine, 5-fluorouracil, cytarabine) and the non-clinical analogue bromodeoxyuridine. Antiretroviral compounds, zidovudine and lamivudine, did not alter cell growth. We compared half-maximal inhibitory concentration (IC50) doses between checkpoint deficient yeast strains, examining culture growth and DNA mis-segregation. Intriguingly, gemcitabine and bromodeoxyuridine doses above the IC50 promoted better growth. Above each compounds IC50 dose we saw that cells were insensitive to nucleoside analogue re-exposure, particularly in DNA replication checkpoint mutants (cds1{Delta}, rad3{Delta}). Thus, pairing nucleoside analogue use with personal genomics may inform drug choice, dose, and schedule. Finally, these data indicate that resistance may be predictable, informing clinical strategy.