title: A Dynamical Framework for the All-or-None G1/S Transition.
abstract: The transition from G1 into DNA replication (S phase) is an emergent behavior resulting from dynamic and complex interactions between cyclin-dependent kinases (Cdks), Cdk inhibitors (CKIs), and the anaphase-promoting complex/cyclosome (APC/C). Understanding the cellular decision to commit to S phase requires a quantitative description of these interactions. We apply quantitative imaging of single human cells to track the expression of G1/S regulators and use these data to parametrize a stochastic mathematical model of the G1/S transition. We show that a rapid, proteolytic, double-negative feedback loop between Cdk2:Cyclin and the Cdk inhibitor p27(Kip1) drives a switch-like entry into S phase. Furthermore, our model predicts that increasing Emi1 levels throughout S phase are critical in maintaining irreversibility of the G1/S transition, which we validate using Emi1 knockdown and live imaging of G1/S reporters. This work provides insight into the general design principles of the signaling networks governing the temporally abrupt transitions between cell-cycle phases.
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
authors.forename: Alexis R
authors.initials: AR
authors.lastname: Barr
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Frank S
authors.initials: FS
authors.lastname: Heldt
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Tongli
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Division of Cancer Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. Electronic address: chris.bakal@icr.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Bakal
authors.affiliation: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address: bela.novak@bioch.ox.ac.uk.
authors.forename: Béla
authors.initials: B
authors.lastname: Novák
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins; D016193:G1 Phase; D006801:Humans; D016196:S Phase
chemical_list: D018797:Cell Cycle Proteins; D064173:Anaphase-Promoting Complex-Cyclosome