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 and Guang Peng ()
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Hui-Ju Hsieh: The University of Texas MD Anderson Cancer Center
Wei Zhang: The University of Texas MD Anderson Cancer Center
Shu-Hong Lin: The University of Texas MD Anderson Cancer Center
Wen-Hao Yang: The University of Texas MD Anderson Cancer Center
Jun-Zhong Wang: National Kaohsiung University of Applied Sciences
Jianfeng Shen: The University of Texas MD Anderson Cancer Center
Yiran Zhang: Georgia Southern University
Yiling Lu: The University of Texas MD Anderson Cancer Center
Hua Wang: Georgia Southern University
Jane Yu: University of Cincinnati College of Medicine
Gordon B. Mills: The University of Texas MD Anderson Cancer Center
Guang Peng: The University of Texas MD Anderson Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05639-x

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