title: DNA damage-induced cell death is enhanced by progression through mitosis.
abstract: Progression through the G(2)/M transition following DNA damage is linked to cytokinesis failure and mitotic death. In four different transformed cell lines and two human embryonic stem cell lines, we find that DNA damage triggers mitotic chromatin decondensation and global phosphorylation of histone H2AX, which has been associated with apoptosis. However, extended time-lapse studies in HCT116 colorectal cancer cells indicate that death does not take place during mitosis, but 72% of cells die within 3 days of mitotic exit. By contrast, only 11% of cells in the same cultures that remained in interphase died, suggesting that progression through mitosis enhances cell death following DNA damage. These time-lapse studies also confirmed that DNA damage leads to high rates of cytokinesis failure, but showed that cells that completed cytokinesis following damage died at higher rates than cells that failed to complete division. Therefore, post-mitotic cell death is not a response to cytokinesis failure or polyploidy. We also show that post-mitotic cell death is largely independent of p53 and is only partially suppressed by the apical caspase inhibitor Z-VAD-FMK. These findings suggest that progression through mitosis following DNA damage initiates a p53- and caspase-independent cell death response that prevents propagation of genetic lesions.
authors.affiliation: Program in Cell and Developmental Dynamics and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Hanne
authors.initials: H
authors.lastname: Varmark
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Sparks
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Nordberg
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Koppetsch
authors.forename: William E
authors.initials: WE
authors.lastname: Theurkauf
mesh_terms: D020169:Caspases; D016923:Cell Death / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D048749:Cytokinesis; D004249:DNA Damage; D053595:Embryonic Stem Cells; D045325:HCT116 Cells; D006801:Humans; D007700:Kinetics; D008938:Mitosis; D016159:Tumor Suppressor Protein p53
chemical_list: D016159:Tumor Suppressor Protein p53; D020169:Caspases