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Published online 9 August 2004. doi:10.1083/jcb.200405167
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 4, 517-526
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Article

 Topoisomerase II and histone deacetylase inhibitors delay the G2/M transition by triggering the p38 MAPK checkpoint pathway

Alexei Mikhailov1, Mio Shinohara1,2, and Conly L. Rieder1,2,3

1 Division of Molecular Medicine, Wadsworth Center, New York State Department of Health, Empire State Plaza, Albany, NY 12201
2 Department of Biomedical Sciences, State University of New York, Albany, NY 12222
3 Marine Biology Laboratory, Woods Hole, MA 02543

Address correspondence to Conly L. Rieder, Lab of Cell Regulation, Division of Molecular Medicine, Wadsworth Center, P.O. Box 509, Albany, NY 12201-0509. Tel.: (518) 474-6774. Fax: (518) 486-4801. email: Rieder{at}Wadsworth.org

When early prophase PtK1 or Indian muntjac cells are exposed to topoisomerase II (topo II) inhibitors that induce little if any DNA damage, they are delayed from entering mitosis. We show that this delay is overridden by inhibiting the p38, but not the ATM, kinase. Treating early prophase cells with hyperosmotic medium or a histone deacetylase inhibitor similarly delays entry into mitosis, and this delay can also be prevented by inhibiting p38. Together, these results reveal that agents or stresses that induce global changes in chromatin topology during G2 delay entry into mitosis, independent of the ATM-mediated DNA damage checkpoint, by activating the p38 MAPK checkpoint. The presence of this pathway obviates the necessity of postulating the existence of multiple "chromatin modification" checkpoints during G2. Lastly, cells that enter mitosis in the presence of topo II inhibitors form metaphase spindles that are delayed in entering anaphase via the spindle assembly, and not the p38, checkpoint.

Key Words: mitosis; DNA; aclarubicin; merbarone; apicidin; ICRF-193

Abbreviations used in this paper: DSB, double-strand break; IMF, immunofluorescence; JNK, Jun-N-terminal; NEB, nuclear envelope breakdown; topo II, topoisomerase II.


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