Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy. The role of the p53 tumor suppressor in WGD has been enigmatic: p53 can block the proliferation of tetraploid cells, acting as a barrier to WGD, but can also promote mitotic bypass, a key step in WGD via endoreduplication. In wild-type (WT) p53 tumors, WGD is frequently associated with activation of the E2F pathway, especially amplification of CCNE1, encoding cyclin E1. Here, we show that elevated cyclin E1 expression causes replicative stress, which activates ATR- and Chk1-dependent G2 phase arrest. p53, via its downstream target p21, together with Wee1, then inhibits mitotic cyclin-dependent kinase activity sufficiently to activate APC/C^Cdh1 and promote mitotic bypass. Cyclin E expression suppresses p53-dependent senescence after mitotic bypass, allowing cells to complete endoreduplication. Our results indicate that p53 can contribute to cancer evolution through the promotion of WGD.

全基因组复制 (WGD) 是癌症进化中的常见事件，也是非整倍体的重要驱动因素。p53 肿瘤抑制因子在 WGD 中的作用一直是个谜：p53 可以阻断四倍体细胞的增殖，作为 WGD 的屏障，但也可以促进有丝分裂旁路，这是通过核内复制实现 WGD 的关键步骤。在野生型 (WT) p53 肿瘤中，WGD 通常与 E2F 通路的激活相关，尤其是编码细胞周期蛋白 E1 的CCNE1的扩增。在这里，我们表明细胞周期蛋白 E1 表达升高会导致复制应激，从而激活 ATR 和 Chk1 依赖性 G2 期停滞。p53 通过其下游靶标 p21 与 Wee1 一起抑制有丝分裂细胞周期蛋白依赖性激酶活性，足以激活 APC/C ^Cdh1并促进有丝分裂旁路。细胞周期蛋白 E 表达抑制有丝分裂旁路后 p53 依赖性衰老，使细胞能够完成核内复制。我们的结果表明 p53 可以通过促进 WGD 促进癌症进化。