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Science 288 (5470): 1425-1429

Copyright © 2000 by the American Association for the Advancement of Science

Rapid Destruction of Human Cdc25A in Response to DNA Damage

Niels Mailand, Jacob Falck, Claudia Lukas, Randi G. Syljuåsen, Markus Welcker, Jiri Bartek, * Jiri Lukas

To protect genome integrity and ensure survival, eukaryotic cells exposed to genotoxic stress cease proliferating to provide time for DNA repair. Human cells responded to ultraviolet light or ionizing radiation by rapid, ubiquitin- and proteasome-dependent protein degradation of Cdc25A, a phosphatase that is required for progression from G1 to S phase of the cell cycle. This response involved activated Chk1 protein kinase but not the p53 pathway, and the persisting inhibitory tyrosine phosphorylation of Cdk2 blocked entry into S phase and DNA replication. Overexpression of Cdc25A bypassed this mechanism, leading to enhanced DNA damage and decreased cell survival. These results identify specific degradation of Cdc25A as part of the DNA damage checkpoint mechanism and suggest how Cdc25A overexpression in human cancers might contribute to tumorigenesis.

Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.
*   To whom correspondence should be addressed. E-mail: bartek{at}biobase.dk

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The Cytokinin Requirement for Cell Division in Cultured Nicotiana plumbaginifolia Cells Can Be Satisfied by Yeast Cdc25 Protein Tyrosine Phosphatase. Implications for Mechanisms of Cytokinin Response and Plant Development.
K. Zhang, L. Diederich, and P. C.L. John (2005)
Plant Physiology 137, 308-316
   Abstract »    Full Text »    PDF »
On the Slowing of S Phase in Response to DNA Damage in Fission Yeast.
S. Kumar and J. A. Huberman (2004)
J. Biol. Chem. 279, 43574-43580
   Abstract »    Full Text »    PDF »
Repression of G0/G1 Traverse in Human Fibroblasts Exposed to Low Levels of Ionizing Radiation.
W. Wharton (2004)
J. Biol. Chem. 279, 43667-43674
   Abstract »    Full Text »    PDF »
Cdc7 Inhibition Reveals a p53-Dependent Replication Checkpoint That Is Defective in Cancer Cells.
A. Montagnoli, P. Tenca, F. Sola, D. Carpani, D. Brotherton, C. Albanese, and C. Santocanale (2004)
Cancer Res. 64, 7110-7116
   Abstract »    Full Text »    PDF »
Discovery and Characterization of Novel Small Molecule Inhibitors of Human Cdc25B Dual Specificity Phosphatase.
M. Brisson, T. Nguyen, A. Vogt, J. Yalowich, A. Giorgianni, D. Tobi, I. Bahar, C. R. J. Stephenson, P. Wipf, and J. S. Lazo (2004)
Mol. Pharmacol. 66, 824-833
   Abstract »    Full Text »    PDF »
5-Fluoro-2'-Deoxyuridine-Induced cdc25A Accumulation Correlates with Premature Mitotic Entry and Clonogenic Death in Human Colon Cancer Cells.
L. A. Parsels, J. D. Parsels, D. C.-H. Tai, D. J. Coughlin, and J. Maybaum (2004)
Cancer Res. 64, 6588-6594
   Abstract »    Full Text »    PDF »
Enhanced 7-Ethyl-10-hydroxycamptothecin (SN-38) Lethality by Methylselenocysteine Is Associated with Chk2 Phosphorylation at Threonine-68 and Down-Regulation of Cdc6 Expression.
M.-B. Yin, Z.-R. Li, S. Cao, F. A. Durrani, R. G. Azrak, C. Frank, and Y. M. Rustum (2004)
Mol. Pharmacol. 66, 153-160
   Abstract »    Full Text »    PDF »
DNA damage responses triggered by a highly cytotoxic monofunctional DNA alkylator, hedamycin, a pluramycin antitumor antibiotic.
L. C. Tu, T. Melendy, and T. A. Beerman (2004)
Mol. Cancer Ther. 3, 577-586
   Abstract »    Full Text »    PDF »
Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated-dependent and -independent mechanisms.
W. Y. Siu, A. Lau, T. Arooz, J. P.H. Chow, H. T.B. Ho, and R. Y.C. Poon (2004)
Mol. Cancer Ther. 3, 621-632
   Abstract »    Full Text »    PDF »
Rad9 Protects Cells from Topoisomerase Poison-induced Cell Death.
D. Loegering, S. J. H. Arlander, J. Hackbarth, B. T. Vroman, P. Roos-Mattjus, K. M. Hopkins, H. B. Lieberman, L. M. Karnitz, and S. H. Kaufmann (2004)
J. Biol. Chem. 279, 18641-18647
   Abstract »    Full Text »    PDF »
Suppression of WEE1 and Stimulation of CDC25A Correlates with Endothelin-dependent Proliferation of Rat Aortic Smooth Muscle Cells.
S. Chen and D. G. Gardner (2004)
J. Biol. Chem. 279, 13755-13763
   Abstract »    Full Text »    PDF »

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