The DNA polymerase Polκ plays a key role in translesion synthesis, an error-prone replication mechanism. Polκ is overexpressed in various tumor types. Here, we found that melanoma and lung and breast cancer cells experiencing stress from oncogene inhibition up-regulated the expression of Polκ and shifted its localization from the cytoplasm to the nucleus. This effect was phenocopied by inhibition of the kinase mTOR, by induction of ER stress, or by glucose deprivation. In unstressed cells, Polκ is continually transported out of the nucleus by exportin-1. Inhibiting exportin-1 or overexpressing Polκ increased the abundance of nuclear-localized Polκ, particularly in response to the BRAFV600E-targeted inhibitor vemurafenib, which decreased the cytotoxicity of the drug in BRAFV600E melanoma cells. These observations were analogous to how Escherichia coli encountering cell stress and nutrient deprivation can up-regulate and activate DinB/pol IV, the bacterial ortholog of Polκ, to induce mutagenesis that enables stress tolerance or escape. However, we found that the increased expression of Polκ was not excessively mutagenic, indicating that noncatalytic or other functions of Polκ could mediate its role in stress responses in mammalian cells. Repressing the expression or nuclear localization of Polκ might prevent drug resistance in some cancer cells.

中文翻译：

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通过致癌信号调节易错 DNA 聚合酶 Polκ 及其对耐药性的贡献。

DNA 聚合酶 Polκ 在易错复制机制跨损伤合成中起着关键作用。Polκ 在各种肿瘤类型中过表达。在这里，我们发现黑色素瘤、肺癌和乳腺癌细胞受到癌基因抑制的压力，上调了 Polκ 的表达，并将其定位从细胞质转移到细胞核。这种效应通过抑制激酶 mTOR、诱导内质网应激或葡萄糖剥夺来表型复制。在未受应激的细胞中，Polκ 通过 exportin-1 不断地转运出细胞核。抑制 exportin-1 或过表达 Polκ 增加了核定位 Polκ 的丰度，特别是对 BRAFV600E 靶向抑制剂威罗菲尼的反应，这降低了药物在 BRAFV600E 黑色素瘤细胞中的细胞毒性。这些观察结果类似于大肠杆菌遇到细胞应激和营养缺乏如何上调和激活 DinB/pol IV（Polκ 的细菌直系同源物）以诱导突变，从而实现应激耐受或逃避。然而，我们发现 Polκ 表达的增加并没有过度致突变，这表明 Polκ 的非催化或其他功能可以介导其在哺乳动物细胞应激反应中的作用。抑制 Polκ 的表达或核定位可能会阻止某些癌细胞的耐药性。表明 Polκ 的非催化或其他功能可以介导其在哺乳动物细胞应激反应中的作用。抑制 Polκ 的表达或核定位可能会阻止某些癌细胞的耐药性。表明 Polκ 的非催化或其他功能可以介导其在哺乳动物细胞应激反应中的作用。抑制 Polκ 的表达或核定位可能会阻止某些癌细胞的耐药性。