Maria Sklodowska-Curie Memorial Cancer Center, Gliwice, Poland.
Mutat Res. 2013 Jul 4;755(1):42-8. doi: 10.1016/j.mrgentox.2013.05.002. Epub 2013 May 10.
Polymorphism of genes coding for proteins which participate in DNA repair may predispose to or protect against development of cancer. Here we studied how common polymorphisms of the genes XPD (Asp312Asn and Lys751Gln), APE1 (Asp148Glu), XRCC1 (Arg399Gln), and NBS1 (Gln185Glu) influence DNA repair and other responses after X-irradiation of lymphocytes from colon carcinoma patients. Genotypes with polymorphic Asp148Glu APE1 and Asp312Asn XPD showed a significantly higher level of DNA incisions immediately after irradiation (p=0.049 and p=0.047 respectively) and Asp312Asn XPD showed a significantly increased capacity to repair of DNA strand breaks as measured 180min after irradiation by comet assays (p=0.004). In contrast, it was the wild type XRCC1 genotype which was associated with a lower level of DNA breaks after irradiation (p=0.014, at 180min after irradiation) and polymorphism of NBS1 did not correlate with any changes in DNA breaks or repair capacity. To confirm the influence of XPD polymorphism on repair, we established stably-transfected HCT116 (colon carcinoma) cells which over-expressed the wild-type or variant XPD protein. Cells over-expressing Asp312Asn XPD showed a higher level of DNA breaks shortly after irradiation and more efficient repair than cells over-expressing the wild-type gene XPD312Asp, and an earlier inhibition of cell cycle transit but faster recovery from this inhibition. Polymorphisms in DNA repair genes therefore influence not only DNA repair capacity but also cell proliferation, and may serve as markers of individual repair capacity and susceptibility to environmental and occupational carcinogens.
基因编码参与 DNA 修复的蛋白质的多态性可能导致癌症的易感性或保护作用。在这里，我们研究了 XPD（Asp312Asn 和 Lys751Gln）、APE1（Asp148Glu）、XRCC1（Arg399Gln）和 NBS1（Gln185Glu）基因的常见多态性如何影响结肠癌患者淋巴细胞经 X 射线照射后的 DNA 修复和其他反应。具有多态性 Asp148Glu APE1 和 Asp312Asn XPD 的基因型在照射后立即表现出更高水平的 DNA 切口（分别为 p=0.049 和 p=0.047），并且 XPD 的 Asp312Asn 显示出在照射后 180 分钟通过彗星试验测量的 DNA 链断裂修复能力显著增加（p=0.004）。相比之下，野生型 XRCC1 基因型与照射后 DNA 断裂水平较低相关（p=0.014，照射后 180 分钟），NBS1 多态性与 DNA 断裂或修复能力的任何变化均无关。为了确认 XPD 多态性对修复的影响，我们建立了稳定转染的 HCT116（结肠癌）细胞，这些细胞过表达野生型或变体 XPD 蛋白。过表达 Asp312Asn XPD 的细胞在照射后不久表现出更高水平的 DNA 断裂，并比过表达野生型 XPD312Asp 的细胞具有更高的修复效率，并且更早地抑制细胞周期转移，但从这种抑制中更快地恢复。因此，DNA 修复基因的多态性不仅影响 DNA 修复能力，还影响细胞增殖，并且可以作为个体修复能力和对环境和职业致癌物易感性的标志物。
