Cdk1-dependent lamin aggregation underlies oxidative stress-induced nuclear shape abnormalities.

Abstract

Altered nuclear morphology, one of the characteristics of cancer cells, is often indicative of tumor prognosis. While reactive oxygen species (ROS) are known to induce nuclear morphology changes, mechanisms underlying these effects remain elusive, particularly regarding nuclear assembly. We hypothesized that mitotic cells might exhibit increased susceptibility to ROSinduced nuclear deformation due to the dynamic nature of nuclear envelope during mitosis, i.e., disassembly and reassembly. Interestingly, we discovered that exposure of mitotic cells to hydrogen peroxide (H2O2) resulted in persistence of lamin aggregates during early mitosis, which coincided with aberrant nuclear morphology. Further investigation revealed a dampening effect of H2O2 on Cdk1, a pivotal kinase governing mitotic entry. Our in vitro kinase assays demonstrated that H2O2 mediated reduction of Cdk1 activity, resulting in diminished phosphorylation of lamin, a key Cdk1 substrate. Notably, restoration of Cdk1 activity rescued lamin phosphorylation, thereby mitigating lamin aggregation. Furthermore, persistence of lamin aggregation during mitotic entry correlated with premature reassembly of lamin during mitotic exit, affecting nuclear envelope reassembly. These findings collectively suggest that ROS-mediated perturbation of Cdk1 activity during early mitosis can trigger lamin aggregation that affects lamin reassembly, thereby disrupting nuclear morphology. Our study elucidates a novel mechanism by which ROS can disrupt nuclear architecture by modulating Cdk1 activity during mitosis.