Increasing cell size remodels the proteome and promotes senescence

Abstract Cell size is tightly controlled in healthy tissues, but it is poorly understood how cell size affects cell physiology. To address this, we measured how the proteome changes with cell size. Protein concentration changes are widespread, depend on the DNA-to-cell size ratio, and are predicted by subcellular localization, size-dependent mRNA concentrations, and protein turnover. As proliferating cells grow larger, concentration changes associated with cellular senescence are increasingly pronounced, suggesting that large size may be a cause rather than just a consequence of cell senescence. Consistent with this hypothesis, larger cells are prone to replicative-, DNA damage-, and CDK4/6i-induced senescence. More broadly, our findings show how cell size could impact many aspects of cell physiology through remodeling the proteome, thereby providing a rationale for cell size control to optimize cell function.