Abstract
Elevated level of oxygen (hyperoxia) is widely used in critical care units and in respiratory insufficiencies. In addition, hyperoxia has been implicated in many diseases such as bronchopulmonary dysplasia or acute respiratory distress syndrome. Although hyperoxia is known to cause DNA base modifications and strand breaks, the DNA damage response has not been adequately investigated. We have investigated the effect of hyperoxia on DNA damage signaling and show that hyperoxia is a unique stress that activates the ataxia telangiectasia mutant (ATM)- and Rad3-related protein kinase (ATR)-dependent p53 phosphorylations (Ser6, -15, -37, and -392), phosphorylation of histone H2AX (Ser139), and phosphorylation of checkpoint kinase 1 (Chk1). In addition, we show that phosphorylation of p53 (Ser6) and histone H2AX (Ser139) depend on both ATM and ATR. We demonstrate that ATR activation precedes ATM activation in hyperoxia. Finally, we show that ATR is required for ATM activation in hyperoxia. Taken together, we report that ATR is the major DNA damage signal transducer in hyperoxia that activates ATM.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Adenocarcinoma
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Apoptosis / physiology
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Ataxia Telangiectasia Mutated Proteins
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Casein Kinase II / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Checkpoint Kinase 1
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DNA Repair
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Histones / genetics
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Histones / metabolism*
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Humans
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Hyperoxia / metabolism
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Hyperoxia / pathology
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Hyperoxia / physiopathology*
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Lung Neoplasms
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Phosphorylation
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Protein Kinases / genetics
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Protein Kinases / metabolism*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Serine / metabolism
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Signal Transduction / physiology
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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ATRIP protein, human
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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DNA-Binding Proteins
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H2AX protein, human
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Histones
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Serine
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Protein Kinases
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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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CHEK1 protein, human
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Casein Kinase II
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Checkpoint Kinase 1
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Protein Serine-Threonine Kinases