Controlling Depth of Cellular Quiescence by an Rb-E2F Network Switch.

Quiescence is a non-proliferative cellular state that is critical to tissue repair and regeneration. Although often described as the G0 phase， quiescence is not a single homogeneous state. As cells remain quiescent for longer durations， they move progressively deeper and display a reduced sensitivity to growth signals. Deep quiescent cells， unlike senescent cells， can still re-enter the cell cycle under physiological conditions. Mechanisms controlling quiescence depth are poorly understood， representing a currently underappreciated layer of complexity in growth control. Here， we show that the activation threshold of a Retinoblastoma (Rb)-E2F network switch controls quiescence depth. Particularly， deeper quiescent cells feature a higher E2F-switching threshold and exhibit a delayed traverse through the restriction point (R-point). We further show that different components of the Rb-E2F network can be experimentally perturbed， following computer model predictions， to coarse- or fine-tune the E2F-switching threshold and drive cells into varying quiescence depths.