A combination of genetic suppressor elements produces resistance to drugs inhibiting DNA replication.

Somatic Cell and Molecular Genetics Pub Date : 1999-01-01 DOI:10.1023/b:scam.0000007136.49230.b3

V V Levenson, E Lausch, D J Kirschling, E V Broude, I A Davidovich, S Libants, V Fedosova, I B Roninson

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引用次数: 27

Abstract

Many anticancer drugs inhibit DNA replication. To investigate the mechanism of permanent growth inhibition after transient arrest of DNA replication, we selected genetic suppressor elements (GSEs) conferring resistance to replication inhibitor Aphidicolin. Starting from a retroviral expression library carrying normalized fragments of human cell cDNA, we isolated four GSEs which, when introduced as a combination, produced resistance to Aphidicolin, doxorubicin and hydroxyurea in HT1080 fibrosarcoma cells. The four GSEs were derived from ORFX bromodomain protein gene, WIZ zinc finger protein gene, the gene for subunit 3 of cytochrome c oxidase, and the gene corresponding to an EST with no known function. A cell line carrying all four GSEs showed a weaker induction of the senescence-like phenotype after treatment with Aphidicolin or doxorubicin; the resistance of this cell line was not associated with decreased doxorubicin accumulation. These results indicate that combined effects of GSEs derived from these four genes increase cellular resistance to replication-inhibiting drugs, possibly by inhibiting drug-induced senescence.

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基因抑制因子的组合对抑制DNA复制的药物产生耐药性。

许多抗癌药物抑制DNA复制。为了研究DNA复制短暂停止后永久生长抑制的机制，我们选择了对复制抑制剂Aphidicolin具有抗性的基因抑制元件(GSEs)。从携带规范化人类细胞cDNA片段的逆转录病毒表达文库开始，我们分离出四种gse，当它们作为组合引入HT1080纤维肉瘤细胞时，产生了对阿飞霉素、阿霉素和羟基脲的抗性。这4个gse分别来源于细胞色素c氧化酶3亚基基因ORFX溴结构域基因、WIZ锌指蛋白基因和一个功能未知的EST对应基因。携带所有四种GSEs的细胞系在阿霉素或阿霉素处理后显示较弱的衰老样表型诱导;该细胞系的耐药性与阿霉素积累的减少无关。这些结果表明，来自这四个基因的GSEs的联合作用可能通过抑制药物诱导的衰老来增强细胞对复制抑制药物的抗性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Somatic Cell and Molecular Genetics

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