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首页> 外文期刊>Mutation research-Fundamental and Molecular Mechanisms of Mutagenesis >Activation of DNA damage repair pathways in response to nitrogen mustard-induced DNA damage and toxicity in skin keratinocytes
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Activation of DNA damage repair pathways in response to nitrogen mustard-induced DNA damage and toxicity in skin keratinocytes

机译：响应氮芥末诱导的DNA损伤和皮肤角蛋白细胞毒性的DNA损伤修复途径的激活

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Nitrogen mustard (NM), a structural analog of chemical warfare agent sulfur mustard (SM), forms adducts and crosslinks with DNA, RNA and proteins. Here we studied the mechanism of NM-induced skin toxicity in response to double strand breaks (DSBs) resulting in cell cycle arrest to facilitate DNA repair, as a model for developing countermeasures against vesicant-induced skin injuries. NM exposure of mouse epidermal JB6 cells decreased cell growth and caused S-phase arrest. Consistent with these biological outcomes, NM exposure also increased comet tail extent moment and the levels of DNA DSB repair molecules phospho H2A.X Ser139 and p53 Ser15 indicating NM-induced DNA DSBs. Since DNA DSB repair occurs via non homologous end joining pathway (NHEJ) or homologous recombination repair (HRR) pathways, next we studied these two pathways and noted their activation as defined by an increase in phospho- and total DNA-PK levels, and the formation of Rad51 foci, respectively. To further analyze the role of these pathways in the cellular response to NM-induced cytotoxicity, NHEJ and HRR were inhibited by DNA-PK inhibitor NU7026 and Rad51 inhibitor BO2, respectively. Inhibition of NHEJ did not sensitize cells to NM-induced decrease in cell growth and cell cycle arrest. However, inhibition of the HRR pathway caused a significant increase in cell death, and prolonged G2M arrest following NM exposure. Together, our findings, indicating that HRR is the key pathway involved in the repair of NM-induced DNA DSBs, could be useful in developing new therapeutic strategies against vesicant-induced skin injury.
机译：氮芥子（NM），化学战争硫芥末（SM）的结构类似物，与DNA，RNA和蛋白质的形式加合物和交联。在这里，我们研究了NM诱导的皮肤毒性的机制，响应双链断裂（DSB），导致细胞周期停滞以促进DNA修复，作为对脓疱病引起的皮肤损伤的对策的模型。小鼠表皮JB6细胞的NM暴露细胞生长降低并引起S相阻滞。与这些生物学结果一致，NM曝光也增加了彗星尾部矩和DNA DSB修复分子磷酸H2A.x Ser139和P53 Ser15的水平，表明NM诱导的DNA DNA DNA。由于DNA DSB修复通过非同源末端连接途径（NHEJ）或同源重组修复（HRR）途径，因此我们研究了这两种途径，并注意到它们通过磷酸和总DNA-PK水平的增加而定义的活化。分别形成Rad51焦点。为了进一步分析这些途径在对NM诱导的细胞毒性对细胞响应中的作用，DNA-PK抑制剂Nu7026和Rad51抑制剂Bo2分别抑制NHEJ和HRR。 NHEJ的抑制不敏感细胞对NM诱导的细胞生长和细胞循环骤停的降低。然而，对HRR途径的抑制导致细胞死亡的显着增加，并且在NM暴露后延长G2M捕获。我们的研究结果在一起，表明HRR是涉及NM诱导的DNA DNA DNA DNA DNAB的关键途径，可用于开发新的菌脓疱病皮肤损伤的新治疗策略。

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