ATM is required for the cellular response to thymidine induced replication fork stress
ATM is required for the cellular response to thymidine induced replication fork stress
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DOI：
10.1093/hmg/ddh316
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发表时间：
2004-12-01
影响因子：
3.5
通讯作者：
Meuth, M
中科院分区：
文献类型：
--
作者：
Bolderson, E;Scorah, J;Meuth, M
遗传上不同的检查点，激活作为一个结果，无论是DNA复制逮捕或电离辐射诱导的DNA损伤，DNA修复反应整合到细胞周期程序。共济失调-毛细血管扩张突变（ATM）蛋白激酶响应DNA双链断裂而阻断细胞周期进程，而相关的ATR对于维持DNA复制装置的完整性很重要。在这里，我们表明，胸苷，它通过耗尽细胞池的dCTP，减缓复制叉的进展，诱导一种新的DNA损伤反应，独特的，依赖于ATM和ATR。胸苷诱导ATM介导的Chk 2和NBS 1磷酸化以及ATM非依赖性的Chk 1和SMC 1磷酸化。AT细胞暴露于胸苷显示活力下降，未能诱导同源重组修复（HRR）。两者合计，我们的研究结果表明ATM在HRR介导的救援复制叉受损胸苷治疗。
Genetically distinct checkpoints, activated as a consequence of either DNA replication arrest or ionizing radiation-induced DNA damage, integrate DNA repair responses into the cell cycle programme. The ataxia-telangiectasia mutated (ATM) protein kinase blocks cell cycle progression in response to DNA double strand breaks, whereas the related ATR is important in maintaining the integrity of the DNA replication apparatus. Here, we show that thymidine, which slows the progression of replication forks by depleting cellular pools of dCTP, induces a novel DNA damage response that, uniquely, depends on both ATM and ATR. Thymidine induces ATM-mediated phosphorylation of Chk2 and NBS1 and an ATM-independent phosphorylation of Chk1 and SMC1. AT cells exposed to thymidine showed decreased viability and failed to induce homologous recombination repair (HRR). Taken together, our results implicate ATM in the HRR-mediated rescue of replication forks impaired by thymidine treatment.