A unified model for the G1/S cell cycle transition

Abstract

Efficient S phase entry is essential for development, tissue repair, and immune defences. However, hyperactive or expedited S phase entry causes replication stress, DNA damage and oncogenesis, highlighting the need for strict regulation. Recent paradigm shifts and conflicting reports demonstrate the requirement for a discussion of the G1/S transition literature. Here, we review the recent studies, and propose a unified model for the S phase entry decision. In this model, competition between mitogen and DNA damage signalling over the course of the mother cell cycle constitutes the predominant control mechanism for S phase entry of daughter cells. Mitogens and DNA damage have distinct sensing periods, giving rise to three Commitment Points for S phase entry (CP1-3). S phase entry is mitogen-independent in the daughter G1 phase, but remains sensitive to DNA damage, such as single strand breaks, the most frequently-occurring lesions that uniquely threaten DNA replication. To control CP1-3, dedicated hubs integrate the antagonistic mitogenic and DNA damage signals, regulating the stoichiometric cyclin: CDK inhibitor ratio for ultrasensitive control of CDK4/6 and CDK2. This unified model for the G1/S cell cycle transition combines the findings of decades of study, and provides an updated foundation for cell cycle research.

Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

“…This is important for efficient S phase entry which is essential for tissue repair and healing. In addition to Rho GTPase-YAP signalling shown in the present study, other important signalling pathways, such as those initiated by mitogens, via MAPK/cyclin D1, and by DNA damage, via p53 and p21, are known to regulate CDK4/6 activity [ 59 ]. The effects of ZA and GGOH on the upstream regulators and potential effectors of CDK6 in MSCs remain unknown and warrant further studies.…”

The structure of the human cell cycle

“…This approach successfully ordered key molecular events regulating the G1/S transition ( Fig. 2A) (33).…”

“…This approach successfully ordered key molecular events regulating the G1/S transition ( Fig. 2A ) ( 33 ). The core molecular unit regulating this decision is the RB-mediated inhibition of E2F transcription factors, which control the expression of various S phase genes ( 34 ).…”

Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27

“…While the premise for the clinical use of CDK4/6 inhibitors is based on a "canonical" model of CDK4/6 activity, recent work has highlighted gaps in our understanding of the role of CDK4/6 in cell cycle entry (Pennycook & Barr, 2020;Hume et al, 2020;Rubin et al, 2020). In this canonical model, Cyclin D:CDK4/6 has a catalytic role, phosphorylating the transcriptional inhibitor Retinoblastoma protein (Rb) during G1, and partially relieving its inhibition of E2F-mediated transcription.…”

“…CDK4/6 inhibitors are able to arrest cells in G1 despite continued mitogen stimulation (Trotter & Hagan, 2020), indicating that p21 is the most likely candidate for mediating an indirect inhibition of CDK2. Mitogen stimulation results in the abrogation of the inhibitory activity of p27 towards CDK4 due to phosphorylation of the Y74 residue by non-receptor tyrosine kinases (NRTK) such as Src (Chu et al, 2007;Grimmler et al, 2007;Guiley et al, 2019;Hume et al, 2020;Tsytlonok et al, 2019). Further, NRTK signalling can also result in Y88 phosphorylation of p27, which ejects the inhibitory 310 helix of p27 from the CDK2 active site, partially restoring CDK2 activity (Grimmler et al, 2007).…”