DNA damage during mitosis invokes a JNK-mediated stress response that leads to cell death.
Mitotic catastrophe is a phenomenon displayed by cells undergoing aberrant mitosis to eliminate cells that fail to repair the errors. Why and how mitotic catastrophe would lead to cell death remains to be resolved and the answer will prove valuable in design of better therapeutic agents that specifically target such cells in mitosis. The antibiotic actinomycin D has been shown to induce chromosomal lesions in lower order organisms as well as in human interphase cells. Relatively few studies have been conducted to elucidate molecular events in the context of mitotic DNA damage. We have previously established a model of mitotic catastrophe in human HeLa cells induced by actinomycin D. Here, we show that actinomycin D induce cellular stress via DNA damage during mitosis. The higher order packing of chromosomes during mitosis might impede efficient DNA repair. gammaH2AX serves as a marker for DNA repair and active JNK interacts with gammaH2AX in actinomycin D-treated mitotic extracts. We believe JNK might be in part, responsible for the phosphorylation of H2AX and thereby, facilitate the propagation of a positive signal for cell death, when repair is not achieved. The mitotic cell activates JNK-mediated cell death response that progresses through a caspase cascade downstream of the mitochondria. In the mean time, remaining checkpoint signals may be sufficient to put a restraining hand on entry into anaphase and the cell eventually dies in mitosis.
Ho
Chin-Yee
CY
Division of Molecular and Cell Biology, School of Biological Sciences, College of Science, Nanyang Technological University, Singapore 637551, Singapore.
Li
Hoi-Yeung
HY
D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004247:DNA / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D048670:MAP Kinase Kinase 4 / Q000187:drug effects / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*
C468783:H2AX protein, human; D006657:Histones; D019384:Nucleic Acid Synthesis Inhibitors; D003609:Dactinomycin; D004247:DNA; D048670:MAP Kinase Kinase 4; D020169:Caspases