Specificity of platinum-DNA adduct repair.
Cell lines with resistance to cisplatin and carboplatin often retain sensitivity to platinum complexes with different carrier ligands (e.g., oxaliplatin and JM216). HeLa cell extracts were shown to excise cisplatin, oxaliplatin, and JM216 adducts with equal efficiency, suggesting that nucleotide excision repair does not contribute to the carrier-ligand specificity of platinum resistance. We have shown previously that the extent of replicative bypass in vivo is influenced by the carrier ligand of the platinum adducts. The specificity of replicative bypass may be determined by the DNA polymerase complexes that catalyze translesion synthesis past Pt-DNA adducts, by the mismatch-repair system that removes newly synthesized DNA opposite Pt-DNA adducts, and/or by DNA damage-recognition proteins that bind to the Pt-DNA adducts and block translesion synthesis. Primer extension on DNA templates containing site-specifically placed cisplatin, oxaliplatin, or JM216 Pt-GG adducts revealed that the eukaryotic DNA polymerases beta, zeta, gamma and HIV-1 RT had a similar specificity for translesion synthesis past Pt-DNA adducts (oxaliplatin > or = cisplatin > JM216). In addition, defects in the mismatch-repair proteins hMSH6 and hMLH1 led to increased replicative bypass of cisplatin adducts, but not of oxaliplatin adducts. Finally, primer extension assays performed in the presence of HMG1, which is known to recognize cisplatin-damaged DNA, revealed that inhibition of translesion synthesis by HMG1 also depended on the carrier ligand of the Pt-DNA adduct (cisplatin > oxaliplatin = JM216). These studies show that DNA polymerases, the mismatch-repair system and damage-recognition proteins can all impart specificity to replicative bypass of Pt-DNA adducts. Replicative bypass, in turn, may influence the carrier-ligand specificity of resistance.
Chaney
S G
SG
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill 27599-7260, USA. Stephen_Chaney@med.unc.edu
Vaisman
A
A
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology*; D020137:Base Pair Mismatch / Q000187:drug effects; D001483:Base Sequence; D002352:Carrier Proteins; D002945:Cisplatin / Q000494:pharmacology*; D018736:DNA Adducts; D004260:DNA Repair / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects / Q000378:metabolism; D005656:Fungal Proteins / Q000187:drug effects / Q000235:genetics; D006609:High Mobility Group Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D029701:Saccharomyces cerevisiae Proteins
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018736:DNA Adducts; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D006609:High Mobility Group Proteins; C501486:MLH1 protein, human; C098790:MSH6 protein, S cerevisiae; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D009944:Organoplatinum Compounds; D029701:Saccharomyces cerevisiae Proteins; C097758:amminedichloro(cyclohexylamine)platinum(II); D000077150:Oxaliplatin; C081294:satraplatin; D004259:DNA-Directed DNA Polymerase; D000070957:MutL Protein Homolog 1; D002945:Cisplatin