Abstract
After exposure to genotoxic stress, proliferating cells actively slow down the DNA replication through a S-phase checkpoint to provide time for repair. We report that in addition to the ataxia-telangiectasia mutated (ATM)-dependent pathway that controls the fast response, there is an ATM-independent pathway that controls the slow response to regulate the S-phase checkpoint after ionizing radiation in mammalian cells. The slow response of S-phase checkpoint, which is resistant to wortmannin, sensitive to caffeine and UCN-01, and related to cyclin-dependent kinase phosphorylation, is much stronger in CHK1 overexpressed cells, and it could be abolished by Chk1 antisense oligonucleotides. These results provide evidence that the ATM-independent slow response of S-phase checkpoint involves CHK1 pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Ataxia Telangiectasia / pathology
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Ataxia Telangiectasia Mutated Proteins
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CDC2-CDC28 Kinases*
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Cell Cycle Proteins
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Checkpoint Kinase 1
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism
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DNA / biosynthesis
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DNA Replication / drug effects
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DNA Replication / radiation effects
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DNA-Binding Proteins
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Enzyme Activation
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Fibroblasts / radiation effects
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Humans
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Oligonucleotides, Antisense / genetics
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Oligonucleotides, Antisense / pharmacology
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Serine-Threonine Kinases / physiology*
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S Phase / drug effects
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S Phase / physiology*
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S Phase / radiation effects
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Tumor Suppressor Proteins
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Oligonucleotides, Antisense
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Tumor Suppressor Proteins
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DNA
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Protein Kinases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases