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

Abstract

Altered nuclear morphology, one of the characteristics ofcancer cells, is often indicative of tumor prognosis. While reactiveoxygen species (ROS) are known to induce nuclear morphologychanges, mechanisms underlying these effects remain elusive,particularly regarding nuclear assembly. We hypothesizedthat mitotic cells might exhibit increased susceptibility to ROSinducednuclear deformation due to the dynamic nature of nuclearenvelope during mitosis, i.e., disassembly and reassembly. Interestingly, we discovered that exposure of mitotic cells tohydrogen peroxide (H2O2) resulted in persistence of laminaggregates during early mitosis, which coincided with aberrantnuclear morphology. Further investigation revealed a dampeningeffect of H2O2 on Cdk1, a pivotal kinase governing mitoticentry. Our in vitro kinase assays demonstrated that H2O2 mediatedreduction of Cdk1 activity, resulting in diminished phosphorylationof lamin, a key Cdk1 substrate. Notably, restorationof Cdk1 activity rescued lamin phosphorylation, thereby mitigatinglamin aggregation. Furthermore, persistence of laminaggregation during mitotic entry correlated with premature reassemblyof lamin during mitotic exit, affecting nuclear envelopereassembly. These findings collectively suggest that ROS-mediatedperturbation of Cdk1 activity during early mitosis can triggerlamin aggregation that affects lamin reassembly, thereby disruptingnuclear morphology. Our study elucidates a novel mechanismby which ROS can disrupt nuclear architecture by modulatingCdk1 activity during mitosis.