Inhibition of DNA decatenation, but not DNA damage, arrests cells at metaphase.
DNA damage by double-strand breaks induces arrest during interphase in mammalian cells. It is not clear whether DNA damage can arrest cells in mitosis. We show here that three human cell lines, HeLa, U2OS, and HCT116, do not delay in mitosis in response to double-strand breaks induced during mitosis by gamma irradiation or by adriamycin. Durable arrest at metaphase occurs, however, with ICRF-193, a topoisomerase II inhibitor that does not damage DNA. Arrest with ICRF-193 is not accompanied by recruitment of Mad2 or Bub1 to kinetochores, nor by phosphorylation of the histone H2AX, indicating arrest by ICRF-193 is not due to activation of the spindle assembly checkpoint, nor is it a response to DNA damage. VP-16, another decatenation inhibitor, induces metaphase arrest only at concentrations well above those that induce DNA damage. We conclude that decatenation failure, but not DNA damage, creates metaphase arrest in mammalian cells.
Skoufias
Dimitrios A
DA
Institut de Biologie Structurale J-P Ebel (CEA-CNRS), 41 rue Jules Horowitz, 38027 Grenoble cedex 1, France.
Lacroix
Françoise B
FB
Andreassen
Paul R
PR
Wilson
Leslie
L
Margolis
Robert L
RL
D045744:Cell Line, Tumor; D004247:DNA / Q000502:physiology*; D004249:DNA Damage; D054659:Diketopiperazines; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008677:Metaphase; D008938:Mitosis / Q000187:drug effects; D015739:Nocodazole / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D005047:Etoposide; D004247:DNA; D015739:Nocodazole