PT  - JOURNAL ARTICLE
AU  - Kelsey Temprine
AU  - Erin M Langdon
AU  - Krisha Mehta
AU  - Averill Clapp
AU  - Richard M White
TI  - Regulation of the error-prone DNA polymerase polκ by oncogenic signaling and its contribution to drug resistance
AID  - 10.1101/316729
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 316729
4099  - http://biorxiv.org/content/early/2018/05/11/316729.short
4100  - http://biorxiv.org/content/early/2018/05/11/316729.full
AB  - Mutations in the proofreading domains of the replicative DNA polymerases polδ and polε are associated with elevated mutation rates in cancer, but the roles of other DNA polymerases in tumorigenesis remain poorly understood. One such polymerase is polκ, an enzyme that plays a key role in translesion synthesis. polκ contributes to cell survival in the face of DNA damage but can be highly mutagenic due to lack of a proofreading domain. Here we demonstrate that cancer cells under stress from oncogene inhibition upregulate polκ and shift its localization from the cytoplasm to the nucleus. This effect can be phenocopied by mTOR inhibition or glucose deprivation, analogous to stress-induced mutagenesis in E. coli whereby cell stress and nutrient deprivation can upregulate and activate DinB/pol IV (the bacterial orthologue of polκ). We find that cancer cells normally sequester polκ in the cytoplasm via exportin-1, likely to prevent excess mutagenesis from the error-prone nature of this polymerase. Subverting the normal nuclear-cytoplasmic shuttling by forced overexpression of nuclear polκ increases resistance of melanoma cells to the BRAFV600E inhibitor vemurafenib. This data suggests a mechanism by which cancer cells regulate the expression and localization of the error-prone polymerase polκ, abrogation of which can contribute to drug resistance.One Sentence Summary: Cancer cells under stress from oncogene or mTOR inhibition dysregulate the error-prone DNA polymerase polκ, which contributes to drug resistance in melanoma cells.