英国牛津大学Francis A. Barr团队近期取得重要工作进展，他们研究提出，MDM2能作为一个计时器报告有丝分裂的长度。相关研究成果2025年1月9日在线发表于《自然—细胞生物学》杂志上。

据介绍，有丝分裂的延迟会触发依赖p53的在下一个细胞周期G1期阻滞，从而防止染色体不稳定性和非整倍体现象的反复出现。

研究人员发现，MDM2（p53泛素连接酶）是触发应对有丝分裂延长而产生G1期阻滞的，计时机制的关键组成部分。这种计时功能源于有丝分裂过程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，在有丝分裂期间MDM2的量会逐渐下降，但在G1期开始时通常仍会保持在p53调控的关键阈值之上。

当有丝分裂因纺锤体组装检查点长时间激活而延长时，MDM2的量会降至该阈值以下，从而使p53趋于稳定。随后依赖p53的p21蛋白积累，会引导G1期细胞进入持续性的细胞周期阻滞状态，而在缺乏p53的细胞中，若这一反应被消除，它们就能绕过这一关键的防御机制。

附：英文原文

Title: MDM2 functions as a timer reporting the length of mitosis

Author: Fulcher, Luke J., Sobajima, Tomoaki, Batley, Caleb, Gibbs-Seymour, Ian, Barr, Francis A.

Issue&Volume: 2025-01-09

Abstract: 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.

DOI: 10.1038/s41556-024-01592-8

Source: https://www.nature.com/articles/s41556-024-01592-8