DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress

作者：Yang Yang, Yanzhe Gao, Liz Mutter-Rottmayer, Anastasia Zlatanou, Michael Durando, Weimin Ding, David W. Wyatt, Dale A. Ramsden, Yuki Tanoue, Satoshi Tateishi, Cyrus Vaziri · 发表于：The Journal of Cell Biology · 年份：2017 · DOI：10.1083/jcb.201702006 · 被引用次数：75 · 研究领域：DNA Repair Mechanisms、Carcinogens and Genotoxicity Assessment、Cancer therapeutics and mechanisms

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.