Novel role of base excision repair in mediating cisplatin cytotoxicity

J Biol Chem. 2011 Apr 22;286(16):14564-74. doi: 10.1074/jbc.M111.225375. Epub 2011 Feb 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Cell Line, Tumor
  • Cisplatin / chemistry
  • Cisplatin / pharmacology*
  • Cross-Linking Reagents / chemistry
  • DNA Adducts
  • DNA Damage
  • DNA Repair / drug effects*
  • DNA-Directed DNA Polymerase / chemistry
  • Drug Resistance
  • Humans
  • Kinetics
  • Mice
  • Uracil-DNA Glycosidase / chemistry


  • Antineoplastic Agents
  • Cross-Linking Reagents
  • DNA Adducts
  • DNA-Directed DNA Polymerase
  • Uracil-DNA Glycosidase
  • Cisplatin