Mutat Res. 2013 Nov-Dec;751-752:1-7. doi: 10.1016/j.mrfmmm.2013.10.002.
Thioredoxin-1 (Trx1) is an antioxidant enzyme with a protective role in the removal of oxidative stress. We investigated the mechanism by which the redox modulator Trx1 affects base excision repair (BER) activity to understand the protective role of Trx1. We constructed a Trx1 knockdown system to demonstrate the specific mechanism of Trx1 shRNA cells compared with that in the wild type cells, leading to increased cellular susceptibility to a sublethal dose of BER-inducible toxicant, nitrosomethylurea (NMU). In addition, we observed a modulatory role of Trx1 in the BER pathway via the p53 downstream gene, growth arrest, and DNA-damage-inducible protein 45 α (Gadd45a). The protein level and function of p53, a Trx1 downstream gene, coincidently decreased in the Trx1 shRNA cells. Futhermore, Trx1 shRNA cells showed decreased Gadd45a expression and interaction of Gadd45a with apurinic/apyrimidinic endonuclease 1 (APE1) as well as APE activity. In conclusion, Trx1 might cooperate in the control of APE1 function by modulating the p53-mediated BER via the protein-protein interaction between Gadd45a and APE1, providing insight into the novel role of redox factor Trx1 in modulation of BER.
硫氧还蛋白-1（Trx1）是一种具有抗氧化作用的酶，可清除氧化应激。我们研究了氧化还原调节剂 Trx1 影响碱基切除修复（BER）活性的机制，以了解 Trx1 的保护作用。我们构建了 Trx1 敲低系统，以证明 Trx1 shRNA 细胞与野生型细胞相比的特定机制，导致细胞对 BER 诱导的毒性物质亚致死剂量的敏感性增加，如亚硝甲基脲（NMU）。此外，我们观察到 Trx1 通过 p53 下游基因生长停滞和 DNA 损伤诱导蛋白 45α（Gadd45a）在 BER 途径中的调节作用。Trx1 下游基因 p53 的蛋白水平和功能在 Trx1 shRNA 细胞中同时降低。此外，Trx1 shRNA 细胞显示出 Gadd45a 表达减少以及 Gadd45a 与无嘌呤/无嘧啶内切核酸酶 1（APE1）以及 APE 活性的相互作用减少。总之，Trx1 可能通过 Gadd45a 与 APE1 之间的蛋白-蛋白相互作用调节 p53 介导的 BER，从而协同控制 APE1 功能，为氧化还原因子 Trx1 在 BER 调节中的新作用提供了深入了解。
