title: Novel role of base excision repair in mediating cisplatin cytotoxicity.
abstract: Using isogenic mouse embryonic fibroblasts and human cancer cell lines, we show that cells defective in base excision repair (BER) display a cisplatin-specific resistant phenotype. This was accompanied by enhanced repair of cisplatin interstrand cross-links (ICLs) and ICL-induced DNA double strand breaks, but not intrastrand adducts. Cisplatin induces abasic sites with a reduced accumulation in uracil DNA glycosylase (UNG) null cells. We show that cytosines that flank the cisplatin ICLs undergo preferential oxidative deamination in vitro, and AP endonuclease 1 (APE1) can cleave the resulting ICL DNA substrate following removal of the flanking uracil. We also show that DNA polymerase β has low fidelity at the cisplatin ICL site after APE1 incision. Down-regulating ERCC1-XPF in BER-deficient cells restored cisplatin sensitivity. Based on our results, we propose a novel model in which BER plays a positive role in maintaining cisplatin cytotoxicity by competing with the productive cisplatin ICL DNA repair pathways.
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo, Health Science Campus, Toledo, Ohio 43614, USA.
authors.forename: Anbarasi
authors.initials: A
authors.lastname: Kothandapani
authors.forename: Venkata Srinivas Mohan Nimai
authors.initials: VS
authors.lastname: Dangeti
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Brown
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Banze
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Wang
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sobol
authors.forename: Steve M
authors.initials: SM
authors.lastname: Patrick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D051379:Mice; D051981:Uracil-DNA Glycosidase / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004259:DNA-Directed DNA Polymerase; D051981:Uracil-DNA Glycosidase; D002945:Cisplatin