Linked Life Data

20399198

Source:http://linkedlifedata.com/resource/pubmed/id/20399198

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2010-6-10
pubmed:abstractText
S23906 belongs to a novel class of alkylating anticancer agents forming bulky monofunctional DNA adducts. A unique feature of S23906 is its "helicase-like" activity leading to the destabilization of the surrounding duplex DNA. We here characterize the recognition and repair of S23906 adducts by the nucleotide excision repair (NER) machinery. All NER-deficient human cell lines tested showed increased sensitivity to S23906, which was particularly pronounced for cells deficient in XPC, CSB and XPA. In comparison, deficiencies in ERCC1 or XPF had lesser impact on the sensitivity to S23906. The sensitivity was, at least in part, linked to the conversion of unrepaired adducts into toxic DNA strand breaks as shown by single cell electrophoresis and gamma-H2AX formation. The pharmacological relevance of these findings was confirmed by the characterization of KB carcinoma cells with acquired S23906 resistance. These cells showed increased NER activity in vivo as well as toward damaged plasmid DNA in vitro. In particular, both global genome NER, as shown by unscheduled DNA synthesis, and transcription-coupled NER, as shown by transcriptional recovery, were up-regulated in the S23906-resistant cells. The increased NER activity was accompanied by up to 5-fold up-regulation of XPC, CSB and XPA proteins without detectable alterations of ERCC1 on the DNA, RNA or protein levels. Our results suggest that S23906 adducts are recognized and repaired by both NER sub-pathways in contrast to other members of this class, that are only recognized by transcription-coupled NER. We further show that NER activity can be up-regulated without changes in ERCC1 expression.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Acronine, http://linkedlifedata.com/resource/pubmed/chemical/Alkylating Agents, http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents, Alkylating, http://linkedlifedata.com/resource/pubmed/chemical/DNA, http://linkedlifedata.com/resource/pubmed/chemical/DNA Adducts, http://linkedlifedata.com/resource/pubmed/chemical/DNA Helicases, http://linkedlifedata.com/resource/pubmed/chemical/DNA Repair Enzymes, http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins, http://linkedlifedata.com/resource/pubmed/chemical/ERCC1 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/ERCC6 protein, human, http://linkedlifedata.com/resource/pubmed/chemical/Endonucleases, http://linkedlifedata.com/resource/pubmed/chemical/Orphan Nuclear Receptors, http://linkedlifedata.com/resource/pubmed/chemical/XPC protein, human, http://linkedlifedata.com/resource/pubmed/chemical/liver X receptor
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1873-2968
pubmed:author
pubmed:copyrightInfo
Copyright (c) 2010 Elsevier Inc. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
80
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
335-43
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
The NER proteins XPC and CSB, but not ERCC1, regulate the sensitivity to the novel DNA binder S23906: implications for recognition and repair of antitumor alkylators.
pubmed:affiliation
Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris 75571, France.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, Non-U.S. Gov't