Fulcher Luke J, Sobajima Tomoaki, Batley Caleb, Gibbs-Seymour Ian, Barr Francis A
Department of Biochemistry, University of Oxford, Oxford, UK.
Nat Cell Biol. 2025 Feb;27(2):262-272. doi: 10.1038/s41556-024-01592-8. Epub 2025 Jan 9.
Delays in mitosis trigger p53-dependent arrest in G1 of the next cell cycle, thus preventing repeated cycles of chromosome instability and aneuploidy. Here we show 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 due to the attenuation of protein synthesis in mitosis. Because MDM2 has a short half-life and ongoing protein synthesis is therefore necessary to maintain its steady-state concentration, 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, stabilizing p53. Subsequent p53-dependent p21 accumulation then channels G1 cells into a sustained cell-cycle arrest, whereas abrogation of the response in p53-deficient cells allows them to bypass this crucial defence mechanism.
有丝分裂延迟会触发下一个细胞周期G1期的p53依赖性停滞，从而防止染色体不稳定和非整倍体的重复循环。我们在此表明，p53泛素连接酶MDM2是触发G1期停滞以响应延长的有丝分裂的计时机制的关键组成部分。这种计时功能源于有丝分裂中蛋白质合成的减弱。由于MDM2半衰期较短，因此需要持续的蛋白质合成来维持其稳态浓度，MDM2的量在有丝分裂期间逐渐下降，但在G1期开始时通常保持在p53调节的临界阈值以上。当通过延长纺锤体组装检查点激活来延长有丝分裂时，MDM2的量降至该阈值以下，使p53稳定。随后p53依赖性的p21积累进而使G1期细胞进入持续的细胞周期停滞，而p53缺陷细胞中该反应的消除则使它们能够绕过这一关键防御机制。
