Limits and constraints on mechanisms of cell-cycle regulation imposed by cell size-homeostasis measurements

High-throughput imaging has led to an explosion of observations regarding cell-size homeostasis across the kingdoms of life. Among bacteria, \"adder\" behavior in which a constant size appears to be added during each cell cycle is ubiquitous, while various eukaryotes show other size-homeostasis behaviors. Since interactions between cell-cycle progression and growth ultimately determine size-homeostasis behaviors, we developed a general model of cell proliferation to: 1) discover how the requirement of cell-size homeostasis limits mechanisms of cell-cycle control; 2) predict how features of cell-cycle control translate into size-homeostasis measurements. Our analyses revealed plausible cell-cycle control scenarios that nevertheless fail to regulate cell size, conditions that generate apparent adder behavior without underlying adder mechanisms, cell-cycle features that play unintuitive roles in causing deviations from adder, and distinguishing predictions for extended size-homeostasis statistics according to the underlying control mechanism. The model thus provides holistic insight into the mechanistic implications of cell-size homeostasis measurements.