title: Epistatic role of base excision repair and mismatch repair pathways in mediating cisplatin cytotoxicity.
abstract: Base excision repair (BER) and mismatch repair (MMR) pathways play an important role in modulating cis-Diamminedichloroplatinum (II) (cisplatin) cytotoxicity. In this article, we identified a novel mechanistic role of both BER and MMR pathways in mediating cellular responses to cisplatin treatment. Cells defective in BER or MMR display a cisplatin-resistant phenotype. Targeting both BER and MMR pathways resulted in no additional resistance to cisplatin, suggesting that BER and MMR play epistatic roles in mediating cisplatin cytotoxicity. Using a DNA Polymerase β (Polβ) variant deficient in polymerase activity (D256A), we demonstrate that MMR acts downstream of BER and is dependent on the polymerase activity of Polβ in mediating cisplatin cytotoxicity. MSH2 preferentially binds a cisplatin interstrand cross-link (ICL) DNA substrate containing a mismatch compared with a cisplatin ICL substrate without a mismatch, suggesting a novel mutagenic role of Polβ in activating MMR in response to cisplatin. Collectively, these results provide the first mechanistic model for BER and MMR functioning within the same pathway to mediate cisplatin sensitivity via non-productive ICL processing. In this model, MMR participation in non-productive cisplatin ICL processing is downstream of BER processing and dependent on Polβ misincorporation at cisplatin ICL sites, which results in persistent cisplatin ICLs and sensitivity to cisplatin.
authors.affiliation: Department of Biochemistry and Cancer Biology, University of Toledo - Health Science Campus, Toledo, OH 43614, USA, Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA 15213, USA and Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA.
authors.forename: Anbarasi
authors.initials: A
authors.lastname: Kothandapani
authors.forename: Akshada
authors.initials: A
authors.lastname: Sawant
authors.forename: Venkata Srinivas Mohan Nimai
authors.initials: VS
authors.lastname: Dangeti
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sobol
authors.forename: Steve M
authors.initials: SM
authors.lastname: Patrick
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000378:metabolism; D053843:DNA Mismatch Repair; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D004843:Epistasis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D018675:Toxicity Tests
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D012319:RNA Polymerase II; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein; D002945:Cisplatin