Document Detail


PI 3 kinase related kinases-independent proteolysis of BRCA1 regulates Rad51 recruitment during genotoxic stress in human cells.
MedLine Citation:
PMID:  21103343     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
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:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-11-24     Completed Date:  2011-04-27     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e14027     Citation Subset:  IM    
Affiliation:
Department of Medicine, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, Québec, Canada.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Alkylating / 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:
CA111480/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
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
Comments/Corrections

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