Cell Growth–Induced Dilution of Cytoplasm Contributes to Senescence

Specific cell types exist in a narrow range of sizes, and changes beyond this range can have significant impacts on cell physiology. Neurohr and colleagues demonstrated that excessive cell size limits the availability of DNA and protein and subsequently impairs a wide range of cellular functions. In yeast, temporary arrest of cell cycle but not growth resulted in large cells and delayed resumption of proliferation and S phase compared with cells arrested while growth was inhibited. Disruption of DNA damage and spindle assembly checkpoints partially rescued these delays, indicating that impaired cell-cycle checkpoints contribute to the effects of large cell size. Large cells also had reduced expression of cell-cycle regulators and generally impaired transcription compared with small cells. These various phenotypes were due to the loss of scaling between cell volume and RNA and protein biosynthesis: Without a corresponding increase in biosynthesis as cell volume expanded, the general transcription and translational machinery become limiting. Conversely, bolstering DNA content via the creation of diploid cells rescued many of the defects associated with excessive cell size in haploid cells, indicating that the DNA:cytoplasm ratio defines the range in which RNA and protein biosynthesis can scale with growth. The phenotypes exhibited by arrested, large cells were also observed in old yeast cells, the majority of which were larger than young cells. Moreover, prolonged cell-cycle arrest in young cells was sufficient to reduce their lifespan, suggesting that cell size contributes to the phenotypes observed in large, aged cells. In human cells, prolonged arrest also increased cell size, decreased the DNA:cytoplasm ratio, and induced senescence. Taken together, these results show that maintaining a cell type–specific range of cell size is critical for maintaining the proper concentration of cellular components and that dysregulation of cell size can lead to pathologies and aging.

Neurohr GE, Terry RL, Lengefeld J, Bonney M, Brittingham GP, Moretto F, et al. Excessive cell growth causes cytoplasm dilution and contributes to senescence. Cell 2019 Feb 7 [Epub ahead of print].

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