Research ArticleDRUG RESISTANCE

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

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Science Signaling  28 Apr 2020:
Vol. 13, Issue 629, eaau1453
DOI: 10.1126/scisignal.aau1453

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Polκ manages stress

DNA polymerase κ (Polκ) is a traditionally error-prone polymerase that is overexpressed in some tumors. Temprine et al. found that Polκ facilitates tumor cell survival in response to oncogenic mutations (such as those in the kinases BRAF or EGFR), targeted kinase inhibition, oxidative stress, or starvation. These cellular stresses shifted Polκ from its largely cytoplasmic distribution to a nuclear localization in various tumor cell types, but without increasing mutagenesis. Knocking down Polκ decreased, whereas blocking its nuclear exit increased, the resistance of melanoma cells to the BRAF-targeted inhibitor vemurafenib, suggesting that targeting Polκ may reduce drug resistance in cancer patients.

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 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.

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