Recognition of O6MeG Lesions by MGMT and Mismatch Repair Proficiency may be a Prerequisite for Low-Dose Radiation Hypersensitivity
Recognition of O6MeG Lesions by MGMT and Mismatch Repair Proficiency may be a Prerequisite for Low-Dose Radiation Hypersensitivity
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DOI：
10.1667/rr1717.1
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发表时间：
2009-09
期刊：
影响因子：
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通讯作者：
Lynn M. Martin;B. Marples;M. Coffey;M. Lawler;D. Hollywood;L. Marignol
中科院分区：
文献类型：
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作者：
Lynn M. Martin;B. Marples;M. Coffey;M. Lawler;D. Hollywood;L. Marignol
低剂量超辐射敏感性（HRS）是一种现象，即细胞暴露于低于~ 0.5 Gy的辐射剂量下，相对于使用线性二次模型反推高剂量生存数据预测的细胞杀伤增加。虽然确切的机制仍有待阐明，但已记录了几种分子修复途径的参与。这些过程反过来也与细胞对o6 -甲基鸟嘌呤（O6MeG）病变的反应有关。我们提出了一个模型，其中低剂量细胞杀伤水平由DNA修复酶o6 -甲基鸟嘌呤甲基转移酶（MGMT）的复制前修复效率和DNA错配修复（MMR）系统的复制后修复效率决定。因此，我们假设细胞对低剂量辐射的反应取决于MGMT和MMR蛋白的表达状态。MMR （MSH2、MSH6、MLH1、PMS1、PMS2）和MGMT蛋白表达特征在正常（PWR1E、RWPE1）和恶性（22RV1、DU145、PC3）前列腺细胞系中被检测，并与克隆生存和细胞周期分析相关。PC3和RWPE1细胞（HRS阳性）与MGMT和MMR熟练程度相关，而HRS阴性细胞系缺乏至少一种（MGMT或MMR）蛋白的表达。MGMT失活对细胞存活无明显影响。这些结果表明，低剂量辐射产生的损伤可能与核磁共振相关的加工有关。
Abstract Low-dose hyper-radiosensitivity (HRS) is the phenomenon whereby cells exposed to radiation doses of less than ∼0.5 Gy exhibit increased cell killing relative to that predicted from back-extrapolating high-dose survival data using a linear-quadratic model. While the exact mechanism remains to be elucidated, the involvement of several molecular repair pathways has been documented. These processes in turn are also associated with the response of cells to O6-methylguanine (O6MeG) lesions. We propose a model in which the level of low-dose cell killing is determined by the efficiency of both pre-replicative repair by the DNA repair enzyme O6-methylguanine methyltransferase (MGMT) and post-replicative repair by the DNA mismatch repair (MMR) system. We therefore hypothesized that the response of cells to low doses of radiation is dependent on the expression status of MGMT and MMR proteins. MMR (MSH2, MSH6, MLH1, PMS1, PMS2) and MGMT protein expression signatures were determined in a panel of normal (PWR1E, RWPE1) and malignant (22RV1, DU145, PC3) prostate cell lines and correlated with clonogenic survival and cell cycle analysis. PC3 and RWPE1 cells (HRS positive) were associated with MGMT and MMR proficiency, whereas HRS negative cell lines lacked expression of at least one (MGMT or MMR) protein. MGMT inactivation had no significant effect on cell survival. These results indicate a possible role for MMR-dependent processing of damage produced by low doses of radiation.