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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}

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Cytokine-driven cell cycling is mediated through Cdc25A.
A. R. Khaled, D. V. Bulavin, C. Kittipatarin, W. Q. Li, M. Alvarez, K. Kim, H. A. Young, A. J. Fornace, and S. K. Durum (2005)
J. Cell Biol. 169, 755-763
   Abstract »    Full Text »    PDF »
{beta}-TrCP recognizes a previously undescribed nonphosphorylated destruction motif in Cdc25A and Cdc25B phosphatases.
Y. Kanemori, K. Uto, and N. Sagata (2005)
PNAS 102, 6279-6284
   Abstract »    Full Text »    PDF »
Inhibition of Human Chk1 Causes Increased Initiation of DNA Replication, Phosphorylation of ATR Targets, and DNA Breakage.
R. G. Syljuasen, C. S. Sorensen, L. T. Hansen, K. Fugger, C. Lundin, F. Johansson, T. Helleday, M. Sehested, J. Lukas, and J. Bartek (2005)
Mol. Cell. Biol. 25, 3553-3562
   Abstract »    Full Text »    PDF »
The Role of Checkpoint Kinase 1 in Sensitivity to Topoisomerase I Poisons.
K. Flatten, N. T. Dai, B. T. Vroman, D. Loegering, C. Erlichman, L. M. Karnitz, and S. H. Kaufmann (2005)
J. Biol. Chem. 280, 14349-14355
   Abstract »    Full Text »    PDF »
Normal Cell Cycle and Checkpoint Responses in Mice and Cells Lacking Cdc25B and Cdc25C Protein Phosphatases.
A. M. Ferguson, L. S. White, P. J. Donovan, and H. Piwnica-Worms (2005)
Mol. Cell. Biol. 25, 2853-2860
   Abstract »    Full Text »    PDF »
Novel hydroxyl naphthoquinones with potent Cdc25 antagonizing and growth inhibitory properties.
V. P. Peyregne, S. Kar, S. W. Ham, M. Wang, Z. Wang, and B. I. Carr (2005)
Mol. Cancer Ther. 4, 595-602
   Abstract »    Full Text »    PDF »
p53 C-Terminal Phosphorylation by CHK1 and CHK2 Participates in the Regulation of DNA-Damage-induced C-Terminal Acetylation.
Y.-H. Ou, P.-H. Chung, T.-P. Sun, and S.-Y. Shieh (2005)
Mol. Biol. Cell 16, 1684-1695
   Abstract »    Full Text »    PDF »
TTK/hMps1 Participates in the Regulation of DNA Damage Checkpoint Response by Phosphorylating CHK2 on Threonine 68.
J.-H. Wei, Y.-F. Chou, Y.-H. Ou, Y.-H. Yeh, S.-W. Tyan, T.-P. Sun, C.-Y. Shen, and S.-Y. Shieh (2005)
J. Biol. Chem. 280, 7748-7757
   Abstract »    Full Text »    PDF »
Methylator-induced, Mismatch Repair-dependent G2 Arrest Is Activated through Chk1 and Chk2.
A. W. Adamson, D. I. Beardsley, W.-J. Kim, Y. Gao, R. Baskaran, and K. D. Brown (2005)
Mol. Biol. Cell 16, 1513-1526
   Abstract »    Full Text »    PDF »
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 »

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