Cdk1-dependent lamin aggregation underlies oxidative stress-induced nuclear shape abnormalities |
Ju-Hyun Ahn1,2,4,# (Post-doc (Researcher)), Min-Guk Cho1,2,5,# (Post-doc (Researcher)), Abdul Basit 1,2,# (Doctoral Student), In-Kang Song3 (Researcher), Kong-Joo Lee3 (Professor), Jae-Ho Lee1,2,* (Professor) |
1Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-721, South Korea, 2Department of Biomedical Sciences, The Graduate School of Ajou University, Suwon 443-721, South Korea, 3College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea, 4present address: Department of Microbiology and Immunology and 5present address: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina 27599, USA |
Abstract
Altered nuclear morphology is one of the characteristics of cancer cells, often indicative of tumor prognosis. While reactive oxygen species (ROS) are known to induce nuclear morphology changes, the mechanisms underlying these effects remain elusive, particularly regarding nuclear assembly. We hypothesized that mitotic cells may exhibit increased susceptibility to ROS-induced nuclear deformation due to the dynamic nature of the nuclear envelope during mitosis, i.e., disassembly and reassembly. Interestingly, we discovered that exposure of mitotic cells to hydrogen peroxide (H2O2) resulted in the 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 H2O2-mediated reduction in Cdk1 activity, resulting in diminished phosphorylation of lamin, a key Cdk1 substrate. Notably, the 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 triggers lamin aggregation that affects lamin reassembly, thereby disrupting nuclear morphology. Our study elucidates a novel mechanism by which ROS disrupts nuclear architecture via modulation of Cdk1 activity during mitosis.
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Abstract, Accepted Manuscript [Submitted on October 21, 2024, Accepted on December 18, 2024] |
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