Restriction point regulation at the crossroads between quiescence and cell proliferation

Pennycook, Betheney R.; Barr, Alexis R.

doi:10.1002/1873-3468.13867

Cited by 57 publications

(73 citation statements)

References 150 publications

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“…It should be noted that other models favour the proteasomal degradation of p21, which also occurs in late G1 at a similar time to APC/C-CDH1 inactivation, as the identity of the final commitment point for S phase entry ( 20 , 90 ). Furthermore, in cells treated with CDK4/6 inhibitors, Rb inactivation becomes the final, DNA damage-resistant commitment point, suggesting that the molecular basis for cell cycle commitment is adaptable, not rigid ( 41 ).…”

Section: Models For S Phase Commitmentmentioning

confidence: 99%

A unified model for the G1/S cell cycle transition

Hume

Dianov

Ramadan

2020

Nucleic Acids Research

130

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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.

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Section: Models For S Phase Commitmentmentioning

confidence: 99%

A unified model for the G1/S cell cycle transition

Hume

Dianov

Ramadan

2020

Nucleic Acids Research

130

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“…Cdks are subject to layers of regulation to ensure quiescent cells only enter the cell cycle in response to appropriate environmental cues. 2 Cdk activation requires Cyclin binding and T-loop phosphorylation in the Cdk-activating segment by Cdk-activating kinase (CAK). Mitogenic signalling promotes Cyclin D expression, which binds Cdk4 (or Cdk6) to initiate progression from G0 into G1.…”

mentioning

confidence: 99%

Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation

Warnecke

et al. 2021

Preprint

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Balanced proliferation-quiescence decisions are vital during normal development and in tissue homeostasis and their dysregulation underlies tumorigenesis. Entry into proliferative cycles is driven by Cyclin/Cyclin-dependent kinases (Cdks). Conserved Cdk inhibitors (CKIs), p21(Cip1/Waf1), p27(Kip1) and p57(Kip2), bind to Cyclin/Cdks and inhibit Cdk activity. p27 tyrosine phosphorylation, in response to mitogenic signalling, promotes activation of CyclinD/Cdk4 and CyclinA/Cdk2. Tyrosine phosphorylation is conserved in p21 and p57, although the number of sites differs. We use molecular dynamics simulations to compare the structural changes in Cyclin/Cdk/CKI trimers induced by single and multiple tyrosine phosphorylation in CKIs and their impact on CyclinD/Cdk4 and CyclinA/Cdk2 activity. Despite shared structural features, CKI binding induces distinct structural responses in Cyclin/Cdks and the predicted effects of CKI tyrosine phosphorylation on Cdk activity are not conserved across CKIs. Our analyses suggest how CKIs may have evolved to be sensitive to different inputs to give context-dependent control of Cdk activity.

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“…Before the Restriction Point (RP), entry of mammalian cells into the cell cycle depends on stimulation by growth factors (GFs); after the RP, further progression through the cell cycle is independent of GF until the cell divides [24-26]. Activation of E2F-dependent transcription underlies the RP.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of signalling-memory governing progression through the eukaryotic cell cycle

Novák

Tyson

2020

Preprint

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As cells pass through each replication-division cycle, they must be able to postpone further progression if they detect any threats to genome integrity, such as DNA damage or misaligned chromosomes. Once a decision is made to proceed, the cell unequivocally enters into a qualitatively different biochemical state, which makes the transitions from one cell cycle phase to the next switch-like and irreversible. Each transition is governed by a unique signalling network; nonetheless, they share a common characteristic of bistable behaviour, a hallmark of molecular memory devices. Comparing the cell cycle signalling mechanisms acting at the Restriction Point, G1/S, G2/M and meta-to-anaphase transitions, we deduce a generic network motif of coupled positive and negative feedback loops underlying each transition.

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Restriction point regulation at the crossroads between quiescence and cell proliferation

Cited by 57 publications

References 150 publications

A unified model for the G1/S cell cycle transition

A unified model for the G1/S cell cycle transition

Conserved Cdk inhibitors show unique structural responses to tyrosine phosphorylation

Mechanisms of signalling-memory governing progression through the eukaryotic cell cycle

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