Evasion of early cellular response mechanisms following low level radiation-induced DNA damage
Evasion of early cellular response mechanisms following low level radiation-induced DNA damage
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DOI：
10.1074/jbc.m409600200
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发表时间：
2004-11-26
影响因子：
4.8
通讯作者：
DeWeese, TL
中科院分区：
文献类型：
--
作者：
Collis, SJ;Schwaninger, JM;DeWeese, TL
不能以高保真度修复的DNA损伤可导致染色体畸变或有丝分裂细胞死亡。到目前为止，还不清楚是什么因素控制了受到低水平DNA损伤的细胞的最终命运（即在突变或细胞死亡增加的风险下存活）。我们研究了DNA损伤是否可以以一定的水平和频率引入人类细胞，从而逃避DNA损伤细胞传感器的检测。为了实现这一点，我们将细胞暴露于以高剂量率（HDR）或连续低剂量率（LDR）递送的等效剂量的电离辐射。我们观察到与HDR暴露相比，LDR后癌细胞和正常人细胞中DNA损伤传感器共济失调-毛细血管扩张突变（ATM）及其下游靶组蛋白H2 A变体（H2 AX）的激活减少。这种DNA损伤信号的缺乏与LDR暴露后细胞杀伤量的增加有关。由LDR辐射增加的杀伤先前被称为“反向剂量率效应”，其效应没有明确的分子过程被描述。这些LDR效应可以通过ATM的预激活或通过抑制ATM功能在HDR处理的细胞中模拟来消除。这些数据首次证明，以降低的速率引入的DNA损伤不会激活DNA损伤传感器ATM，并且未能激活ATM相关的修复途径有助于增加连续LDR辐射暴露的致死率。这种失活可能反映了一种策略，通过这种策略，细胞可以避免由于易错DNA修复而积累突变，并且可能对致癌作用以及潜在的实体瘤临床治疗具有广泛的影响。
DNA damage that is not repaired with high fidelity can lead to chromosomal aberrations or mitotic cell death. To date, it is unclear what factors control the ultimate fate of a cell receiving low levels of DNA damage (i.e. survival at the risk of increased mutation or cell death). We investigated whether DNA damage could be introduced into human cells at a level and frequency that could evade detection by cellular sensors of DNA damage. To achieve this, we exposed cells to equivalent doses of ionizing radiation delivered at either a high dose rate (HDR) or a continuous low dose rate (LDR). We observed reduced activation of the DNA damage sensor ataxia-telangiectasia mutated (ATM) and its downstream target histone H2A variant (H2AX) following LDR compared with HDR exposures in both cancerous and normal human cells. This lack of DNA damage signaling was associated with increased amounts of cell killing following LDR exposures. Increased killing by LDR radiation has been previously termed the "inverse dose rate effect," an effect for which no clear molecular processes have been described. These LDR effects could be abrogated by the preactivation of ATM or simulated in HDR-treated cells by inhibiting ATM function. These data are the first to demonstrate that DNA damage introduced at a reduced rate does not activate the DNA damage sensor ATM and that failure to activate ATM-associated repair pathways contributes to the increased lethality of continuous LDR radiation exposures. This inactivation may reflect one strategy by which cells avoid accumulating mutations as a result of error-prone DNA repair and may have a broad range of implications for carcinogenesis and, potentially, the clinical treatment of solid tumors.