Mutational alteration of the breakage/resealing subunit of bacteriophage T4 DNA topoisomerase confers resistance to antitumor agent m-AMSA.
Mutational alteration of the breakage/resealing subunit of bacteriophage T4 DNA topoisomerase confers resistance to antitumor agent m-AMSA.
复制标题
噬菌体 T4 DNA 拓扑异构酶的断裂/重新密封亚基的突变改变赋予抗肿瘤剂 m-AMSA 抗性。
DOI：
10.1007/bf00280363
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发表时间：
1990
期刊：
影响因子：
--
通讯作者：
Kreuzer,KN
中科院分区：
文献类型：
--
作者：
Huff,AC;Ward4th,RE;Kreuzer,KN
噬菌体 T4 提供了一个简单的模型系统，用于检查已被提议攻击 II 型 DNA 拓扑异构酶的抗肿瘤药物的作用机制。先前的结果表明，在噬菌体感染的大肠杆菌中，T4 II 型 DNA 拓扑异构酶是抗肿瘤剂 4'-(9-吖啶氨基)甲磺酰苯胺 (m-AMSA) 的靶标：拓扑异构酶结构基因 39 中的点突变显示出赋予 m-AMSA 抗性噬菌体生长和 m-AMSA 不敏感拓扑异构酶活性。我们在此报道，T4拓扑异构酶结构基因52的点突变也可以独立地使噬菌体生长和拓扑异构酶活性抵抗tom-AMSA。这种新分离的突变型拓扑异构酶的 DNA 松弛和 DNA 切割活性对 tom-AMSA 显着不敏感。基因 52 以及基因 39 中的耐药突变改变了野生型 T4 拓扑异构酶的 DNA 切割位点特异性。这种涉水与药物作用机制一致，其中拓扑异构酶和 DNA 都参与药物结合位点的形成。
Bacteriophage T4 provides a simple model system in which to examine the mechanism of action of antitumor agents that have been proposed to attack type II DNA topoisomerases. Prior results demonstrated that T4 type II DNA topoisomerase is the target of antitumor agent 4′-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in phage-infectedEscherichia coli: a point mutation in topoisomerase structural gene 39 was shown to confer bothm-AMSA-resistant phage growth andm-AMSA-insensitive topoisomerase activity. We report here that a point mutation in T4 topoisomerase structural gene 52 can also independently render both phage growth and topoisomerase activity resistant tom-AMSA. The DNA relaxation and DNA cleavage activities of this newly isolated mutant topoisomerase were significantly insensitive tom-AMSA. The drug-resistance mutation in gene 52, as well as that in gene 39, alters the DNA cleavage site specificity of wild-type T4 topoisomerase. This fording is consistent with a mechanism of drug action in which both topoisomerase and DNA participate in formation of the drug-binding site.