The Greatwall/PP2A-B55α axis remodels the G2/M boundary and shapes cellular dependence on PKMYT1
- 1University of Sussex
Abstract
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.
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BibTeX
@misc{zach2026greatwallpp2ab55α,
title = {{The Greatwall/PP2A-B55α axis remodels the G2/M boundary and shapes cellular dependence on PKMYT1}},
author = {R. Zach and A. Herbert and C.-M. Dragoi and M. Meredith and L. Gadelkarim and W. Foster and H. Hochegger},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749407},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749407v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - The Greatwall/PP2A-B55α axis remodels the G2/M boundary and shapes cellular dependence on PKMYT1
AU - R. Zach
AU - A. Herbert
AU - C.-M. Dragoi
AU - M. Meredith
AU - L. Gadelkarim
AU - W. Foster
AU - H. Hochegger
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749407
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749407v1
AB - 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.
ER -