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

ABSTRACT: 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 BRAF^V600E-targeted inhibitor vemurafenib, which decreased the cytotoxicity of the drug in BRAF^V

SUBMITTER: Temprine K 

PROVIDER: S-EPMC7428051 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature