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

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）：细胞周期是生长中的细胞复制其基因组并在分裂时将每条染色体的两个拷贝分配给两个子细胞的过程。这些复制（DNA 合成）和分配（有丝分裂）过程的精确执行对于生命的延续至关重要。在真核细胞中，DNA 合成（S 期）和有丝分裂（M 期）在时间上被两个间隙（G1 和 G2）分开。 S期和M期的适当交替是通过“检查点”强制执行的，如果细胞的基因组完整性以任何方式受到损害，这些“检查点”就会阻止细胞周期的进展。例如，如果 DNA 在 G1 期受损，检查点会阻止进展到 S 期，直到损伤得到修复。如果复制的染色体未在有丝分裂纺锤体上正确对齐，则不同的检查点会阻止进入后期（姐妹染色单体分离的阶段），直到所有姐妹染色单体正确附着到纺锤体的相反两极。检查点能够通过向控制特定细胞周期转变（G1-S、G2-M 和 M-G1）的分子机制发送 STOP 信号来阻止细胞周期进程。控制这些转变的分子机制有一个特殊的特性，称为“双稳态”。在生理条件下，控制机制可以无限期地持续在两种特征状态中的任何一种：关闭状态，相当于将细胞周期保持在转换前阶段； ON 状态，对应于将细胞周期推入转换后阶段。检查点停止信号似乎是通过将适当的双稳态开关稳定在关闭状态来起作用的。由于这些检查点对于维持生物体基因组从一代细胞到下一代细胞的完整性至关重要，因此即使面对像酵母细胞这样小的细胞中不可避免的随机分子波动，它们也能可靠地发挥作用，这一点至关重要。 30 液升）。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，检查点功能在野生型芽殖酵母细胞中确实很强大，但在携带特定检查点基因突变的菌株中可能会受到损害。尽管如此，酵母细胞周期进程的准确随机模型仍处于起步阶段，并且由于缺乏可靠的实验而受到阻碍 测量单个酵母细胞中的分子丰度，以及受损突变菌株的表型特性。该提案的目的是提供所需的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运行以及它们如何在突变细胞中失效。为了实现这一目标，需要随机建模以及测量单个酵母细胞中 mRNA 和蛋白质分子的技术取得新进展。由于所有真核生物似乎都采用相同的基本分子机制来控制细胞分裂周期的进展，因此对酵母细胞检查点操作的理解将转化为更好地理解 其他类型细胞（尤其是人类细胞）中的检查点功能和故障。