Development of APE1 enzymatic DNA repair assays: low APE1 activity is associated with increase lung cancer risk.
Development of APE1 enzymatic DNA repair assays: low APE1 activity is associated with increase lung cancer risk.
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DOI：
10.1093/carcin/bgv082
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发表时间：
2015-09
期刊：
影响因子：
4.7
通讯作者：
Livneh Z
中科院分区：
文献类型：
--
作者：
Sevilya Z;Leitner-Dagan Y;Pinchev M;Kremer R;Elinger D;Lejbkowicz F;Rennert HS;Freedman LS;Rennert G;Paz-Elizur T;Livneh Z
我们开发了基于放射性和基于荧光的DNA修复酶APE1的分析方法，并表明其活性降低与肺癌风险增加有关。这表明“DNA修复不良”而不是“运气不佳”与癌症病因学有关。DNA修复在消除DNA损伤和最大限度减少突变方面的关键作用使其成为癌症风险评估和预防的一个有吸引力的目标。在这里，我们描述了一种可靠的脱嘌呤/脱嘧啶(AP)核酸内切酶1(APE1；APEX1)的测定方法，APE1；APEX1是参与DNA氧化损伤修复的关键酶。外周血单个核细胞蛋白提取物中APE1DNA修复酶活性的测定采用基于放射性的分析方法，并用条件Logistic回归方法确定其与肺癌的相关性。病例组APE1酶活性平均值为691[95%可信区间(CI)=655~727]单位/ng蛋白质，显著低于对照组(平均值=793，95%CI=751~834单位/ng蛋白质，P=0.0006)。肺癌患者APE1活性降低1 SD(211个单位)的调整优势比为2(95%CI=1.3~3.1；P=0.002)。基于放射性和基于荧光的检测结果的比较表明，这两种检测方法是等效的，表明荧光标记没有干扰。APE1Asp148Glu SNP与APE1酶活性无关，也与肺癌风险无关。综上所述，我们的结果表明，APE1活性低与肺癌风险有关，这与癌症病因学中涉及“糟糕的DNA修复”而不是“糟糕的运气”的假设是一致的。这样的检测与额外的DNA修复生物标记物一起，可能对肺癌和其他癌症的风险评估以及选择接受早期检测技术(如低剂量CT)的个体有用。
We developed radioactivity-based and fluorescence-based assays for the DNA repair enzyme APE1 and showed that its decreased activity is associated with increased lung cancer risk. This suggests that ‘bad DNA repair’ rather than ‘bad luck’ is involved in cancer etiology. The key role of DNA repair in removing DNA damage and minimizing mutations makes it an attractive target for cancer risk assessment and prevention. Here we describe the development of a robust assay for apurinic/apyrimidinic (AP) endonuclease 1 (APE1; APEX1), an essential enzyme involved in the repair of oxidative DNA damage. APE1 DNA repair enzymatic activity was measured in peripheral blood mononuclear cell protein extracts using a radioactivity-based assay, and its association with lung cancer was determined using conditional logistic regression with specimens from a population-based case–control study with 96 lung cancer cases and 96 matched control subjects. The mean APE1 enzyme activity in case patients was 691 [95% confidence interval (CI) = 655–727] units/ng protein, significantly lower than in control subjects (mean = 793, 95% CI = 751–834 units/ng protein, P = 0.0006). The adjusted odds ratio for lung cancer associated with 1 SD (211 units) decrease in APE1 activity was 2.0 (95% CI = 1.3–3.1; P = 0.002). Comparison of radioactivity- and fluorescence-based assays showed that the two are equivalent, indicating no interference by the fluorescent tag. The APE1Asp148Glu SNP was associated neither with APE1 enzyme activity nor with lung cancer risk. Taken together, our results indicate that low APE1 activity is associated with lung cancer risk, consistent with the hypothesis that ‘bad DNA repair’, rather than ‘bad luck’, is involved in cancer etiology. Such assays may be useful, along with additional DNA repair biomarkers, for risk assessment of lung cancer and perhaps other cancers, and for selecting individuals to undergo early detection techniques such as low-dose CT.