Condensin I recruitment and uneven chromatin condensation precede mitotic cell death in response to DNA damage.
Mitotic cell death (MCD) is a prominent but poorly defined form of death that stems from aberrant mitosis. One of the early steps in MCD is premature mitosis and uneven chromatin condensation (UCC). The mechanism underlying this phenomenon is currently unknown. In this study, we show that DNA damage in cells with a compromised p53-mediated G2/M checkpoint triggers the unscheduled activation of cyclin-dependent kinase 1 (Cdk1), activation and chromatin loading of the condensin I complex, and UCC followed by the appearance of multimicronucleated cells, which is evidence of MCD. We demonstrate that these processes engage some of the players of normal mitotic chromatin packaging but not those that drive the apoptotic chromatin condensation. Our findings establish a link between the induction of DNA damage and mitotic abnormalities (UCC) through the unscheduled activation of Cdk1 and recruitment of condensin I. These results demonstrate a clear distinction between the mechanisms that drive MCD-associated and apoptosis-related chromatin condensation and provide mechanistic insights and new readouts for a major cell death process in treated tumors.
Blank
Michael
M
The David and Inez Myers Laboratory for Genetic Research, Department of Molecular Genetics and Biochemistry, and Interdepartmental Core Facility, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Lerenthal
Yaniv
Y
Mittelman
Leonid
L
Shiloh
Yosef
Y
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D016923:Cell Death; D002466:Cell Nucleolus / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D016195:G2 Phase / Q000235:genetics; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D008957:Models, Genetic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D021381:Protein Transport; D014407:Tumor Cells, Cultured; D000097722:Cohesins
D000251:Adenosine Triphosphatases; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D000097722:Cohesins; C108312:condensin complexes