The Structure of the Human Cell Cycle

Understanding the organization of cell cycle progression has been a longstanding goal in cell biology. Models inspired by physical systems—including clocks, dominoes, and oscillators—have captured key aspects of cell cycle progression and reconciled disparate genetic and biochemical data. However, recent studies show that individual cells can take alternate molecular trajectories through the cell cycle and exit into distinct arrest states. These observations demand a revised model that faithfully captures cell cycle heterogeneity and plasticity. We combined time-lapse microscopy, multiplexed single-cell imaging, and manifold learning to render the underlying “structure” of the human cell cycle. We discovered an intricate network of molecular routes connecting states of proliferation, quiescence, senescence, endoreduplication, and polyploidy. The structure revealed a general principle in which arrested cells re-enter the cell cycle through excessive cyclin-CDK signaling rather than reversal of pro-arrest mechanisms. These findings enable study of alternate cell cycle mechanisms in development and disease.