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rdf:type |
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lifeskim:mentions |
umls-concept:C0012854,
umls-concept:C0012920,
umls-concept:C0024660,
umls-concept:C0031715,
umls-concept:C0205263,
umls-concept:C0596311,
umls-concept:C0674679,
umls-concept:C0871261,
umls-concept:C1172465,
umls-concept:C1330957,
umls-concept:C1334862,
umls-concept:C1417250,
umls-concept:C1419239,
umls-concept:C1427803,
umls-concept:C1704241,
umls-concept:C1704632,
umls-concept:C1705041,
umls-concept:C1706817,
umls-concept:C1879547,
umls-concept:C2911692
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pubmed:issue |
22
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pubmed:dateCreated |
2003-5-26
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pubmed:abstractText |
DNA double-strand breaks originating from diverse causes in eukaryotic cells are accompanied by the formation of phosphorylated H2AX (gammaH2AX) foci. Here we show that gammaH2AX formation is also a cellular response to topoisomerase I cleavage complexes known to induce DNA double-strand breaks during replication. In HCT116 human carcinoma cells exposed to the topoisomerase I inhibitor camptothecin, the resulting gammaH2AX formation can be prevented with the phosphatidylinositol 3-OH kinase-related kinase inhibitor wortmannin; however, in contrast to ionizing radiation, only camptothecin-induced gammaH2AX formation can be prevented with the DNA replication inhibitor aphidicolin and enhanced with the checkpoint abrogator 7-hydroxystaurosporine. This gammaH2AX formation is suppressed in ATR (ataxia telangiectasia and Rad3-related) deficient cells and markedly decreased in DNA-dependent protein kinase-deficient cells but is not abrogated in ataxia telangiectasia cells, indicating that ATR and DNA-dependent protein kinase are the kinases primarily involved in gammaH2AX formation at the sites of replication-mediated DNA double-strand breaks. Mre11- and Nbs1-deficient cells are still able to form gammaH2AX. However, H2AX-/- mouse embryonic fibroblasts exposed to camptothecin fail to form Mre11, Rad50, and Nbs1 foci and are hypersensitive to camptothecin. These results demonstrate a conserved gammaH2AX response for double-strand breaks induced by replication fork collision. gammaH2AX foci are required for recruiting repair and checkpoint protein complexes to the replication break sites.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Camptothecin,
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Repair Enzymes,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Topoisomerases, Type I,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Histones,
http://linkedlifedata.com/resource/pubmed/chemical/MRE11A protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Mre11a protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/NBN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/RAD50 protein, S cerevisiae,
http://linkedlifedata.com/resource/pubmed/chemical/Saccharomyces cerevisiae Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Topoisomerase I Inhibitors
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0021-9258
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pubmed:author |
pubmed-author:AladjemMirit IMI,
pubmed-author:AuneGregory JGJ,
pubmed-author:BonnerWilliam MWM,
pubmed-author:CelesteArkadyA,
pubmed-author:ChenHua TangHT,
pubmed-author:FurutaTakahisaT,
pubmed-author:LiaoZhi-YongZY,
pubmed-author:NussenzweigAndreA,
pubmed-author:PilchDuane RDR,
pubmed-author:PommierYvesY,
pubmed-author:RedonChristopheC,
pubmed-author:RogakouEmmy PEP,
pubmed-author:SedelnikovaOlga AOA,
pubmed-author:TakemuraHaruyukiH
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pubmed:issnType |
Print
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pubmed:day |
30
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pubmed:volume |
278
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
20303-12
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:12660252-Animals,
pubmed-meshheading:12660252-Blotting, Western,
pubmed-meshheading:12660252-Camptothecin,
pubmed-meshheading:12660252-Cell Cycle Proteins,
pubmed-meshheading:12660252-DNA Damage,
pubmed-meshheading:12660252-DNA Repair Enzymes,
pubmed-meshheading:12660252-DNA Replication,
pubmed-meshheading:12660252-DNA Topoisomerases, Type I,
pubmed-meshheading:12660252-DNA-Binding Proteins,
pubmed-meshheading:12660252-Enzyme Inhibitors,
pubmed-meshheading:12660252-Histones,
pubmed-meshheading:12660252-Humans,
pubmed-meshheading:12660252-Hydrolysis,
pubmed-meshheading:12660252-Mice,
pubmed-meshheading:12660252-Mice, Knockout,
pubmed-meshheading:12660252-Microscopy, Confocal,
pubmed-meshheading:12660252-Nuclear Proteins,
pubmed-meshheading:12660252-Phosphorylation,
pubmed-meshheading:12660252-Saccharomyces cerevisiae Proteins,
pubmed-meshheading:12660252-Topoisomerase I Inhibitors,
pubmed-meshheading:12660252-Tumor Cells, Cultured
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pubmed:year |
2003
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pubmed:articleTitle |
Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes.
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pubmed:affiliation |
Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255, USA.
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pubmed:publicationType |
Journal Article
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