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

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.

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