| PI 3 kinase related kinases-independent proteolysis of BRCA1 regulates Rad51 recruitment during genotoxic stress in human cells. | |
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MedLine Citation:
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PMID: 21103343 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: The function of BRCA1 in response to ionizing radiation, which directly generates DNA double strand breaks, has been extensively characterized. However previous investigations have produced conflicting data on mutagens that initially induce other classes of DNA adducts. Because of the fundamental and clinical importance of understanding BRCA1 function, we sought to rigorously evaluate the role of this tumor suppressor in response to diverse forms of genotoxic stress. METHODOLOGY/PRINCIPAL FINDINGS: We investigated BRCA1 stability and localization in various human cells treated with model mutagens that trigger different DNA damage signaling pathways. We established that, unlike ionizing radiation, either UVC or methylmethanesulfonate (MMS) (generating bulky DNA adducts or alkylated bases respectively) induces a transient downregulation of BRCA1 protein which is neither prevented nor enhanced by inhibition of PIKKs. Moreover, we found that the proteasome mediates early degradation of BRCA1, BARD1, BACH1, and Rad52 implying that critical components of the homologous recombination machinery need to be functionally abrogated as part of the early response to UV or MMS. Significantly, we found that inhibition of BRCA1/BARD1 downregulation is accompanied by the unscheduled recruitment of both proteins to chromatin along with Rad51. Consistently, treatment of cells with MMS engendered complete disassembly of Rad51 from pre-formed ionizing radiation-induced foci. Following the initial phase of BRCA1/BARD1 downregulation, we found that the recovery of these proteins in foci coincides with the formation of RPA and Rad51 foci. This indicates that homologous recombination is reactivated at later stage of the cellular response to MMS, most likely to repair DSBs generated by replication blocks. CONCLUSION/SIGNIFICANCE: Taken together our results demonstrate that (i) the stabilities of BRCA1/BARD1 complexes are regulated in a mutagen-specific manner, and (ii) indicate the existence of mechanisms that may be required to prevent the simultaneous recruitment of conflicting signaling pathways to sites of DNA damage. |
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Authors:
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Ian Hammond-Martel; Helen Pak; Helen Yu; Raphael Rouget; Andrew A Horwitz; Jeffrey D Parvin; Elliot A Drobetsky; El Bachir Affar |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-11-17 |
Journal Detail:
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Title: PloS one Volume: 5 ISSN: 1932-6203 ISO Abbreviation: PLoS ONE Publication Date: 2010 |
Date Detail:
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Created Date: 2010-11-24 Completed Date: 2011-04-27 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 101285081 Medline TA: PLoS One Country: United States |
Other Details:
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Languages: eng Pagination: e14027 Citation Subset: IM |
Affiliation:
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Department of Medicine, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, Québec, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents, Alkylating
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pharmacology Apoptosis / drug effects, radiation effects BRCA1 Protein / metabolism* Cell Cycle / drug effects, radiation effects Cell Cycle Proteins / metabolism Cell Line, Tumor Cells, Cultured Chromatin / metabolism DNA Damage* DNA-Activated Protein Kinase / metabolism DNA-Binding Proteins / metabolism Down-Regulation / drug effects, radiation effects HCT116 Cells HEK293 Cells Hela Cells Humans Immunoblotting Male Methyl Methanesulfonate / pharmacology Phosphatidylinositol 3-Kinases / metabolism Protein-Serine-Threonine Kinases / metabolism* Rad51 Recombinase / metabolism* Tumor Suppressor Proteins / metabolism Ubiquitin-Protein Ligases / metabolism Ultraviolet Rays |
| Grant Support | |
ID/Acronym/Agency:
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CA111480/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents, Alkylating; 0/BARD1 protein, human; 0/BRCA1 Protein; 0/Cell Cycle Proteins; 0/Chromatin; 0/DNA-Binding Proteins; 0/Tumor Suppressor Proteins; 66-27-3/Methyl Methanesulfonate; EC 2.7.1.-/ATR protein, human; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/DNA-Activated Protein Kinase; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/ataxia telangiectasia mutated protein; EC 2.7.7.-/Rad51 Recombinase; EC 6.3.2.19/Ubiquitin-Protein Ligases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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