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

Authors: Yang, Yang; Gao, Yanzhe; Mutter-Rottmayer, Liz; Zlatanou, Anastasia; Durando, Michael; Ding, Weimin; Wyatt, David; Ramsden, Dale; Tanoue, Yuki; Tateishi, Satoshi; Vaziri, Cyrus

Published In J Cell Biol, (2017 Oct 02)

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.

PubMed ID: 28835467

MeSH Terms: No MeSH terms associated with this publication