Novel Role of Base Excision Repair in Mediating Cisplatin Cytotoxicity

• Published in: The Journal of biological chemistry 2011-04, Vol.286 (16), p.14564-14574
• Main Authors: Kothandapani, Anbarasi, Dangeti, Venkata Srinivas Mohan Nimai, Brown, Ashley R., Banze, Lauren A., Wang, Xiao-Hong, Sobol, Robert W., Patrick, Steve M.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Base Excision Repair; Binding Sites; Cell Line, Tumor; Cisplatin; Cisplatin - chemistry; Cisplatin - pharmacology; Cross-Linking Reagents - chemistry; DNA Adducts; DNA and Chromosomes; DNA Damage; DNA Polymerase; DNA Repair; DNA Repair - drug effects; DNA-Directed DNA Polymerase - chemistry; Drug Resistance; Humans; Kinetics; Mice; Nucleic Acid Enzymology; Uracil-DNA Glycosidase - chemistry
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.225375

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.