MDM2 acts as a timer reporting the length of mitosis

Delays in mitosis trigger p53-dependent arrest in G1 of the following cell cycle, enabling cells to respond to changes that would otherwise promote chromosome instability and aneuploidy 1-10. We find that MDM2, the p53 ubiquitin ligase, is a key component of the timer mechanism triggering G1 arrest in response to prolonged mitosis. This timer function arises because MDM2 has a short half-life and ongoing protein synthesis is therefore necessary to maintain its steady-state concentration. Due to the attenuation of protein synthesis in mitosis, the amount of MDM2 gradually falls during mitosis, but normally remains above a critical threshold for p53 regulation at the onset of G1. When mitosis is extended by prolonged spindle assembly checkpoint activation, the amount of MDM2 drops below this threshold, stabilising p53. Subsequent p53-dependent p21 accumulation in the following G1 then channels cells into a prolonged cell cycle arrest, whereas abrogation of the response in p53-deficient cells allows them to bypass this crucial defence mechanism.