Stier Alma Beatrix, Bonaiuti Paolo, Juhász János, Gross Fridolin, Ciliberto Andrea
Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary.
IFOM-ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
PLoS Comput Biol. 2025 Mar 19;21(3):e1012879. doi: 10.1371/journal.pcbi.1012879. eCollection 2025 Mar.
Drugs that impair microtubule dynamics alter microtubule-kinetochore attachment and invoke the mitotic checkpoint which arrests cells in mitosis. The arrest can last for hours, but it is leaky: cells adapt (i.e., slip out of it) and exit from mitosis. Here, we investigate the mechanism that allows cells to escape, and whether it is possible to prevent it. Based on a model of the mitotic checkpoint which includes the presence of a positive feedback loop, the escape from the arrest is described as a stochastic transition driven by fluctuations of molecular components from a checkpoint ON to a checkpoint OFF state. According to the model, drug removal further facilitates adaptation, a prediction we confirmed in budding yeast. The model suggests two ways to avoid adaptation: inhibition of APC/C and strengthening the mitotic checkpoint. We confirmed experimentally that both alterations decrease the chance of cells slipping out of mitosis, during a prolonged arrest and after washing out the drug. Our results may be relevant for increasing the efficiency of microtubule depolymerizing drugs.
破坏微管动力学的药物会改变微管与动粒的附着，并激活有丝分裂检查点，从而使细胞停滞在有丝分裂阶段。这种停滞可持续数小时，但并不完全：细胞会适应（即从中逃脱）并退出有丝分裂。在此，我们研究细胞逃脱的机制以及是否有可能阻止这种逃脱。基于包含正反馈回路的有丝分裂检查点模型，从停滞状态的逃脱被描述为由分子成分从检查点开启状态到检查点关闭状态的波动驱动的随机转变。根据该模型，去除药物会进一步促进适应，我们在芽殖酵母中证实了这一预测。该模型提出了两种避免适应的方法：抑制后期促进复合物/细胞周期体（APC/C）和强化有丝分裂检查点。我们通过实验证实，在长时间停滞期间以及洗去药物后，这两种改变都会降低细胞从有丝分裂中逃脱的几率。我们的结果可能与提高微管解聚药物的效率相关。
