Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase
Survival of DNA damage in yeast directly depends on increased dNTP levels allowed by relaxed feedback inhibition of ribonucleotide reductase
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DOI：
10.1016/s0092-8674(03)00075-8
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发表时间：
2003-02-07
期刊：
影响因子：
64.5
通讯作者：
Thelander, L
中科院分区：
文献类型：
--
作者：
Chabes, A;Georgieva, B;Thelander, L
在真核生物中，DNA损伤引起多方面的反应，包括细胞周期停滞，DNA修复基因的转录激活，以及多细胞生物中的细胞凋亡。我们证明，在酿酒酵母中，DNA损伤导致dNTP水平增加6至8倍。这种增加是由核糖核苷酸还原酶（RNR）的不寻常的放松的dATP反馈抑制所赋予的。通过RNR中变构活性位点的突变完全消除dATP反馈抑制导致在正常生长条件下高1.6-2倍的dNTP池，并且在DNA损伤期间池额外增加11- 17倍。dNTP池的增加显著提高了DNA损伤后的存活率，但同时导致更高的突变率。我们提出，在升高的dNTP浓度下，更有效的跨损伤DNA合成导致了存活率和突变率的增加。
In eukaryotes, DNA damage elicits a multifaceted response that includes cell cycle arrest, transcriptional activation of DNA repair genes, and, in multicellular organisms, apoptosis. We demonstrate that in Saccharomyces cerevisiae, DNA damage leads to a 6- to 8-fold increase in dNTP levels. This increase is conferred by an unusual, relaxed dATP feedback inhibition of ribonucleotide reductase (RNR). Complete elimination of dATP feedback inhibition by mutation of the allosteric activity site in RNR results in 1.6-2 times higher dNTP pools under normal growth conditions, and the pools increase an additional 11- to 17-fold during DNA damage. The increase in dNTP pools dramatically improves survival following DNA damage, but at the same time leads to higher mutation rates' We propose that increased survival and mutation rates result from more efficient translesion DNA synthesis at elevated dNTP concentrations.