Marquez Davila V Abigail, Gadgil Pallavi, Zike Anna, Cairo Gisela, Wang Renyu, Setayeshgar Sima, Lacefield Soni
bioRxiv. 2025 Aug 11:2025.08.09.669466. doi: 10.1101/2025.08.09.669466.
Meiosis ensures formation of haploid gametes through two rounds of chromosome segregation after one round of DNA replication. How this complex cell cycle process is restricted to two and only two divisions is poorly understood. In budding yeast, RNA-binding protein Rim4 binds various mRNAs to prevent their translation. At the onset of meiosis II, phosphorylation and degradation of Rim4, along with the concomitant release of sequestered mRNA, has an important role in ensuring meiotic exit. Building on previous work, we developed a parsimonious mathematical model of meiotic termination that elucidates the role of Rim4-mRNA release and translation of mRNA in the fidelity of meiotic exit. Central to our model is the accumulation of Ama1 protein, a meiosis-specific activator of APC/C. Our mathematical model predicted further outcomes, which we tested experimentally. We found that either slowing Rim4 degradation or disrupting APC/C activity delayed meiosis II. In some cells, this disruption prevented meiotic exit entirely, leading them to re-enter cell cycle oscillations after meiosis II. These findings demonstrate that the timely activation of this regulatory network is crucial for ensuring irreversible meiotic exit.
减数分裂通过一轮DNA复制后的两轮染色体分离确保单倍体配子的形成。目前人们对这个复杂的细胞周期过程如何被限制在两轮且仅两轮分裂知之甚少。在芽殖酵母中，RNA结合蛋白Rim4与各种mRNA结合以阻止其翻译。在减数分裂II开始时，Rim4的磷酸化和降解，以及伴随的被隔离mRNA的释放，在确保减数分裂退出方面具有重要作用。基于之前的研究工作，我们开发了一个简洁的减数分裂终止数学模型，阐明了Rim4-mRNA释放和mRNA翻译在减数分裂退出保真度中的作用。我们模型的核心是Ama1蛋白的积累，Ama1是一种减数分裂特异性的后期促进复合体/细胞周期体（APC/C）激活剂。我们的数学模型预测了进一步的结果，并进行了实验验证。我们发现，要么减缓Rim4降解，要么破坏APC/C活性，都会延迟减数分裂II。在一些细胞中，这种破坏完全阻止了减数分裂退出，导致它们在减数分裂II后重新进入细胞周期振荡。这些发现表明，这个调控网络的及时激活对于确保不可逆的减数分裂退出至关重要。
