期刊
SCIENCE SIGNALING
卷 13, 期 629, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aau1453
关键词
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资金
- Ruth L. Kirschstein Predoctoral Individual (F31) National Research Service Award [5F31CA200341-03]
- Ruth L. Kirschstein M.D./Ph.D. Predoctoral Individual (F30) National Research Service Award [F30CA220954]
- Medical Scientist Training Program Grant [T32GM007739]
- NIH Director's New Innovator Award [DP2CA186572]
- Mentored Clinical Scientist Research Career Development Award [K08AR055368]
- Melanoma Research Alliance
- Pershing Square Sohn Foundation
- Alan and Sandra Gerry Metastasis Research Initiative at the Memorial Sloan Kettering Cancer Center
- Harry J. Lloyd Foundation and Consano
The DNA polymerase Pol kappa plays a key role in translesion synthesis, an error-prone replication mechanism. Pol kappa 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 kappa 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 kappa is continually transported out of the nucleus by exportin-1. Inhibiting exportin-1 or overexpressing Pol kappa increased the abundance of nuclear-localized Pol kappa, particularly in response to the BRAF(V600E)-targeted inhibitor vemurafenib, which decreased the cytotoxicity of the drug in BRAF(V600E) melanoma cells. These observations were analogous to how Escherichia coil encountering cell stress and nutrient deprivation can up-regulate and activate DinB/pol IV, the bacterial ortholog of Pol kappa, to induce mutagenesis that enables stress tolerance or escape. However, we found that the increased expression of Pol kappa was not excessively mutagenic, indicating that noncatalytic or other functions of Pol kappa could mediate its role in stress responses in mammalian cells. Repressing the expression or nuclear localization of Pol kappa might prevent drug resistance in some cancer cells.
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