Source:http://linkedlifedata.com/resource/pubmed/id/17942895
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
20
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pubmed:dateCreated |
2007-10-18
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pubmed:abstractText |
The breast cancer susceptibility gene BRCA1 encodes a large protein thought to contribute to a variety of cellular processes, although the critical determinants of BRCA1-deficient tumorigenesis remain unclear. Given that BRCA1 is required for cell proliferation, suppressor mutations are believed to modify BRCA1 phenotypes and contribute to the etiology of BRCA1-deficient tumors. Here, we show that overexpression of the homologous recombinase RAD51 in a DT40 BRCA1Delta/Delta mutant rescues defects in proliferation, DNA damage survival, and homologous recombination (HR). In addition, epistasis analysis with BRCA1 and the DNA end-joining factor KU70 indicates that these factors operate independently of one another to repair double-strand breaks. Consistent with this genetic finding, cell synchronization studies show that the ability of BRCA1 to promote radioresistance is restricted to the late S and G2 phases of the cell cycle, as predicted for genes whose function is specific to homology-mediated repair rather than nonhomologous end-joining. Notably, retrospective analyses of microarray expression data reveal elevated expression of RAD51 and two of its late-acting cofactors, RAD54 and RAD51AP1, in BRCA1-deficient versus sporadic breast tumors. Taken together, our results indicate that up-regulation of HR provides a permissive genetic context for cells lacking BRCA1 function by circumventing its requirement in RAD51 subnuclear assembly. Furthermore, the data support a model in which enhanced HR activity contributes to the etiology of BRCA1-deficient tumors.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antigens, Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/BRCA1 Protein,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Ku autoantigen,
http://linkedlifedata.com/resource/pubmed/chemical/RAD51 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Rad51 Recombinase
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0008-5472
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
67
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
9658-65
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pubmed:meshHeading |
pubmed-meshheading:17942895-Animals,
pubmed-meshheading:17942895-Antigens, Nuclear,
pubmed-meshheading:17942895-BRCA1 Protein,
pubmed-meshheading:17942895-Breast Neoplasms,
pubmed-meshheading:17942895-Cell Cycle,
pubmed-meshheading:17942895-Cell Growth Processes,
pubmed-meshheading:17942895-Cell Line, Tumor,
pubmed-meshheading:17942895-Chickens,
pubmed-meshheading:17942895-DNA Damage,
pubmed-meshheading:17942895-DNA-Binding Proteins,
pubmed-meshheading:17942895-G2 Phase,
pubmed-meshheading:17942895-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:17942895-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:17942895-Genes, BRCA1,
pubmed-meshheading:17942895-Humans,
pubmed-meshheading:17942895-Rad51 Recombinase,
pubmed-meshheading:17942895-Radiation Tolerance,
pubmed-meshheading:17942895-S Phase,
pubmed-meshheading:17942895-Up-Regulation
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pubmed:year |
2007
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pubmed:articleTitle |
RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors.
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pubmed:affiliation |
Department of Radiation, Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois 60637, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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