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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >The relationship between dNTP pool levels and mutagenesis in an Escherichia coli NDP kinase mutant
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The relationship between dNTP pool levels and mutagenesis in an Escherichia coli NDP kinase mutant

机译：大肠杆菌NDP激酶突变体中dNTP库水平与诱变之间的关系

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摘要

Loss of nucleoside diphosphate kinase (Ndk) function in Escherichia coli results in an increased frequency of spontaneous mutation and an imbalance in dNTP pool levels. It is presumed that the imbalance in dNTP pool levels is responsible for the mutator phenotype of an E. coli ndk mutant. A human homologue of Ndk and potential suppressor of tumor metastasis, nm23-H2, can complement the mutagenic phenotype of an E. coli ndk mutant. Here, we show that the antimutagenic property of nm23-H2 in E. coli is independent of dNTP pool levels, indicating that dNTP pool imbalance is not responsible for the mutator phenotype associated with the loss of ndk function. We have identified multiple genetic interactions between ndk and genes involved in the metabolism of dUTP, a potentially mutagenic precursor of thymidine biosynthesis. We show that loss of ndk function is synergistic with a dut-1 mutation and synthetically lethal with the loss of thymidine kinase function. Our results suggest that Ndk prevents the accumulation of dUTP in vivo. Based on these results and biochemical studies of Ndk, we propose that the mutagenic phenotype of an ndk mutant is caused by excess misincorporation of uracil in place of thymidine combined with a defect in the uracil base excision pathway.
机译：大肠杆菌中核苷二磷酸激酶（Ndk）功能的丧失导致自发突变的频率增加和dNTP库水平的失衡。据推测，dNTP库水平的不平衡是大肠杆菌ndk突变体的突变体表型的原因。 Ndk的人类同源物和潜在的肿瘤转移抑制因子nm23-H2可与大肠杆菌ndk突变体的诱变表型互补。在这里，我们显示nm23-H2在大肠杆菌中的抗诱变特性与dNTP库水平无关，这表明dNTP库不平衡不负责与ndk功能丧失相关的突变体表型。我们已经确定了ndk与dUTP代谢相关基因之间的多种遗传相互作用，dUTP是胸苷生物合成的潜在诱变前体。我们表明，ndk功能的丧失与dut-1突变协同作用，并与胸苷激酶功能的丧失致死性合成。我们的结果表明，Ndk阻止了dUTP在体内的积累。根据这些结果和Ndk的生化研究，我们认为ndk突变体的诱变表型是由尿嘧啶替代胸腺嘧啶的尿素过量错误掺入以及尿嘧啶碱基切除途径的缺陷引起的。

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