DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress.
Yang YangYanzhe GaoLiz Mutter-RottmayerAnastasia ZlatanouMichael DurandoWeimin DingDavid WyattDale RamsdenYuki TanoueSatoshi TateishiCyrus VaziriPublished in: The Journal of cell biology (2017)
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.
Keyphrases
- dna repair
- dna damage
- cell cycle
- induced apoptosis
- cell cycle arrest
- circulating tumor
- dna damage response
- endoplasmic reticulum stress
- transcription factor
- cell death
- signaling pathway
- oxidative stress
- single molecule
- dendritic cells
- small molecule
- endothelial cells
- regulatory t cells
- nucleic acid
- mass spectrometry
- amino acid
- tyrosine kinase
- binding protein
- high resolution
- protein protein
- heat stress