Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication

Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneu-ploidy. 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 suf-ficiently to activate APC/CCdh1 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.

Automated summary

Whole-genome duplication (WGD) is a frequent event in cancer evolution, and the p53 tumor suppressor plays a dual role in this process. It can act as a barrier to WGD by blocking the proliferation of tetraploid cells, but it can also promote mitotic bypass, a key step in WGD. In wild-type p53 tumors, WGD is often associated with activation of the E2F pathway, particularly the amplification of CCNE1. High expression of cyclin E1 causes replicative stress, leading to G2 phase arrest. p53, along with its downstream target p21 and Wee1, inhibits mitotic cyclin-dependent kinase activity, activating APC/CCdh1 and promoting mitotic bypass.