WIP1 mutations suppress DNA damage triggered bypass of the mitotic timer

Prolonged mitosis results in the destruction of MDM2, initiating a p53-dependent G1 cell-cycle arrest in the absence of DNA damage. Here, we investigate how DNA damage earlier in the cell cycle affects this mitotic-timer response. We find that G2-DNA damage triggers highly penetrant bypass of mitosis and of the mitotic timer, generating tetraploid cells arrested in G1. Collapse of G2 to G1 after DNA damage is initiated by p21-mediated CDK2 inhibition and rendered irreversible by the destruction of G2/M-cyclins A and B. This behaviour is altered in cells with cancer-associated mutations in the p53-phosphatase WIP1 (PPM1D), which increase the threshold for DNA-damage signalling, enabling DNA-damaged G2 cells to enter mitosis with elevated levels of MDM2, thereby suppressing mitotic-timer-dependent G1 cell-cycle arrest. Importantly, neither WIP1 mutations nor knockout prevent p53-dependent G1-arrest in response to prolonged mitosis in the absence of DNA damage. Prolonged mitosis and G2-DNA damage thus promote p53-dependent G1 cell-cycle exit through discrete routes with differential requirements for WIP1 and genotoxic stress.