Bolderson Emma, Scorah Jennifer, Helleday Thomas, Smythe Carl, Meuth Mark
Institute for Cancer Studies, School of Medicine, University of Sheffield, UK.
Hum Mol Genet. 2004 Dec 1;13(23):2937-45. doi: 10.1093/hmg/ddh316. Epub 2004 Sep 30.
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.
由于DNA复制停滞或电离辐射诱导的DNA损伤而激活的基因上不同的检查点，将DNA修复反应整合到细胞周期程序中。共济失调毛细血管扩张症突变（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在维持DNA复制装置的完整性方面很重要。在这里，我们表明，胸苷通过耗尽细胞内的dCTP池来减缓复制叉的进程，从而诱导一种新的DNA损伤反应，这种反应独特地依赖于ATM和ATR。胸苷诱导Chk2和NBS1的ATM介导的磷酸化以及Chk1和SMC1的不依赖于ATM的磷酸化。暴露于胸苷的AT细胞显示活力下降，并且未能诱导同源重组修复（HRR）。综上所述，我们的结果表明ATM参与了由HRR介导的对胸苷处理受损的复制叉的挽救。
