Abstract
The current paradigm based upon ionizing radiation (IR) studies states that cells deficient in either ataxia-telangiectasia-mutated kinase (ATM) or related phosphatidylinositol 3 (PI 3) -kinases (ATR and DNA-PK) are hypersensitive to DNA strand breaks because they are unable to rapidly activate downstream effectors such as p53. Here we have contrasted cell responses to IR and C-1027, a radiomimetic antibiotic that induces DNA strand breaks. At equal levels of DNA double strand breaks, cell lines with inactive ATM or other phosphatidylinositol 3-kinases displayed classical hypersensitivity to IR but not to C-1027. Moreover, phosphorylation of p53 Ser-15 induced by C-1027 was independent of ATM, ATR, or DNA-PK function. We have concluded that the model based on IR studies cannot always be directly applied to DNA damage induced by other strand-scission agents.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aminoglycosides*
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Anti-Bacterial Agents / pharmacology*
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Antibiotics, Antineoplastic / pharmacology*
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins*
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DNA / drug effects*
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DNA Damage*
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DNA-Activated Protein Kinase
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DNA-Binding Proteins*
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Enediynes
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Humans
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Nuclear Proteins
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism*
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Serine / metabolism
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins
Substances
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Aminoglycosides
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Anti-Bacterial Agents
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Antibiotics, Antineoplastic
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Cell Cycle Proteins
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DNA-Binding Proteins
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Enediynes
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Nuclear Proteins
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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C 1027
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Serine
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DNA
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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DNA-Activated Protein Kinase
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PRKDC protein, human
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Protein Serine-Threonine Kinases