Abstract
Entosis was proposed to promote aneuploidy and genome instability by cell-in-cell mediated engulfment in tumor cells. We reported here, in epithelial cells, that entosis coupled with mitotic arrest functions to counteract genome instability by targeting aneuploid mitotic progenies for engulfment and elimination. We found that the formation of cell-in-cell structures associated with prolonged mitosis, which was sufficient to induce entosis. This process was controlled by the tumor suppressor p53 (wild-type) that upregulates Rnd3 expression in response to DNA damages associated with prolonged metaphase. Rnd3-compartmentalized RhoA activities accumulated during prolonged metaphase to drive cell-in-cell formation. Remarkably, this prolonged mitosis-induced entosis selectively targets non-diploid progenies for internalization, blockade of which increased aneuploidy. Thus, our work uncovered a heretofore unrecognized mechanism of mitotic surveillance for entosis, which eliminates newly born abnormal daughter cells in a p53-dependent way, implicating in the maintenance of genome integrity.
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Acknowledgements
We thank Dr. Overholtzer from Memorial Sloan-Kettering Cancer Center and Dr. Qinong Ye from Beijing Institute of Biotechnology for providing cell lines and reagents. We thank Dr. Louis Hodgson from Albert Einstein College of Medicine of Yeshiva University for assistance in FRET. We thank Dr. Dangsheng Li for discussions and critical reading of the manuscript. This work was supported by the National Key Research & Development Program of China (2016YFC1303303, 2019YFA09003801, 2018YFA0900804), the National Natural Science Foundation of China (31970685, 31671432, 81872314, 31770975, 81572799). QS conceived the project and conception. QS, HH, and JL designed experiments with the advice from XNW and ZC. JL performed majority of the experiments with the assistance of XY for RNA interference, phenotype, and qPCR, and ZN for pathology, immunostaining, and FISH. MW, BZ, and HQ helped in protein expression and detection. SG and LG assisted imaging. YT provided patient samples and related information. QS, HH, and JL analyzed the data with the assistance of YZ, CW, HR, BR, XZ, XS. QS, and JL wrote the paper with input from XNW, LM, and HH, and all authors reviewed the manuscript.
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Liang, J., Niu, Z., Zhang, B. et al. p53-dependent elimination of aneuploid mitotic offspring by entosis. Cell Death Differ 28, 799–813 (2021). https://doi.org/10.1038/s41418-020-00645-3
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DOI: https://doi.org/10.1038/s41418-020-00645-3
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