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

ABSTRACT: The DNA polymerase Pol? plays a key role in translesion synthesis, an error-prone replication mechanism. Pol? 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? 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? is continually transported out of the nucleus by exportin-1. Inhibiting exportin-1 or overexpressing Pol? increased the abundance of nuclear-localized Pol?, 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 Pol?, to induce mutagenesis that enables stress tolerance or escape. However, we found that the increased expression of Pol? was not excessively mutagenic, indicating that noncatalytic or other functions of Pol? could mediate its role in stress responses in mammalian cells. Repressing the expression or nuclear localization of Pol? might prevent drug resistance in some cancer cells.

SUBMITTER: Temprine K 

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

REPOSITORIES: biostudies-literature