Constitutively high dNTP concentration inhibits cell cycle progression and the DNA damage checkpoint in yeast Saccharomyces cerevisiae
Constitutively high dNTP concentration inhibits cell cycle progression and the DNA damage checkpoint in yeast Saccharomyces cerevisiae
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DOI：
10.1073/pnas.0610585104
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发表时间：
2007-01-23
影响因子：
11.1
通讯作者：
Stillman, Bruce
中科院分区：
文献类型：
--
作者：
Chabes, Andrei;Stillman, Bruce
在真核细胞中，dNTP的浓度在S期最高，在G1期最低，并受核糖核苷酸还原酶（RNR）的控制。在所有真核生物中，RNR活性在G（1）期通过多种机制被消除：转录调节、小抑制蛋白和蛋白质降解。在进入S期后激活RNR后，dATP反馈抑制确保dNTP浓度不超过某一最大水平。不清楚为什么在G1相中必须限制dNTP浓度。原则上，dATP反馈抑制应足以将dNTP产生与利用偶联。我们证明，在酿酒酵母组成性高dNTP浓度瞬时逮捕细胞周期的进展，在后期G，阶段，影响激活的复制起点，并抑制DNA损伤检查点。我们提出dNTP浓度的波动控制细胞周期进程和DNA复制的起始。
In eukaryotic cells the concentration of dNTP is highest in S phase and lowest in G, phase and is controlled by ribonucleotide reductase (RNR). RNR activity is eliminated in all eukaryotes in G(1) 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 G, 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 G, 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.