Loss of CDK4/6 activity in S/G2 phase leads to cell cycle reversal

Abstract In mammalian cells, the decision to proliferate is thought be irreversibly made at restriction point of cell cycle 1,2 , when mitogen signalling engages a positive feedback loop between cyclin A2/cyclin-dependent kinase 2 (CDK2) and retinoblastoma protein 3–5 . Contrary this textbook model, here we show that actually fully reversible. Instead, find all cycling cells will exit in absence mitogens unless they make it mitosis divide first. This temporal competition two fates, exit, arises because A2/CDK2 activity depends upon CDK4/6 throughout cycle, not just G1 phase. Without mitogens, only observed half-life A2 long enough sustain CDK2 G2/M. Thus, are dependent on maintain phosphorylation interphase. Consequently, even 2-h delay cell’s progression towards can induce if lost. Our results uncover molecular mechanism underlying phenomenon, reveal an unexpected role for S G2 phases explain behaviour following loss signalling.