Abstract
SummaryCell size varies greatly between cell types, yet within a specific cell type and growth condition, cell size is narrowly distributed. Why maintenance of a cell-type specific cell size is important remains poorly understood. Here we show that growing budding yeast and primary mammalian cells beyond a certain size impairs gene induction, cell-cycle progression, and cell signaling. These defects are due to the inability of large cells to scale nucleic acid and protein biosynthesis in accordance with cell volume increase, which effectively leads to cytoplasm dilution. We further show that loss of scaling beyond a certain critical size is due to DNA becoming limiting. Based on the observation that senescent cells are large and exhibit many of the phenotypes of large cells, we propose that the range of DNA:cytoplasm ratio that supports optimal cell function is limited and that ratios outside these bounds contribute to aging.
Highlights
In multicellular organisms, cell size ranges over several orders of magnitude
While cell size varies greatly between cell types, size is narrowly constrained for a given cell type and growth condition, suggesting that a specific size is important for cell function
To distinguish between phenotypes caused by a prolonged G1 arrest and phenotypes that are a consequence of increased cell size, we generated two G1 arrested cell populations in all our experiments: (1) Cells that were arrested in G1 and allowed to grow to their maximal size and (2) cells that were arrested in G1 but were prevented from growing large by addition of a low concentration of cycloheximide or by limiting glucose (Figure 1A)
Summary
Cell size ranges over several orders of magnitude. This is most extreme in gametes and polyploid cells but is seen in diploid somatic cells and unicellular organisms. While cell size varies greatly between cell types, size is narrowly constrained for a given cell type and growth condition, suggesting that a specific size is important for cell function. Changes in cell size are often observed in pathological conditions such as cancer, with tumor cells frequently being smaller and heterogeneous in size (Ginzberg et al, 2015; Lloyd, 2013). Cellular senescence in human cell lines and budding yeast cells is associated with a dramatic alteration in size. Senescing cells becoming exceedingly large (Hayflick and Moorhead, 1961; Mortimer and Johnston, 1959)
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