Laboratory of Cell Engineering, Institute of Biotechnology, 20 Dongda Street, Beijing, 100071, China.
State Key Laboratory of Genetic Engineering, School of Life Science, Fudan University, 2005 Songhu Road, Shanghai, 200438, China.
Cell Death Differ. 2021 Feb;28(2):799-813. doi: 10.1038/s41418-020-00645-3. Epub 2020 Oct 27.
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.
细胞吞噬作用介导的细胞内吞作用被提出可促进肿瘤细胞的非整倍体和基因组不稳定性。我们在这里报告，在上皮细胞中，与有丝分裂阻滞偶联的细胞内吞作用通过靶向非整倍体有丝分裂后代的吞噬和消除来抵抗基因组不稳定性。我们发现，与有丝分裂延长相关的细胞内吞结构的形成足以诱导细胞内吞作用。这个过程由肿瘤抑制因子 p53（野生型）控制，它会响应与中期延长相关的 DNA 损伤而上调 Rnd3 的表达。在中期延长期间，Rnd3 分隔的 RhoA 活性积累，从而驱动细胞内吞的形成。值得注意的是，这种由延长的有丝分裂诱导的细胞内吞作用选择性地将非整倍体后代内化，阻断该过程会增加非整倍体。因此，我们的工作揭示了一种迄今尚未被认识的有丝分裂监视的细胞内吞作用机制，该机制以 p53 依赖的方式消除新产生的异常子细胞，从而维持基因组的完整性。
