DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress
Year: 2017
Type: article
Abstract: The mechanisms by which neoplastic cells tolerate oncogene-induced DNA replication stress are poorly understood. Cyclin-dependent kinase 2 (CDK2) is a major mediator of oncogenic DNA replication stress. In this study, we show that CDK2-inducing stimuli (including Cyclin E overexpression, oncogenic RAS, and WEE1 inhibition) activate the DNA repair protein RAD18. CDK2-induced RAD18 activation required initiation of DNA synthesis and was repressed by p53. RAD18 and its effector, DNA polymerase κ (Polκ), sustained ongoing DNA synthesis in cells harboring elevated CDK2 activity. RAD18-deficient cells aberrantly accumulated single-stranded DNA (ssDNA) after CDK2 activation. In RAD18-depleted cells, the G2/M checkpoint was necessary to prevent mitotic entry with persistent ssDNA. Rad18−/− and Polκ−/− cells were highly sensitive to the WEE1 inhibitor MK-1775 (which simultaneously activates CDK2 and abrogates the G2/M checkpoint). Collectively, our results show that the RAD18–Polκ signaling axis allows tolerance of CDK2-mediated oncogenic stress and may allow neoplastic cells to breach tumorigenic barriers.
Source: The Journal of Cell Biology
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Funders: University of Northern Colorado, Institute of Clinical and Translational Sciences, National Institutes of Health, University of North Carolina at Chapel Hill, Japan Society for the Promotion of Science, National Cancer Institute, National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill
OpenAlex ID: W2748645776