Abstract
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.
Highlights
The living cell is a dynamical system demonstrating considerable organization manifested in its metabolism, morphology and function
Under genome-rewiring conditions in which HIS3 is rewired to be under the exclusive control of a foreign regulatory promoter, the cells could not produce an alternative metabolic pathway or detour the challenge by other regulatory pathways that do not involve the regulation of the rewired HIS3 [19,24,25]
By rewiring the promoter of each of these genes to regulate exclusively the essential metabolic HIS3 gene, in parallel of its native regulation of the cell cycle process (Figs. 1b-d), we were able to compare the susceptibility of these essential nodes of the cell cycle network to the rewiring perturbation
Summary
The living cell is a dynamical system demonstrating considerable organization manifested in its metabolism, morphology and function. Understanding the internal regulation of the cell cycle as well as its interface with numerous other cellular processes is fundamental to many fields of biological research, such as development and cancer. The operational principles of the eukaryotic cell cycle have been found to be universal across a wide range of organisms, from yeast to mammals [1,2,3,4]. Despite the success in deciphering the cell cycle circuitry and genomic makeup, two basic inter-related issues beyond its autonomous normal operation remain largely open: its flexibility to respond to environmental stresses and accommodate internal perturbations [10], and its interface with the other intracellular processes, in particular the metabolic system [11,12,13]
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