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

Autor:	Temprine K; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Campbell NR; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.; Tri-Institutional M.D./Ph.D. Program, Weill Cornell Medical College, New York, NY 10065, USA., Huang R; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Langdon EM; University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA., Simon-Vermot T; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Mehta K; Division of General Internal Medicine, Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA., Clapp A; University of Chicago, Chicago, IL 60637, USA., Chipman M; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., White RM; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. whiter@mskcc.org.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2020 Apr 28; Vol. 13 (629). Date of Electronic Publication: 2020 Apr 28.
DOI:	10.1126/scisignal.aau1453
Abstrakt:	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 V600E 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. (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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