Biology subjects

Dragoi, C.-M.

Publications and source records attributed to Dragoi, C.-M..

5 recordsLinked to original sources

bioRxiv2026

The Greatwall/PP2A-B55α axis remodels the G2/M boundary and shapes cellular dependence on PKMYT1

The switch-like G2/M transition and mitotic exit depend on a feedback loop comprising CDK1, Greatwall kinase, and the PP2A-B55 phosphatase. Monogenic disruptions of these regulators impair cellular functions, drive genomic instability, and promote cancer-associated characteristics. Yet how perturbations of this feedback loop interact, and whether their effects depend on cellular context, remain unclear. Here, we assess how combinatorial perturbations of CDK1, Greatwall, and PP2A-B55 affect cell-cycle control in non-transformed RPE-1 and tumour-derived HeLa cells. We identify PP2A-B55 as a context-dependent G2/M repressor with a critical role in cancer cells, where it cooperates with PKMYT1 and, to a lesser extent, WEE1 to prevent premature mitosis. In cancer cells, but not in non-transformed cells, reduced PP2A-B55 activity and Greatwall overexpression produce marked sensitisation to the PKMYT1-selective RP-6306 and modest sensitisation to the WEE1-selective adavosertib. This asymmetric sensitisation reflects a functional separation between WEE1 and PKMYT1 in S- and G2-phase control. Our work outlines fundamental and cell-type-specific contributions of CDK1, Greatwall and PP2A-B55 to cell-cycle regulation and proposes G2/M plasticity as a vulnerability with utility in PKMYT1-targeted therapy.

cell biology↗

bioRxiv2025

Wee1 opposes APC/C(Cdh1) activity to promote S-phase entry

Wee1 phosphorylates and inhibits CDK activity to inhibit mitotic entry and establish a G2 DNA damage checkpoint. Consequently, Wee1 inhibitors are in clinical trials, developed to be synthetically lethal in TP53 mutant tumours that become reliant on a Wee1-mediated DNA damage checkpoint. However, Wee1 inhibitors have efficacy in TP53 wild-type tumours and many trials have been terminated due to high levels of toxic side-effects, suggesting that Wee1 has unknown functions. Here, we show that Wee1 promotes cell cycle re-entry from quiescence (G0) by opposing the activity of the E3 ubiquitin ligase, APC/CCdh1. Wee1 phosphorylates Cdh1 (FZR1) at key residues that mediate the interaction between Cdh1 and APC/C. Cells with loss-of-function of Wee1 during G0/G1 have delayed S-phase entry, an impaired G1/S transition, abnormal S-phase accumulation of the CDK inhibitor p21 and enter a p21-dependent G2 arrest. Reduced expression of APC/CCdh1 or p21 renders cells more sensitive to acute Wee1 inhibition and both pathways are downregulated in acquired Wee1 inhibitor resistance. Our study reveals a new cell cycle control mechanism that has implications for how Wee1 inhibitors should be used in the clinic.

cell biology↗

bioRxiv2025

A Wheel of Fortune: the eukaryotic cell cycle as a tetra-stable excitable system

Progression through the eukaryotic cell cycle is governed by a complex biochemical network controlling the activation of cyclin-dependent kinases. Dynamically, the cell cycle control network can be viewed as a multi-stable system, in which nonlinear feedback loops generate multiple stable attractors, corresponding to distinct cell cycle phases (G1, S, G2, M). Transitions between these states are typically irreversible, ensuring ordered phase progression. However, recent studies of endocycles - variants in which subsets of phases are abrogated - have prompted the development of more general regulatory models, allowing for reversible transitions or the decoupling of autonomous oscillatory modules. The current paper combines minimal ODE modelling, phase plane analysis, and bifurcation theory to demonstrate that two prior frameworks - Newtons Cradle and Latching Gate - are alternative representations of a shared architecture based on mutually regulated oscillators. Leveraging this insight, a generalized model is introduced that captures a broader spectrum of physiological endocycles than previously acknowledged. To provide an intuitive representation of the principles identified by the new model, a Wheel of Fortune analogy for cell cycle dynamics is introduced.

systems biology↗

bioRxiv2024

Newton's Cradle: Cell Cycle Regulation by Two Mutually Inhibitory Oscillators

The cell division cycle is a fundamental physiological process displaying a great degree of plasticity during the course of multicellular development. This plasticity is evident in the transition from rapid and stringently-timed divisions of the early embryo to subsequent size-controlled mitotic cycles. Later in development, cells may pause and restart cell proliferation in response to myriads of internal or external signals, or permanently exit the cell cycle following terminal differentiation or senescence. Beyond this, cells can undergo modified cell division variants, such as endoreplication, which increases their ploidy, or meiosis, which reduces their ploidy. This wealth of behaviours has led to numerous conceptual analogies intended as frameworks for understanding the proliferative program. Here, we aim to unify these mechanisms under one dynamical paradigm. To this end, we take a control theoretical approach to frame the cell cycle as a pair of arrestable and mutually-inhibiting, doubly amplified, negative feedback oscillators controlling chromosome replication and segregation events, respectively. Under appropriate conditions, this framework can reproduce fixed-period oscillations, checkpoint arrests of variable duration, and endocycles. Subsequently, we use phase plane and bifurcation analysis to explain the dynamical basis of these properties. Then, using a physiologically realistic, biochemical model, we show that the very same regulatory structure underpins the diverse functions of the cell cycle control network. We conclude that Newtons cradle may be a suitable mechanical analogy of how the cell cycle is regulated. Declaration of interestThe authors declare no competing or financial interests.

systems biology↗

bioRxiv2023

The oscillation of mitotic kinase governs cell cycle latches in mammalian cells

The mammalian cell cycle alternates between two phases: S-G2-M with high levels of A- and B-type cyclin-dependent kinases (CycA,B:CDK); and G1 with persistent degradation of CycA,B by Cdh1-activated APC/C (anaphase promoting complex/cyclosome). Because CDKs phosphorylate and inactivate Cdh1, these two phases are mutually exclusive. This toggle switch is flipped from G1 to S by cyclin-E (CycE:CDK), which is not degraded by Cdh1:APC/C; and from M to G1 by Cdc20:APC/C, which is not inactivated by CycA,B:CDK. After flipping the switch, cyclin E is degraded and Cdc20:APC/C is inactivated. Combining mathematical modelling with single-cell timelapse imaging, we show that dysregulation of CycB:CDK disrupts strict alternation of the G1-S and M-G1 switches. Inhibition of CycB:CDK results in Cdc20-independent Cdh1 endocycles, and sustained activity of CycB:CDK drives Cdh1-independent Cdc20 endocycles. Our model provides one mechanistic explanation for how whole genome doubling can arise, a common event in tumorigenesis that can drive tumour evolution.

systems biology↗