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

G1/S过渡的代谢控制-一个新的开始模型生长和分裂是对营养的响应。如果营养供应不足，细胞就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。虽然很明显营养供应会影响Start，但尚不清楚营养供应如何影响已经通过Start的酵母细胞。通过分析单个细胞，我们发现营养剥夺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wh5，其核出口允许CDK在开始时激活，可以重新进入细胞核。目前的不可逆细胞周期承诺模型无法解释wh5核再入。这种逆转发生在复制开始前的任何时间，是由Snf1信号下游的wh5去磷酸化引起的。如果起点不是不可逆的终点，那么什么才是呢？哪些下游监管机构将营养信号整合到最终决策中？细胞是否保持CDK激活的记忆？为了解决这些问题，我们现在将单细胞分析与蛋白质生物化学结合起来。在哺乳动物中，普遍限制点的模型受到了挑战，但细胞周期承诺作为一个多步骤过程的共识模型仍然缺乏。我们的发现也在酵母细胞周期承诺是一个多步骤的过程，提供了一个优秀的更简单的模型来获得真核G1/S控制的机制理解。

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.