Mutagenicity of the cytidine analog zebularine in Escherichia coli
Mutagenicity of the cytidine analog zebularine in Escherichia coli
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DOI：
10.1016/j.dnarep.2003.10.010
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发表时间：
2004-02-03
期刊：
影响因子：
3.8
通讯作者：
Miller, JH
中科院分区：
文献类型：
--
作者：
Lee, G;Wolff, E;Miller, JH
我们检查了 zebularine 的诱变特性，zebularine 是一种 C-4 处缺乏氨基的胞苷类似物，在化疗中具有潜在用途。由于该水合物是胞苷脱氨酶的强抑制剂，因此使用它可以增强其他胞嘧啶基化合物的效力，例如被胞苷脱氨酶灭活的 5-氮杂胞苷 (5AzaC) 和胞嘧啶阿拉伯糖苷 (ara-C)。利用大肠杆菌中新开发的 rpoB/Rif(r) 系统，我们检查了染色体 rpoB 基因中由 zebularine 引起的碱基替换突变。 Zebularine 是一种强效诱变剂，主要引起 G : C --> A : T 转变并有利于某些热点。突变并非 rpoB 基因特有的，因为 thyA 基因也强烈诱导突变。在没有错配修复的情况下，zebularine 诱导碱基取代和移码的速率远高于用 zebularine 处理的野生型菌株或未经处理的错配修复缺陷菌株中观察到的速率。这些诱导突变的性质表明，除了靶向 G : C --> A : T 突变之外，zebularine 还刺激诱导增加的复制错误，并且这些错误通常由错配修复系统修复。 (C) 2003 Elsevier B.V. 保留所有权利。
We have examined the mutagenic properties of zebularine, a cytidine analog lacking the amino group at C-4 that has potential use in chemotherapy. Because the hydrate is a strong inhibitor of cytidine deaminase, its use can enhance the potency of other cytosine based compounds such as 5-azacytidine (5AzaC) and cytosine arabinoside (ara-C) that are inactivated by cytidine deaminase. Using the newly developed rpoB/Rif(r) system in Escherichia coli, we examined base substitution mutations caused by zebularine in the chromosomal rpoB gene. Zebularine is a potent mutagen that causes mainly G : C --> A : T transitions and favors certain hotspots. Mutations are not specific to the rpoB gene, since there is also a strong induction of mutations in the thyA gene. In the absence of mismatch repair, zebularine induces both base substitutions and frame shifts at rates well above those seen in wild-type strains treated with zebularine or in mismatch repair deficient strains without treatment. The nature of these induced mutations indicates that zebularine is stimulating the induction of increased replication errors, in addition to the targeted G : C --> A : T mutations, and that these errors are normally repaired by the mismatch repair system. (C) 2003 Elsevier B.V. All rights reserved.