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.
Highlights
Checkpoint recovery, the process that checkpoint-arrested cells with normal DNA repair capacity resume cell cycle progression, is essential for genome stability
We report that the mechanistic target of rapamycin complex 1 pathway is required for mitotic entry after DNA
Raptor-depleted cells produced phenocopies of mTORdepleted cells that showed a significantly impaired capacity to induce CCNB1 and PLK1 mRNA expression after ionizing radiation (IR), but rictordepleted cells did not (Fig. 3b and Supplementary Fig. 3c). These results indicate that mechanistic target of rapamycin complex 1 (mTORC1) is required for the transcriptional induction of CCNB1 and PLK1, which permits mitotic onset in
Summary
Checkpoint recovery, the process that checkpoint-arrested cells with normal DNA repair capacity resume cell cycle progression, is essential for genome stability. 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. These molecular determinants of DNA damage checkpoint recovery are essential for cells to resume the cell cycle and continue their physiology program in order to maintain survival after. Cells with hypermTORC1 activity caused by depletion of tuberous sclerosis 2
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