| Ataxia telangiectasia mutated- and Rad3-related kinase drives both the early and the late DNA-damage response to the monofunctional antitumour alkylator S23906. | |
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MedLine Citation:
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PMID: 21470188 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Numerous anticancer agents and environmental mutagens target DNA. Although all such compounds interfere with the progression of the replication fork and inhibit DNA synthesis, there are marked differences in the DNA-damage response pathways they trigger, and the relative impact of the proximal or the distal signal transducers on cell survival is mainly lesion-specific. Accordingly, checkpoint kinase inhibitors in current clinical development show synergistic activity with some DNA-targeting agents, but not with others. In the present study, we characterize the DNA-damage response to the antitumour acronycine derivative S23906, which forms monofunctional adducts with guanine residues in the minor groove of DNA. S23906 exposure is accompanied by specific recruitment of RPA (replication protein A) at replication sites and rapid Chk1 activation. In contrast, neither MRN (Mre11-Rad50-Nbs1) nor ATM (ataxia-telangiectasia mutated), contributes to the initial response to S23906. Interestingly, genetic attenuation of ATR (ATM- and Ras3-related) activity inhibits not only the early phosphorylation of histone H2AX and Chk1, but also interferes with the late phosphorylation of Chk2. Moreover, loss of ATR function or pharmacological inhibition of the checkpoint kinases by AZD7762 is accompanied by abrogation of the S-phase arrest and increased sensitivity towards S23906. These findings identify ATR as a central co-ordinator of the DNA-damage response to S23906, and provide a mechanistic rationale for combinations of S23906 and similar agents with checkpoint abrogators. |
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Authors:
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Daniele G Soares; Aude Battistella; Céline J Rocca; Renata Matuo; João A P Henriques; Annette K Larsen; Alexandre E Escargueil |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Biochemical journal Volume: 437 ISSN: 1470-8728 ISO Abbreviation: Biochem. J. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-14 Completed Date: 2011-08-30 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 2984726R Medline TA: Biochem J Country: England |
Other Details:
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Languages: eng Pagination: 63-73 Citation Subset: IM |
Affiliation:
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Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris 75571, France. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Acronine
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analogs & derivatives*,
pharmacology Antineoplastic Agents, Alkylating / pharmacology* Cell Cycle Proteins / genetics, metabolism, physiology* DNA Damage* DNA Repair Enzymes / metabolism DNA-Binding Proteins / metabolism Hela Cells Histones / metabolism Humans Microscopy, Fluorescence Mutation* Nuclear Proteins / metabolism Protein Kinases / metabolism Protein-Serine-Threonine Kinases / genetics, metabolism, physiology* Replication Protein A / metabolism Thiophenes / pharmacology Urea / analogs & derivatives, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/1,2-diacetoxy-3,14-dihydro-3,3,14-trimethyl-6-methoxy-7H-benz(b)pyrano(3,2-d)acridin-7-one; 0/3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; 0/Antineoplastic Agents, Alkylating; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/H2AFX protein, human; 0/Histones; 0/MRE11A protein, human; 0/NBN protein, human; 0/Nuclear Proteins; 0/Rad50 protein, human; 0/Replication Protein A; 0/Thiophenes; 57-13-6/Urea; 7008-42-6/Acronine; EC 2.7.-/Protein Kinases; EC 2.7.1.-/ATR protein, human; EC 2.7.1.11/checkpoint kinase 2; EC 2.7.11.1/Checkpoint kinase 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 6.5.1.-/DNA Repair Enzymes |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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