The molecular architecture of cell cycle arrest

The cellular decision governing the transition between proliferative and arrested states is crucial to the development and function of every tissue. While the molecular mechanisms that regulate the proliferative cell cycle are well established, we know comparatively little about what happens to cells as they diverge into cell cycle arrest. We performed hyperplexed imaging of 47 cell cycle effectors to obtain a map of the molecular architecture that governs cell cycle exit and progression into reversible (“quiescent”) and irreversible (“senescent”) arrest states. Using this map, we found multiple points of divergence from the proliferative cell cycle; identified stress‐specific states of arrest; and resolved the molecular mechanisms governing these fate decisions, which we validated by single‐cell, time‐lapse imaging. Notably, we found that cells can exit into senescence from either G1 or G2; however, both subpopulations converge onto a single senescent state with a G1‐like molecular signature. Cells can escape from this “irreversible” arrest state through the upregulation of G1 cyclins. This map provides a more comprehensive understanding of the overall organization of cell proliferation and arrest.