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首页> 外文期刊>Gene Therapy and Molecular Biology >Caffeine affects the level of gene repair inmammalian cells; implications for a role of DNAreplication in the correction of single base mutations
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Caffeine affects the level of gene repair inmammalian cells; implications for a role of DNAreplication in the correction of single base mutations

机译：咖啡因影响哺乳动物细胞中基因修复的水平; DNA复制在纠正单碱基突变中的作用的意义

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Single stranded DNA oligonucleotides have been used to direct the correction of point mutations in mammalian cells. The introduction of a single-stranded oligonucleotide sets in motion a cascade of events that eventually leads to a stalling of DNA replication forks, which enables the oligo-mediated correction event to occur more readily. This is due to the fact that cells in S phase are more amenable to gene correction and a role for DNA replication in the gene repair reaction has been established. Here, we develop a mechanistic view of how cell cycle arrest might influence the gene repair reaction using the radiosensitizing agent, caffeine, as a tool. First, we demonstrate that ATM activation is enhanced and sustained by caffeine then we identify multiple roles for caffeine in the modulation of the gene repair reaction. Finally, we show that caffeine-treated cells retain the oligonucleotides for longer periods of time, perhaps enabling the oligo to assimilate into the target site more readily. Our results may define ATM activation upon the entry of the oligonucleotide as a likely block to the proliferation of corrected cells.
机译：单链DNA寡核苷酸已被用于指导哺乳动物细胞中点突变的校正。单链寡核苷酸的引入推动了一系列事件的进行，这些事件最终导致DNA复制叉的停滞，这使得寡核苷酸介导的校正事件更容易发生。这是由于以下事实：处于S期的细胞更易于进行基因校正，并且已经确立了DNA复制在基因修复反应中的作用。在这里，我们用放射增敏剂咖啡因作为一种工具，研究了细胞周期停滞如何影响基因修复反应的机理。首先，我们证明咖啡因可增强和维持ATM激活，然后我们确定咖啡因在基因修复反应调节中的多种作用。最后，我们显示了咖啡因处理的细胞可以长时间保留寡核苷酸，这可能使寡核苷酸更容易同化到目标位点。我们的结果可能将寡核苷酸进入时的ATM激活定义为可能阻止了校正细胞的增殖。

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