The protein kinase snf1 is required for tolerance to the ribonucleotide reductase inhibitor hydroxyurea
The protein kinase snf1 is required for tolerance to the ribonucleotide reductase inhibitor hydroxyurea
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DOI：
10.1128/mcb.24.6.2560-2572.2004
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发表时间：
2004-03-01
影响因子：
5.3
通讯作者：
Mann, C
中科院分区：
文献类型：
--
作者：
Dubacq, C;Chevalier, A;Mann, C
在真核细胞中，Snf1/AMP激活的蛋白激酶参与了广泛的应激反应。我们发现了Snf1激酶在酵母细胞对遗传毒性应激反应中的一个新的作用。SNF1突变体对羟基脲(HU)、甲基甲烷磺酸盐和镉过敏，但对其他几种遗传毒性物质不敏感。HU抑制核苷酸还原酶(RNR)，SNF1的缺失也增加了rnr4核苷酸还原酶突变体的生长缺陷。SNF1突变体对HU具有功能检查点反应，即细胞正常停止分裂并抑制RNR基因的转录。SNF1对HU或RNR4缺失的敏感性可能是由于RNR功能的转录后缺陷，或者是由于停滞的复制叉子的修复和恢复方面的缺陷。Mig3抑制子被确定为Snf1在该途径中的一个靶点。遗传和生化分析表明，弱的激酶活性足以产生对HU的抗性，而高水平的激酶活性是在葡萄糖以外的碳源上最佳生长所必需的。Snf1激酶活性的定量调节可能有助于其控制的效应器反应的特异性。
The Snf1/AMP-activated kinases are involved in a wide range of stress responses in eukaryotic cells. We discovered a novel role for the Snf1 kinase in the cellular response to genotoxic stress in yeast. snf1 mutants are hypersensitive to hydroxyurea (HU), methyl-methane sulfonate, and cadmium, but they are not sensitive to several other genotoxic agents. HU inhibits ribunucleotide reductase (RNR), and deletion of SNF1 also increased the growth defects of an rnr4 ribonucleotide reductase mutant. The snf1 mutant has a functional checkpoint response to HU insofar as cells arrest division normally and derepress the transcription of RNR genes. The sensitivity of snf1 to HU or to RNR4 deletion may be due to posttranscriptional defects in RNR function or to defects in the repair of, and recovery from, stalled replication forks. The Mig3 repressor was identified as one target of Snf1 in this pathway. Genetic and biochemical analyses suggest that a weak kinase activity is sufficient to confer resistance to HU, whereas a high level of kinase activity is required for optimal growth on carbon sources other than glucose. Quantitative regulation of Snf1 kinase activity may contribute to the specificity of the effector responses that it controls.