Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
20
pubmed:dateCreated
2007-10-18
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
67
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
9658-65
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
pubmed:year
2007
pubmed:articleTitle
RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors.
pubmed:affiliation
Department of Radiation, Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois 60637, USA.
pubmed:publicationType
Journal Article, Research Support, N.I.H., Extramural