Metabolic control of the G1/S transition - a new model of Start

G1/S转换的代谢控制-一种新的启动模式生长和分裂是受营养素调节的。如果营养供应不足，细胞不会进行另一轮分裂。不可逆地进入细胞周期的决定发生在哺乳动物的G1“限制点”和酵母的“开始”，这是我们选择的模型。虽然营养供应明显影响Start，但营养供应如何影响已经通过Start的酵母细胞尚不清楚。通过分析单个细胞，我们发现营养缺乏可以延迟细胞周期的所有阶段。一些饥饿的细胞表现出令人惊讶的行为：细胞周期抑制剂Whi 5，其核出口允许CDK在开始时激活，可以重新进入细胞核。Whi 5核重返无法用当前不可逆转的细胞周期承诺模型来解释。Start的逆转发生在复制开始之前的任何时间，是由Snf 1信号下游Whi 5的去磷酸化引起的。如果Start不是不可逆性的终点，那么是什么？哪些下游调节器整合了营养信号以做出最终决定？细胞是否保持CDK激活的记忆？为了解决这些问题，我们现在将联合收割机单细胞分析与蛋白质生物化学相结合。在哺乳动物中，普遍限制点的模型受到了挑战，但仍然缺乏细胞周期定型作为多步骤过程的共识模型。我们的发现，也在酵母细胞周期的承诺是一个多步骤的过程，提供了一个很好的简单的模型，以获得真核细胞G1/S控制的机制的理解。

Metabolic Control of the G1/S transition – A new model for StartGrowth and division are regulated in response to nutrients. If nutrient supply is insufficient, cells do not commit to another round of division. The decision to irreversibly commit to the cell cycle takes place in G1 at the “restriction point” in mammals and “Start” in yeast, our model of choice. While clearly nutrient supply affects Start, it is not clear how nutrient supply affects yeast cells that have already passed Start.By analysing single cells, we found that nutrient-deprivation can delay all phases of the cell cycle. Some starved cells showed a surprising behaviour: The cell cycle inhibitor Whi5, whose nuclear exit allows CDK activation at Start, can re-enter the nucleus. Whi5 nuclear re-entry cannot be explained by the current model of irreversible cell cycle commitment. This reversal of Start happens any time before replication begins, and is caused by dephosphorylation of Whi5, downstream of Snf1 signalling.If Start is not the final point of irreversibility, then what is? Which downstream regulators integrate nutrient signalling for the final decision? And do cells maintain a memory of CDK activation? To solve these questions, we will now combine single cell analysis with protein biochemistry In mammals, the model of a universal restriction point has been challenged, but a consensus model of cell cycle commitment as a multi-step process is still lacking. Our discovery that also in yeast cell cycle commitment is a multi-step process, provides an excellent simpler model to gain a mechanistic understanding of eukaryotic G1/S control.