Rapid destruction of human Cdc25A in response to DNA damage
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Rapid destruction of human Cdc25A in response to DNA damage. / Mailand, Niels; Falck, J; Lukas, C; Syljuåsen, Randi Gussgard; Welcker, M; Bartek, J; Lukas, J.
In: Science (New York, N.Y.), Vol. 288, No. 5470, 26.05.2000, p. 1425-9.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Rapid destruction of human Cdc25A in response to DNA damage
AU - Mailand, Niels
AU - Falck, J
AU - Lukas, C
AU - Syljuåsen, Randi Gussgard
AU - Welcker, M
AU - Bartek, J
AU - Lukas, J
PY - 2000/5/26
Y1 - 2000/5/26
N2 - 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.
AB - 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.
KW - CDC2-CDC28 Kinases
KW - Cell Line
KW - Cell Survival
KW - Cyclin E
KW - Cyclin-Dependent Kinase 2
KW - Cyclin-Dependent Kinases
KW - Cysteine Endopeptidases
KW - DNA Damage
KW - DNA Repair
KW - DNA Replication
KW - G1 Phase
KW - Humans
KW - Multienzyme Complexes
KW - Phosphorylation
KW - Phosphotyrosine
KW - Proteasome Endopeptidase Complex
KW - Protein Kinase Inhibitors
KW - Protein Kinases
KW - Protein-Serine-Threonine Kinases
KW - Recombinant Fusion Proteins
KW - S Phase
KW - Transfection
KW - Tumor Cells, Cultured
KW - Tumor Suppressor Protein p53
KW - Ultraviolet Rays
KW - cdc25 Phosphatases
U2 - DOI: 10.1126/science.288.5470.1425
DO - DOI: 10.1126/science.288.5470.1425
M3 - Journal article
C2 - 10827953
VL - 288
SP - 1425
EP - 1429
JO - Science
JF - Science
SN - 0036-8075
IS - 5470
ER -
ID: 124905234