Topoisomerase II and histone deacetylase inhibitors delay the G2/M transition by triggering the p38 MAPK checkpoint pathway.
When early prophase PtK(1) 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.
Division of Molecular Medicine, Wadsworth Center, P.O. Box 509, Albany, NY 12201-0509, USA.
Alexei
A
Mikhailov
Mio
M
Shinohara
Conly L
CL
Rieder
D015250:Aclarubicin / Q000494:pharmacology; D000705:Anaphase; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002384:Catalysis; D045744:Cell Line, Tumor; D002843:Chromatin / Q000648:ultrastructure; D002875:Chromosomes / Q000187:drug effects / Q000648:ultrastructure; D004249:DNA Damage; D054659:Diketopiperazines; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D016195:G2 Phase; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007834:Lasers; D018715:Microscopy, Video; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008938:Mitosis; D009995:Osmosis; D010879:Piperazines / Q000494:pharmacology; D008941:Spindle Apparatus; D013858:Thiobarbiturates / Q000494:pharmacology; D013997:Time Factors; D059005:Topoisomerase II Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002843:Chromatin; D054659:Diketopiperazines; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010879:Piperazines; D013858:Thiobarbiturates; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D015250:Aclarubicin; D004317:Doxorubicin; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C045459:merbarone