Novel role of base excision repair in mediating cisplatin cytotoxicity |
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Authors: | Kothandapani Anbarasi Dangeti Venkata Srinivas Mohan Nimai Brown Ashley R Banze Lauren A Wang Xiao-Hong Sobol Robert W Patrick Steve M |
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Institution: | Department of Biochemistry and Cancer Biology, University of Toledo, Health Science Campus, Toledo, Ohio 43614, USA. |
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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. |
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Keywords: | DNA Damage DNA Polymerase DNA Repair Drug Resistance Nucleic Acid Enzymology Base Excision Repair Cisplatin |
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