Increasing cell size remodels the proteome and promotes senescence

Cell size is tightly controlled in healthy tissues, but it is poorly understood how variations in cell size affect cell physiology. To address this, we employed a high-accuracy mass spectrometry-based approach to measure how the proteome changes with cell size. Protein concentration changes are widespread, measurable in both asynchronous and G1-arrested cell populations, and predicted by subcellular localization, size-dependent changes in mRNA concentrations, and protein turnover. As proliferating cells grow larger, protein concentration changes typically associated with cellular senescence are increasingly pronounced. This suggests that large size is 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. Size-dependent changes to the proteome, including those associated with senescence, are not observed when an increase in cell size is accompanied by a similar increase in ploidy. This shows that proteome composition is determined by the DNA-to-ploidy ratio rather than cell size per se and that polyploidization is an elegant method to generate large non-senescent cells as is commonly found in nature. Together, 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 and polyploidization.