Systems biology approach reveals a link between mTORC1 and G2/M DNA damage checkpoint recovery

Hui Ju Hsieh, Wei Zhang, Shu Hong Lin, Wen Hao Yang, Jun Zhong Wang, Jianfeng Shen, Yiran Zhang, Yiling Lu, Hua Wang, Jane Yu, Gordon B. Mills, Guang Peng

    Research output: Contribution to journalArticle

    6 Scopus citations

    Abstract

    Checkpoint recovery, the process that checkpoint-arrested cells with normal DNA repair capacity resume cell cycle progression, is essential for genome stability. However, the signaling network of the process has not been clearly defined. Here, we combine functional proteomics, mathematical modeling, and molecular biology to identify mTORC1, the nutrient signaling integrator, as the determinant for G2/M checkpoint recovery. Inhibition of the mTORC1 pathway delays mitotic entry after DNA damage through KDM4B-mediated regulation of CCNB1 and PLK1 transcription. Cells with hyper-mTORC1 activity caused by TSC2 depletion exhibit accelerated G2/M checkpoint recovery. Those Tsc2-null cells are sensitive to WEE1 inhibition in vitro and in vivo by driving unscheduled mitotic entry and inducing mitotic catastrophe. These results reveal that mTORC1 functions as a mediator between nutrition availability sensing and cell fate determination after DNA damage, suggesting that checkpoint inhibitors may be used to treat mTORC1-hyperactivated tumors such as those associated with tuberous sclerosis complex.

    Original languageEnglish (US)
    Article number3982
    JournalNature communications
    Volume9
    Issue number1
    DOIs
    StatePublished - Dec 1 2018

    ASJC Scopus subject areas

    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Physics and Astronomy(all)

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  • Cite this

    Hsieh, H. J., Zhang, W., Lin, S. H., Yang, W. H., Wang, J. Z., Shen, J., Zhang, Y., Lu, Y., Wang, H., Yu, J., Mills, G. B., & Peng, G. (2018). Systems biology approach reveals a link between mTORC1 and G2/M DNA damage checkpoint recovery. Nature communications, 9(1), [3982]. https://doi.org/10.1038/s41467-018-05639-x