Stochastic models of cell cycle regulation in eukaryotes

真核生物细胞周期调控的随机模型

• 批准号: 9247333
• 负责人: Jean M Peccoud
• 金额: $ 43.72万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-06 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247333
• 关键词: Stochastic; models; cell; cycle; regulation; Stochastic; models; cell; cycle; regulation

DESCRIPTION (provided by applicant): The cell cycle is the process by which a growing cell replicates its genome and partitions the two copies of each chromosome to two daughter cells at division. It is of utmost importance to the perpetuation of life that these processes of replication (DNA synthesis) and partitioning (mitosis) be carried out with great fidelity. In eukaryotic cells, DNA synthesis (S phase) and mitosis (M phase) are separated in time by two gaps (G1 and G2). Proper alternation of S phase and M phase is enforced by 'checkpoints' that block progression through the cell cycle if the genomic integrity of the cell is compromised in any way. For example, if DNA is damaged in G1 phase, a checkpoint blocks progression into S phase until the damage can be repaired. If replicated chromosomes are not properly aligned on the mitotic spindle, a different checkpoint blocks progression into anaphase (the phase of sister chromatid separation) until all sister chromatids are properly attached to opposite poles of the spindle. Checkpoints are able to block cell cycle progression by sending a STOP signal to the molecular mechanisms that govern specific cell-cycle transitions (G1-S, G2-M, and M-G1). The molecular mechanisms that govern each of these transitions have a peculiar property called 'bistability.' Under physiological conditions, the control mechanism can persist indefinitely in either of two characteristic states: the OFF state, which corresponds to holding the cell cycle in the pre-transition phase; and the ON state, which corresponds to pushing the cell cycle into the post-transition phase. Checkpoint STOP signals seem to act by stabilizing the appropriate bistable switch in its OFF state. Because these checkpoints are crucial to maintaining the integrity of an organism's genome from one generation of cells to the next, it is vital that they function reliably even in the face of random molecular fluctuations that are inevitable in a cell a small as a yeast cell (30 fL). Calculations based on stochastic models of the molecular mechanisms governing cell cycle progression suggest that checkpoint functions are indeed robust in wild-type budding yeast cells, but they may be compromised in strains carrying mutations of specific checkpoint genes. Nonetheless, accurate stochastic modeling of yeast cell cycle progression is still in its infancy, and it is hampered by a paucity of reliable experimental measurements of molecular abundances in single yeast cells, and of the phenotypic properties of compromised mutant strains. The purpose of this proposal is to provide the mathematical models and experimental data needed to understand how cell cycle checkpoints operate reliably in wild-type yeast cells and how they fail in mutant cells. To reach this goal will require new advances in stochastic modeling, and in the technology of measuring mRNA and protein molecules in single yeast cells. Because all eukaryotic organisms seem to employ the same fundamental molecular machinery that governs progression through the cell division cycle, the understanding of checkpoint operations in yeast cells will translate into a better understanding of checkpoint functions and failures in other types of cells, most notably human cells.

描述（由申请人提供）：细胞周期是生长细胞复制其基因组并将每个染色体的两个副本分配给分裂处的两个子细胞的过程。对于生命的延续至关重要的是，这些复制过程（DNA合成）和分区（有丝分裂）的忠诚度很高。在真核细胞中，DNA合成（S相）和有丝分裂（M相）在时间上分离有两个间隙（G1和G2）。如果细胞的基因组完整性以任何方式损害，则可以通过“检查点”来阻止S相和M相的正确交替交替。例如，如果DNA在G1相中受损，则检查点会阻止进程到S相，直到可以修复损伤为止。如果在有丝分裂主轴上未正确对齐复制的染色体，则不同的检查点会阻止向期（姐妹染色单体分离的相），直到将所有姐妹染色单体正确连接到纺锤体的相对杆上。检查点能够通过向控制特定细胞周期过渡（G1-S，G2-M和M-G1）的分子机制发送停止信号来阻止细胞周期进程。控制这些过渡中每一个的分子机制具有“双重性”。在生理条件下，在两个特征状态之一中，控制机制可以无限期地持续：OFF状态，这与在过渡阶段保持细胞周期相对应；和对应于将细胞周期推向过渡后阶段的状态。检查点停止信号似乎是通过稳定其关闭状态的适当的双态开关来起作用。由于这些检查点对于维持从一代细胞到下一个细胞的完整性的完整性至关重要，因此即使面对随机分子波动，它们在酵母细胞（30 fl）的细胞中不可避免的是不可避免的。基于控制细胞周期进程的分子机制的随机模型的计算表明，检查点功能确实在野生型芽芽的酵母菌细胞中确实很强，但在携带特定检查点基因突变的菌株中可能会损害它们。尽管如此，酵母细胞周期进程的准确随机建模仍处于起步阶段，并且由于缺乏可靠的实验而受到阻碍 单酵母细胞中分子丰度的测量以及突变菌株受损的表型特性的测量。该建议的目的是提供数学模型和实验数据，以了解细胞周期检查点如何在野生型酵母细胞中可靠地工作以及它们在突变细胞中的失败。为了实现这一目标，将需要在随机建模和测量单酵母细胞中测量mRNA和蛋白质分子的技术方面取得新的进步。因为所有真核生物似乎都采用了控制通过细胞分裂周期发展的相同基本分子机制，因此对酵母细胞检查点操作的理解将转化为更好地理解对 检查点在其他类型的细胞中功能和失败，最著名的是人类细胞。