Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance
Mutations in the proofreading domains of the replicative DNA polymerases pol{delta} and pol{varepsilon} are associated with elevated mutation rates in cancer, but the roles of other DNA polymerases in tumorigenesis remain poorly understood. One such polymerase is pol{kappa}, an enzyme that plays a key role in translesion synthesis. pol{kappa} contributes to cell survival in the face of DNA damage but can be highly mutagenic due to lack of a proofreading domain. Here we demonstrate that cancer cells under stress from oncogene inhibition upregulate pol{kappa} and shift its localization from the cytoplasm to the nucleus. This effect can be phenocopied by mTOR inhibition or glucose deprivation, analogous to stress-induced mutagenesis in E. coli whereby cell stress and nutrient deprivation can upregulate and activate DinB/pol IV (the bacterial orthologue of pol{kappa}). We find that cancer cells normally sequester pol{kappa} in the cytoplasm via exportin-1, likely to prevent excess mutagenesis from the error-prone nature of this polymerase. Subverting the normal nuclear-cytoplasmic shuttling by forced overexpression of nuclear pol{kappa} increases resistance of melanoma cells to the BRAFV600E inhibitor vemurafenib. This data suggests a mechanism by which cancer cells regulate the expression and localization of the error-prone polymerase pol{kappa}, abrogation of which can contribute to drug resistance.\n\nOne Sentence Summary: Cancer cells under stress from oncogene or mTOR inhibition dysregulate the error-prone DNA polymerase pol{kappa}, which contributes to drug resistance in melanoma cells.