Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays.
Functional characterization of polymorphisms in DNA repair genes using cytogenetic challenge assays.
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DOI：
10.1289/ehp.6632
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发表时间：
2003-11
影响因子：
10.4
通讯作者：
Sierra-Torres, Carlos H
中科院分区：
文献类型：
--
作者：
Au, William W;Salama, Salama A;Sierra-Torres, Carlos H
理解多态性DNA修复基因在环境癌症中的作用的一个主要障碍是变异基因型的功能在很大程度上是未知的。使用我们的细胞遗传学激发试验，我们进行了一项调查，以解决缺陷。使用X射线或紫外线（UV）光，我们照射血液淋巴细胞从80个非吸烟供体挑战细胞修复诱导的DNA损伤，我们分析了染色体畸变（CA）的表达特异性的诱导剂。我们有基因型多态性DNA修复基因优先参与碱基切除修复（BER）和核苷酸切除修复（NER）活动（XRCC 1，XRCC 3，APE 1，XPD）相应的X射线和紫外线诱导的DNA损伤的修复，分别。我们预计，由于多态性导致的特异性DNA修复途径的缺陷将导致特异性CA的相应增加。根据我们的数据，与相应的纯合野生型相比，XRCC 1 399 Gln和XRCC 3 241 Met与染色体缺失的显著增加相关（分别为18.27 ± 1.1 vs 14.79 ± 1.2和18.22 ± 0.99 vs 14.20 ± 1.39）;与野生型相比，XPD 312 Asn和XPD 751 Gln与染色单体断裂的显著增加相关（分别为16.09 ± 1.36 vs 11.41 ± 0.98和16.87 ± 1.27 vs 10.54 ± 0.87），p < 0.05。结果表明，XRCC 1 399 Gln和XRCC 3 241 Met在BER上存在显著缺陷，XPD 312 Asn和XPD 751 Gln在NER上存在显著缺陷。此外，变异基因型之间存在显着相互作用，两种不同修复途径的重叠有限。
A major barrier to understanding the role of polymorphic DNA repair genes for environmental cancer is that the functions of variant genotypes are largely unknown. Using our cytogenetic challenge assays, we conducted an investigation to address the deficiency. Using X-rays or ultraviolet (UV) light, we irradiated blood lymphocytes from 80 nonsmoking donors to challenge the cells to repair the induced DNA damage, and we analyzed expression of chromosome aberrations (CA) specific to the inducing agents. We have genotyped polymorphic DNA repair genes preferentially involved with base excision repair (BER) and nucleotide excision repair (NER) activities (XRCC1, XRCC3, APE1, XPD) corresponding to the repair of X-ray- and UV light-induced DNA damage, respectively. We expected that defects in specific DNA repair pathways due to polymorphisms would cause corresponding increases of specific CA. From our data, XRCC1 399Gln and XRCC3 241Met were associated with significant increases in chromosome deletions compared with the corresponding homozygous wild types (18.27 1.1 vs 14.79 1.2 and 18.22 0.99 vs 14.20 1.39, respectively); XPD 312Asn and XPD 751Gln were associated with significant increases in chromatid breaks compared with wild types (16.09 1.36 vs 11.41 0.98 and 16.87 1.27 vs 10.54 0.87, respectively), p < 0.05. The data indicate that XRCC1 399Gln and XRCC3 241Met are significantly defective in BER, and the XPD 312Asn and XPD 751Gln are significantly defective in NER. In addition, the variant genotypes interact significantly, with limited overlap of the two different repair pathways.