Constitutively high dNTP concentration inhibits cell cycle progression and the DNA damage checkpoint in yeast Saccharomyces cerevisiae.
In eukaryotic cells the concentration of dNTP is highest in S phase and lowest in G1 phase and is controlled by ribonucleotide reductase (RNR). RNR activity is eliminated in all eukaryotes in G1 phase by a variety of mechanisms: transcriptional regulation, small inhibitory proteins, and protein degradation. After activation of RNR upon commitment to S phase, dATP feedback inhibition ensures that the dNTP concentration does not exceed a certain maximal level. It is not apparent why limitation of dNTP concentration is necessary in G1 phase. In principle, dATP feedback inhibition should be sufficient to couple dNTP production to utilization. We demonstrate that in Saccharomyces cerevisiae constitutively high dNTP concentration transiently arrests cell cycle progression in late G1 phase, affects activation of origins of replication, and inhibits the DNA damage checkpoint. We propose that fluctuation of dNTP concentration controls cell cycle progression and the initiation of DNA replication.
Chabes
Andrei
A
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. andrei.chabes@medchem.umu.se
Stillman
Bruce
B
D000483:Alleles; D002453:Cell Cycle / Q000187:drug effects*; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004271:DNA, Fungal / Q000187:drug effects; D009711:Nucleotides / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics
D002843:Chromatin; D004271:DNA, Fungal; D009711:Nucleotides