The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
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The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. / Falck, J; Mailand, Niels; Syljuåsen, R G; Bartek, J; Lukas, J.
In: Nature, Vol. 410, No. 6830, 12.04.2001, p. 842-7.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
AU - Falck, J
AU - Mailand, Niels
AU - Syljuåsen, R G
AU - Bartek, J
AU - Lukas, J
PY - 2001/4/12
Y1 - 2001/4/12
N2 - When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the IR-induced S-phase checkpoint cause 'radioresistant DNA synthesis', a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia, a disease caused by mutations in the ATM gene. The Cdc25A phosphatase activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) and Cdc25A, and implicate this mechanism in controlling the S-phase checkpoint. We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. An IR-induced loss of Cdc25A protein prevents dephosphorylation of Cdk2 and leads to a transient blockade of DNA replication. We also show that tumour-associated Chk2 alleles cannot bind or phosphorylate Cdc25A, and that cells expressing these Chk2 alleles, elevated Cdc25A or a Cdk2 mutant unable to undergo inhibitory phosphorylation (Cdk2AF) fail to inhibit DNA synthesis when irradiated. These results support Chk2 as a candidate tumour suppressor, and identify the ATM-Chk2-Cdc25A-Cdk2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.
AB - When exposed to ionizing radiation (IR), eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the IR-induced S-phase checkpoint cause 'radioresistant DNA synthesis', a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia, a disease caused by mutations in the ATM gene. The Cdc25A phosphatase activates the cyclin-dependent kinase 2 (Cdk2) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Here we report a functional link between ATM, the checkpoint signalling kinase Chk2/Cds1 (Chk2) and Cdc25A, and implicate this mechanism in controlling the S-phase checkpoint. We show that IR-induced destruction of Cdc25A requires both ATM and the Chk2-mediated phosphorylation of Cdc25A on serine 123. An IR-induced loss of Cdc25A protein prevents dephosphorylation of Cdk2 and leads to a transient blockade of DNA replication. We also show that tumour-associated Chk2 alleles cannot bind or phosphorylate Cdc25A, and that cells expressing these Chk2 alleles, elevated Cdc25A or a Cdk2 mutant unable to undergo inhibitory phosphorylation (Cdk2AF) fail to inhibit DNA synthesis when irradiated. These results support Chk2 as a candidate tumour suppressor, and identify the ATM-Chk2-Cdc25A-Cdk2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis.
KW - Alleles
KW - Animals
KW - Ataxia Telangiectasia Mutated Proteins
KW - Cell Cycle
KW - Cell Cycle Proteins
KW - Cell Line
KW - Checkpoint Kinase 2
KW - DNA Replication
KW - DNA-Binding Proteins
KW - Humans
KW - Mice
KW - Phosphorylation
KW - Protein Kinases
KW - Protein-Serine-Threonine Kinases
KW - Radiation Tolerance
KW - Radiation, Ionizing
KW - S Phase
KW - Serine
KW - Signal Transduction
KW - Transfection
KW - Tumor Suppressor Proteins
KW - cdc25 Phosphatases
U2 - 10.1038/35071124
DO - 10.1038/35071124
M3 - Journal article
C2 - 11298456
VL - 410
SP - 842
EP - 847
JO - Nature
JF - Nature
SN - 0028-0836
IS - 6830
ER -
ID: 124905001