MDM2 acts as a timer reporting the length of mitosis

Abstract

AbstractDelays in mitosis trigger a p53-dependent arrest in G1 of the following cell cycle, enabling cells to react to changes promoting aneuploidy [1-10]. How delays in mitosis are sensed and result in cells becoming arrested in the subsequent G1 phase is unclear. We have identified MDM2, the p53 ubiquitin ligase, as the key molecular timer that enables cells to respond to defects in mitosis by arresting in the subsequent G1. We demonstrate that MDM2 has a short half-life and ongoing protein synthesis is therefore necessary to maintain its steady-state concentration. Because protein synthesis is attenuated in mitosis, the amount of MDM2 falls during mitosis but remains above a crucial threshold for p53 regulation at the onset of G1. However, when mitosis is prolonged and the amount of MDM2 drops below this threshold level, p53 is stabilised in new G1 cells, triggering increased p21 synthesis and cell cycle arrest. Our findings shed light on how abrogation of this process enables p53 mutant cancer cells to bypass the key regulation that senses and responds to aneuploidy in normal cells.