Control of cell proliferation by the MDM2 mitotic timer: every double minute counts!
Thursday 11 January 2024
Joint MRC PPU / MCDB / SoM Alumni Seminar by Dr Luke Fulcher, University of Oxford
University of Dundee
Dundee DD1 5HL
Host: Tony Ly, Gopal Sapkota and Adrian Saurin
Venue: MSI Small Lecture Theatre, SLS
Delays in mitosis trigger a p53-dependent arrest in G1 of the following cell cycle, enabling cells to react to changes promoting aneuploidy. We find that MDM2, the p53 ubiquitin ligase, is a key component of the molecular timer that enables cells to respond to prolonged mitosis by arresting in the following G1. Because MDM2 has a short half-life and catalyses its own destruction, ongoing protein synthesis is necessary to maintain its steady-state concentration. Due to the attenuation of protein synthesis in mitosis, the amount of MDM2 falls, but normally remains above a critical threshold for p53 regulation at the onset of G1. Therefore, when mitosis is prolonged by spindle assembly checkpoint activation, the amount of MDM2 drops below this threshold, and p53-dependent p21 accumulation in new G1 cells triggers a cell cycle arrest. Through this function in mitosis, MDM2 thereby protects against genome instability and aneuploidy, whereas abrogation of the response in p53 mutant cells allows them to bypass this crucial defence.
Luke undertook his PhD studies in Gopal Sapkota’s lab in the MRC-PPU, where he investigated the FAM83 family of proteins and their role as anchoring proteins for isoforms of the CK1 family of protein kinases. Through identifying FAM83D as the molecular anchor that directs CK1α to the mitotic spindle in order to regulate spindle positioning, Luke developed his interests in the post-translational control of cell division. In 2020, Luke moved to Francis Barr’s lab in the Department of Biochemistry at the University of Oxford, where he is continuing his research on the post-translational regulation of the cell cycle.