Isolation of full-length ATM cDNA and correction of the ataxia-telangiectasia cellular phenotype
Isolation of full-length ATM cDNA and correction of the ataxia-telangiectasia cellular phenotype
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DOI：
10.1073/pnas.94.15.8021
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发表时间：
1997-07-22
影响因子：
11.1
通讯作者：
Lavin, MF
中科院分区：
文献类型：
--
作者：
Zhang, N;Chen, P;Lavin, MF
ATM是近年来通过定位克隆技术发现的一个在人类遗传性疾病共济失调-毛细血管扩张症（ataxia-telangiectasia，A-T）中发生突变的基因，属于磷脂酰肌醇-3-激酶超家族，该家族中的一些蛋白激酶在细胞周期调控和辐射信号转导中起重要作用。据我们所知，我们在此首次描述了ATM全长cDNA的克隆和通过用该cDNA转染来校正A-T细胞的放射敏感性表型的多个方面。ATM cDNA在A-T细胞中的过表达增强了这些细胞响应于辐射暴露的存活，减少了辐射诱导的染色体畸变，减少了放射抗性DNA合成，并部分纠正了细胞周期检查点缺陷和应激激活蛋白激酶的诱导。A-T细胞中缺陷的这种纠正提供了ATM蛋白的效应子功能多样性的进一步证据，并提出了基因治疗的可能方法。
A gene mutated in the human genetic disorder ataxia-telangiectasia (A-T), ATM, was recently identified by positional cloning, ATM is a member of the phosphatidyl-inositol-3-kinase superfamily, some of which are protein kinases and appear to have important roles in cell cycle control and radiation signal transduction. We describe herein, to our knowledge, for the first time, the cloning of a full-length cDNA for ATM and correction of multiple aspects of the radio-sensitive phenotype of A-T cells by transfection with this cDNA, Overexpression of ATM cDNA in A-T cells enhanced the survival of these cells in response to radiation exposure, decreased radiation-induced chromosome aberrations, reduced radio-resistant DNA synthesis, and partially corrected defective cell cycle checkpoints and induction of stress-activated protein kinase. This correction of the defects in A-T cells provides further evidence of the multiplicity of effector functions of the ATM protein and suggests possible approaches to gene therapy.