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

The G2/M transition and mitotic exit rely on a feedback loop involving CDK1, Greatwall kinase, and the PP2A-B55 phosphatase. Disruptions in these regulators cause cellular dysfunction, genomic instability, and cancer-like traits. However, the interaction of these factors and their context-dependence remain unknown. This study examines how the combined perturbation of CDK1, Greatwall, and PP2A-B55 affects cell-cycle control in non-transformed RPE-1 and cancerous HeLa cells.

The researchers find that PP2A-B55 acts as a G2/M repressor in cancer cells, working alongside PKMYT1 and WEE1 to prevent premature mitosis. When PP2A-B55 activity is reduced and Greatwall expression is increased, there is heightened sensitivity to the PKMYT1-specific drug RP-6306 and moderate sensitivity to the WEE1-specific adavosertib in cancer cells.

This differential sensitivity reveals a functional distinction between WEE1 and PKMYT1 in S- and G2-phase regulation. The findings highlight the cell-type-specific roles of CDK1, Greatwall, and PP2A-B55 in cell-cycle regulation and suggest G2/M plasticity as a potential vulnerability for targeting in PKMYT1-mediated therapies.