Competing memories of mitogen and p53 signalling control cell-cycle entry

Abstract

Regulation of cell proliferation is necessary for immune responses, tissue repair, and upkeep of organ function to maintain human health. When proliferating cells complete mitosis, a fraction of newly born daughter cells immediately enter the next cell cycle, while the remaining cells in the same population exit to a transient or persistent quiescent state. Whether this choice between two cell-cycle pathways is due to natural variability in mitogen signalling or other underlying causes is unknown. Here we show that human cells make this fundamental cell-cycle entry or exit decision based on competing memories of variable mitogen and stress signals. Rather than erasing their signalling history at cell-cycle checkpoints before mitosis, mother cells transmit DNA damage-induced p53 protein and mitogen-induced cyclin D1 (CCND1) mRNA to newly born daughter cells. After mitosis, the transferred CCND1 mRNA and p53 protein induce variable expression of cyclin D1 and the CDK inhibitor p21 that almost exclusively determines cell-cycle commitment in daughter cells. We find that stoichiometric inhibition of cyclin D1-CDK4 activity by p21 controls the retinoblastoma (Rb) and E2F transcription program in an ultrasensitive manner. Thus, daughter cells control the proliferation-quiescence decision by converting the memories of variable mitogen and stress signals into a competition between cyclin D1 and p21 expression. We propose a cell-cycle control principle based on natural variation, memory and competition that maximizes the health of growing cell populations.

Evidence that the human cell cycle is a series of uncoupled, memoryless phases

“…We next introduced the DNA damaging agent neocarzinostatin (NCS) to mother cells and measured the phase durations for daughter cells (Fig J, Appendix Fig S9A). Recent work in human cells has shown that DNA damage signaling in the mother cell's G2 can persist through mitosis to lengthen the duration of G1, suggesting that coupling of maternal G2 and daughter G1 could potentially arise under genotoxic stress (Arora et al , ; Barr et al , ; Yang et al , ). As expected, at the highest NCS dosages that permitted cells to finish a cell cycle without permanent arrest, we confirmed that DNA damage significantly lengthened G1 in daughter cells (Fig K, Appendix Fig S8P).…”

EMI1 switches from being a substrate to an inhibitor of APC/CCDH1 to start the cell cycle

“… Mammalian cells integrate mitogen and stress signaling prior to the end of G1 phase to decide whether or not to enter the cell cycle 1–4 . Before cells can replicate their DNA in S phase, they have to activate cyclin-dependent kinases (CDKs), induce an E2F transcription program, and inactivate an E3 ubiquitin ligase, the anaphase promoting complex/cyclosome (APC/C Cdh1 ).…”

Eternal sunshine of the spotless cycle

“…Variability in protein concentration due to stochasticity in gene expression, protein partitioning during cell division, stress signals, coupling to the circadian clock, and environmental changes have all been implicated in regulating the inherent variability in cell cycle phase durations in individual cells. On the other hand, recent work (Arora et al , ; Yang et al , ) has also shown that heritable factors from mother to daughter cells enable similarities in cell cycle phase dynamics between sister cells across cell lineages.…”