Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
Computational Bioscience program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
PLoS Comput Biol. 2024 Aug 2;20(8):e1012048. doi: 10.1371/journal.pcbi.1012048. eCollection 2024 Aug.
Budding yeast, Saccharomyces cerevisiae, is widely used as a model organism to study the genetics underlying eukaryotic cellular processes and growth critical to cancer development, such as cell division and cell cycle progression. The budding yeast cell cycle is also one of the best-studied dynamical systems owing to its thoroughly resolved genetics. However, the dynamics underlying the crucial cell cycle decision point called the START transition, at which the cell commits to a new round of DNA replication and cell division, are under-studied. The START machinery involves a central cyclin-dependent kinase; cyclins responsible for starting the transition, bud formation, and initiating DNA synthesis; and their transcriptional regulators. However, evidence has shown that the mechanism is more complicated than a simple irreversible transition switch. Activating a key transcription regulator SBF requires the phosphorylation of its inhibitor, Whi5, or an SBF/MBF monomeric component, Swi6, but not necessarily both. Also, the timing and mechanism of the inhibitor Whi5's nuclear export, while important, are not critical for the timing and execution of START. Therefore, there is a need for a consolidated model for the budding yeast START transition, reconciling regulatory and spatial dynamics. We built a detailed mathematical model (START-BYCC) for the START transition in the budding yeast cell cycle based on established molecular interactions and experimental phenotypes. START-BYCC recapitulates the underlying dynamics and correctly emulates key phenotypic traits of ~150 known START mutants, including regulation of size control, localization of inhibitor/transcription factor complexes, and the nutritional effects on size control. Such a detailed mechanistic understanding of the underlying dynamics gets us closer towards deconvoluting the aberrant cellular development in cancer.
芽殖酵母，酿酒酵母，被广泛用作研究真核细胞过程和与癌症发展密切相关的细胞生长的遗传基础的模式生物，例如细胞分裂和细胞周期进程。芽殖酵母细胞周期也是研究最深入的动态系统之一，这要归功于其彻底解决的遗传学。然而，在称为 START 转换的关键细胞周期决策点（细胞决定开始新一轮 DNA 复制和细胞分裂的地方）的动态仍然研究不足。START 机制涉及中央细胞周期依赖性激酶；负责启动过渡、芽形成和启动 DNA 合成的细胞周期蛋白；及其转录调节剂。然而，有证据表明，该机制比简单的不可逆转换开关更为复杂。激活关键转录调节剂 SBF 需要其抑制剂 Whi5 的磷酸化，或 SBF/MBF 单体成分 Swi6，但不一定同时需要。此外，抑制剂 Whi5 的核输出的时间和机制虽然重要，但对于 START 的时间和执行并不关键。因此，需要一个整合的芽殖酵母 START 转换模型，协调调节和空间动态。我们基于已建立的分子相互作用和实验表型，为芽殖酵母细胞周期中的 START 转换构建了一个详细的数学模型（START-BYCC）。START-BYCC 再现了潜在的动态，并正确模拟了约 150 种已知 START 突变体的关键表型特征，包括大小控制的调节、抑制剂/转录因子复合物的定位以及对大小控制的营养影响。对潜在动态的这种详细的机械理解使我们更接近于剖析癌症中异常的细胞发育。
