Regulation of the error-prone DNA polymerase Polκ by oncogenic signaling and its contribution to drug resistance

The DNA polymerase Pol kappa plays a key role in translesion synthesis, an error-prone replication mechanism. Pol kappa 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 Pol kappa 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, Pol kappa is continually transported out of the nucleus by exportin-1. Inhibiting exportin-1 or overexpressing Pol kappa increased the abundance of nuclear-localized Pol kappa, particularly in response to the BRAF(V600E)-targeted inhibitor vemurafenib, which decreased the cytotoxicity of the drug in BRAF(V600E) melanoma cells. These observations were analogous to how Escherichia coil encountering cell stress and nutrient deprivation can up-regulate and activate DinB/pol IV, the bacterial ortholog of Pol kappa, to induce mutagenesis that enables stress tolerance or escape. However, we found that the increased expression of Pol kappa was not excessively mutagenic, indicating that noncatalytic or other functions of Pol kappa could mediate its role in stress responses in mammalian cells. Repressing the expression or nuclear localization of Pol kappa might prevent drug resistance in some cancer cells.