A major role for mitotic CDC2 kinase inactivation in the establishment of the mitotic DNA damage checkpoint.
Cdc2 kinase is inactivated when DNA damage occurs during the spindle assembly checkpoint. Here, we show that the level of mitotic Bloom syndrome protein phosphorylation reflects the level of cdc2 activity. A complete inactivation of cdc2 by either introduction of DNA double-strand breaks or roscovitine treatment prevents exit from mitosis. Thus, mitotic cdc2 inactivation plays a major role in the establishment of the mitotic DNA damage checkpoint. In response to mitotic cdc2 inactivation, the M/G(1) transition is delayed after releasing the drug block in nonmalignant cells, whereas tumor cells exit mitosis without dividing and rereplicate their DNA, which results in mitotic catastrophe. This opens the way for new chemotherapeutic strategies.
Bayart
Emilie
E
CNRS, UMR 8126 and CNRS, UMR 8125, Institut Gustave Roussy, Villejuif, France.
Grigorieva
Olga
O
Leibovitch
Serge
S
Onclercq-Delic
Rosine
R
Amor-Guéret
Mounira
M
D000251:Adenosine Triphosphatases / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D002738:Chloroquine / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004265:DNA Helicases / Q000378:metabolism; D004789:Enzyme Activation; D016193:G1 Phase / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D053484:RecQ Helicases; D000077546:Roscovitine; D013347:Subcellular Fractions / Q000378:metabolism
D006877:Hydroxamic Acids; D011687:Purines; D000077546:Roscovitine; C012589:trichostatin A; D002738:Chloroquine; D004247:DNA; D016203:CDC2 Protein Kinase; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases