Inhibition of DNA replication in Saccharomyces cerevisiae by araCMP.
Cytosine arabinoside (araC), a potent inhibitor of DNA replication in mammalian cells, was found to be completely ineffective in Saccharomyces cerevisiae. The 5' monophosphate derivative, araCMP, is toxic and effectively inhibits both nuclear and mitochondrial DNA synthesis in this organism. Although wild-type strains can be inhibited by araCMP, dTMP permeable (tup-) strains were found to be much more sensitive to the analogue. In vivo labelling experiments indicate that araC enters yeast cells; however, it is extensively catabolized by deamination and breakage of the glycosidic bond. In addition, the analogue is not efficiently phosphorylated in S. cerevisiae owing to an apparent lack of deoxynucleoside kinase activity. These results provide further evidence that deoxyribonucleotides can be synthesized only through de novo pathways in this organism. Finally, araCMP was found to be recombinagenic in S. cerevisiae which suggests, together with other previous studies, that, in general, inhibition of DNA synthesis in yeast promotes mitotic recombination events.
McIntosh
E M
EM
Department of Biology, York University, Toronto, Ontario, Canada.
Kunz
B A
BA
Haynes
R H
RH
D001088:Arabinonucleotides / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000378:metabolism; D003568:Cytidine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D003597:Cytosine Nucleotides / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects*; D004271:DNA, Fungal / Q000096:biosynthesis; D008938:Mitosis / Q000187:drug effects; D011995:Recombination, Genetic / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism; D013942:Thymine Nucleotides / Q000378:metabolism
D001088:Arabinonucleotides; D003597:Cytosine Nucleotides; D004271:DNA, Fungal; D013942:Thymine Nucleotides; D003561:Cytarabine; C024888:1-beta-D-arabinofuranosylcytosine 5'-monophosphate; D003568:Cytidine Monophosphate