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Genome-wide screen identifies novel machineries required for both ciliogenesis and cell cycle arrest upon serum starvation.

ABSTRACT: Biogenesis of the primary cilium, a cellular organelle mediating various signaling pathways, is generally coordinated with cell cycle exit/re-entry. Although the dynamic cell cycle-associated profile of the primary cilium has been largely accepted, the mechanism governing the link between ciliogenesis and cell cycle progression has been poorly understood. Using a human genome-wide RNAi screen, we identify genes encoding subunits of the spliceosome and proteasome as novel regulators of ciliogenesis. We demonstrate that 1) the mRNA processing-related hits are essential for RNA expression of molecules acting in cilia disassembly, such as AURKA and PLK1, and 2) the ubiquitin-proteasome systems (UPS)-involved hits are necessary for proteolysis of molecules acting in cilia assembly, such as IFT88 and CPAP. In particular, we show that these screen hit-associated mechanisms are crucial for both cilia assembly and cell cycle arrest in response to serum withdrawal. Finally, our data suggest that the mRNA processing mechanism may modulate the UPS-dependent decay of cilia assembly regulators to control ciliary resorption-coupled cell cycle re-entry.

SUBMITTER: Kim JH

PROVIDER: S-EPMC4886714 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Genome-wide screen identifies novel machineries required for both ciliogenesis and cell cycle arrest upon serum starvation.

Kim Ji Hyun JH Ki Soo Mi SM Joung Je-Gun JG Scott Eric E Heynen-Genel Susanne S Aza-Blanc Pedro P Kwon Chang Hyuk CH Kim Joon J Gleeson Joseph G JG Lee Ji Eun JE

Biochimica et biophysica acta 20160328 6 Pt A

Biogenesis of the primary cilium, a cellular organelle mediating various signaling pathways, is generally coordinated with cell cycle exit/re-entry. Although the dynamic cell cycle-associated profile of the primary cilium has been largely accepted, the mechanism governing the link between ciliogenesis and cell cycle progression has been poorly understood. Using a human genome-wide RNAi screen, we identify genes encoding subunits of the spliceosome and proteasome as novel regulators of ciliogenes ...[more]

PMID: 27033521

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Project description:It is widely believed that, owing to the limitation of nutrients in natural environments, bacteria spend most of their life in a non-growing state. However, despite its major clinical and ecological implications, very little is known about what determines the phenotype of starved bacteria, in particular what controls the concentration of different gene products inside the cells. Using microfluidics and quantitative fluorescence microscopy, we monitored growth and gene expression in many independent E. coli lineages as we switched them from exponential growth to starvation. We observed that all cells stopped growing immediately and that no cell death occurred for more than two days. At the same time, gene expression undergoes a dramatic remodeling upon entry into starvation in a promoter-dependent manner. Some promoters, including ribosomal protein promoters, arrest gene expression immediately, others show a slow exponential decay of expression on a 10 h time scale, while a third category exhibits a transient burst of activity before decaying exponentially. Remarkably, the time dynamics of these changes are highly homogeneous across single cells. In addition, we demonstrated that the gene expression response does not qualitatively depend on the dynamics of starvation entry. Combining the observed time-dependent protein production and decay rates, we showed with mathematical modeling that a delay between growth arrest and shutdown of gene expression allows a massive increase in the concentration of certain proteins without requiring an upregulation of their expression. Moreover, protein concentrations deep in starvation appeared to be mainly determined by the expression dynamics during the first 10 h of starvation. Finally, we established that this expression program at the onset of starvation is critical for cell viability. In particular, by inhibiting gene expression during different periods of starvation, we were able to show that the tolerance to stress after 2 days is determined by gene expression occurring during the first 10 h, which thus constitutes a preventive response. These results provide a starting point for quantitative studies of cell maintenance and the emergence of specific phenotypes when nutrients become scarce.

Dataset Information

Genome-wide screen identifies novel machineries required for both ciliogenesis and cell cycle arrest upon serum starvation.

Publications

Genome-wide screen identifies novel machineries required for both ciliogenesis and cell cycle arrest upon serum starvation.

Similar Datasets

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