Rapid destruction of human Cdc25A in response to DNA damage

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 - 10.1126/science.288.5470.1425

DO - 10.1126/science.288.5470.1425

M3 - Journal article

C2 - 10827953

SN - 0036-8075

VL - 288

SP - 1425

EP - 1429

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 5470

ER -