Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
Nucleic Acids Res. 2010 Jun;38(10):3245-51. doi: 10.1093/nar/gkq069. Epub 2010 Feb 11.
Non-homologous end-joining (NHEJ) and homologous recombination repair (HRR), contribute to repair ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Mre11 binding to DNA is the first step for activating HRR and Ku binding to DNA is the first step for initiating NHEJ. High-linear energy transfer (LET) IR (such as high energy charged particles) killing more cells at the same dose as compared with low-LET IR (such as X or gamma rays) is due to inefficient NHEJ. However, these phenomena have not been demonstrated at the animal level and the mechanism by which high-LET IR does not affect the efficiency of HRR remains unclear. In this study, we showed that although wild-type and HRR-deficient mice or DT40 cells are more sensitive to high-LET IR than to low-LET IR, NHEJ deficient mice or DT40 cells are equally sensitive to high- and low-LET IR. We also showed that Mre11 and Ku respond differently to shorter DNA fragments in vitro and to the DNA from high-LET irradiated cells in vivo. These findings provide strong evidence that the different DNA DSB binding properties of Mre11 and Ku determine the different efficiencies of HRR and NHEJ to repair high-LET radiation induced DSBs.
非同源末端连接 (NHEJ) 和同源重组修复 (HRR) 有助于修复电离辐射 (IR) 诱导的 DNA 双链断裂 (DSB)。Mre11 与 DNA 的结合是激活 HRR 的第一步，而 Ku 与 DNA 的结合是启动 NHEJ 的第一步。高线性能量转移 (LET) 的 IR（如高能带电粒子）与低 LET 的 IR（如 X 射线或伽马射线）相比，在相同剂量下杀死更多的细胞，这是由于 NHEJ 效率低下。然而，这些现象尚未在动物水平上得到证明，高 LET 的 IR 不影响 HRR 效率的机制仍不清楚。在这项研究中，我们表明，尽管野生型和 HRR 缺陷型小鼠或 DT40 细胞对高 LET 的 IR 比低 LET 的 IR 更敏感，但 NHEJ 缺陷型小鼠或 DT40 细胞对高 LET 和低 LET 的 IR 同样敏感。我们还表明，Mre11 和 Ku 在体外对较短的 DNA 片段以及对高 LET 照射细胞的体内 DNA 的反应不同。这些发现为 Mre11 和 Ku 对不同的 DNA DSB 结合特性决定 HRR 和 NHEJ 修复高 LET 辐射诱导的 DSB 的不同效率提供了有力证据。
