|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
41
|
|
pubmed:dateCreated |
2008-10-16
|
|
pubmed:abstractText |
RAD51 and other members of the RecA family of strand exchange proteins assemble on ssDNA to form presynaptic filaments, which carry out the central steps of homologous recombination. A microplate-based assay was developed for high-throughput measurement of hRAD51 filament formation on ssDNA. With this method, a 10,000 compound library was screened, leading to the identification of a small molecule (RS-1) that enhances hRAD51 binding in a wide range of biochemical conditions. Salt titration experiments showed that RS-1 can enhance filament stability. Ultrastructural analysis of filaments formed on ssDNA showed that RS-1 can increase both protein-DNA complex lengths and the pitch of helical filament turns. RS-1 stimulated hRAD51-mediated homologous strand assimilation (D-loop) activity by at least 5- to 11-fold, depending on the condition. This D-loop stimulation occurred even in the presence of Ca(2+) or adenylyl-imidodiphosphate, indicating that the mechanism of stimulation was distinct from that conferred by Ca(2+) and/or inhibition of ATPase. No D-loop activity was observed in the absence of a nucleotide triphosphate cofactor, indicating that the compound does not substitute for this requirement. These results indicate that RS-1 enhances the homologous recombination activity of hRAD51 by promoting the formation of active presynaptic filaments. Cell survival assays in normal neonatal human dermal fibroblasts demonstrated that RS-1 promotes a dose-dependent resistance to the cross-linking chemotherapeutic drug cisplatin. Given that RAD51-dependent recombination is a major determinant of cisplatin resistance, RS-1 seems to function in vivo to stimulate homologous recombination repair proficiency. RS-1 has many potential applications in both research and medical settings.
|
|
pubmed:grant |
|
|
pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-10490626,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-11259830,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-11283264,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-11376695,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-11459983,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-11459984,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-11551925,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-11751635,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-11839741,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-11842113,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-12065428,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-12390247,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-12442171,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-12655440,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-14580352,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-15033353,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-1522597,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-15226506,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-15235592,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-15657438,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-15703751,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-16204247,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-16979659,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-17483448,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-17515904,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-17942895,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-2195545,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-3486003,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-7050731,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-7603995,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-7988572,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-8929543,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-9012806,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18840682-9590697
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Oct
|
|
pubmed:issn |
1091-6490
|
|
pubmed:author |
|
|
pubmed:issnType |
Electronic
|
|
pubmed:day |
14
|
|
pubmed:volume |
105
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
15848-53
|
|
pubmed:dateRevised |
2010-9-22
|
|
pubmed:meshHeading |
pubmed-meshheading:18840682-Cell Survival,
pubmed-meshheading:18840682-Cisplatin,
pubmed-meshheading:18840682-DNA, Single-Stranded,
pubmed-meshheading:18840682-Drug Resistance, Neoplasm,
pubmed-meshheading:18840682-Enzyme Stability,
pubmed-meshheading:18840682-Fibroblasts,
pubmed-meshheading:18840682-Humans,
pubmed-meshheading:18840682-Infant, Newborn,
pubmed-meshheading:18840682-Ligands,
pubmed-meshheading:18840682-Rad51 Recombinase,
pubmed-meshheading:18840682-Small Molecule Libraries
|
|
pubmed:year |
2008
|
|
pubmed:articleTitle |
A chemical compound that stimulates the human homologous recombination protein RAD51.
|
|
pubmed:affiliation |
Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA.
|
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
|
