Faculty of Medicine, Technion, Haifa, Israel.
PLoS One. 2012;7(9):e45184. doi: 10.1371/journal.pone.0045184. Epub 2012 Sep 18.
The fundamental dynamics of the cell cycle, underlying cell growth and reproduction, were previously found to be robust under a wide range of environmental and internal perturbations. This property was commonly attributed to its network structure, which enables the coordinated interactions among hundreds of proteins. Despite significant advances in deciphering the components and autonomous interactions of this network, understanding the interfaces of the cell cycle with other major cellular processes is still lacking. To gain insight into these interfaces, we used the process of genome-rewiring in yeast by placing an essential metabolic gene HIS3 from the histidine biosynthesis pathway, under the exclusive regulation of different cell-cycle promoters. In a medium lacking histidine and under partial inhibition of the HIS3p, the rewired cells encountered an unforeseen multitasking challenge; the cell-cycle regulatory genes were required to regulate the essential histidine-pathway gene in concert with the other metabolic demands, while simultaneously driving the cell cycle through its proper temporal phases. We show here that chemostat cell populations with rewired cell-cycle promoters adapted within a short time to accommodate the inhibition of HIS3p and stabilized a new phenotypic state. Furthermore, a significant fraction of the population was able to adapt and grow into mature colonies on plates under such inhibiting conditions. The adapted state was shown to be stably inherited across generations. These adaptation dynamics were accompanied by a non-specific and irreproducible genome-wide transcriptional response. Adaptation of the cell-cycle attests to its multitasking capabilities and flexible interface with cellular metabolic processes and requirements. Similar adaptation features were found in our previous work when rewiring HIS3 to the GAL system and switching cells from galactose to glucose. Thus, at the basis of cellular plasticity is the emergence of a yet-unknown general, non-specific mechanism allowing fast inherited adaptation to unforeseen challenges.
细胞周期的基本动力学，是细胞生长和繁殖的基础，先前被发现能够在广泛的环境和内部干扰下保持稳健。这种特性通常归因于其网络结构，该结构能够协调数百种蛋白质之间的相互作用。尽管在破译这个网络的组成部分和自主相互作用方面取得了重大进展，但对细胞周期与其他主要细胞过程的接口的理解仍然不足。为了深入了解这些接口，我们利用酵母中的基因组重布线过程，将组氨酸生物合成途径中的必需代谢基因 HIS3 置于不同细胞周期启动子的独家调控下。在缺乏组氨酸的培养基中和 HIS3p 的部分抑制下，重布线细胞遇到了一个意想不到的多任务挑战；细胞周期调控基因需要与其他代谢需求一起协调调控必需的组氨酸途径基因，同时通过适当的时间阶段推动细胞周期。我们在这里表明，具有重布线细胞周期启动子的恒化器细胞群体在短时间内适应了 HIS3p 的抑制，并稳定了一个新的表型状态。此外，在这种抑制条件下，相当一部分群体能够适应并在平板上生长为成熟菌落。适应状态被证明可以在几代之间稳定遗传。这些适应动力学伴随着非特异性和不可重复的全基因组转录反应。细胞周期的适应证明了它的多任务能力以及与细胞代谢过程和需求的灵活接口。当我们将 HIS3 重布线到 GAL 系统并将细胞从半乳糖切换到葡萄糖时，我们在之前的工作中也发现了类似的适应特征。因此，细胞可塑性的基础是出现了一种未知的、一般性的、非特异性的机制，允许快速遗传适应意外的挑战。
