Abstract
Some DNA damage-recognition proteins, transcription factors, mismatch repair proteins and DNA polymerases discriminate between cisplatin (CP)- and oxaliplatin (OX)-GG DNA adducts, and this is thought to help explain differences in efficacy, toxiCity and mutageniCity of CP and OX. In addition, differential recognition of CP- and OX-GG adducts by some proteins has been shown to be highly dependent on the sequence context of the Pt-GG adduct. We have postulated that CP- and OX-GG adducts cause differences in the conformation and/or conformational dynamics of the DNA that provide the basis for differential protein recognition of the adducts. We have determined the NMR solution structure of CP-GG adducts, OX-GG adducts and undamaged DNA in the AGGC sequence context, and of OX-GG adducts and undamaged DNA in the TGGT sequence context. We have also employed molecular dynamics (MD) simulations to investigate the conformational dynamics of CP-GG adducts, OX-GG adducts and undamaged DNA in the AGGC and TGGA sequence contexts. These studies showed clear differences in the conformation dynamics between CP- and OX-GG adducts which correlated with the average conformational differences observed in the NMR solution structures and with conformations previously reported for the CP-GG DNA·HMG1a complex. When the conformational dynamics in both sequence contexts were compared it became evident that: (a) the patterns of hydrogen bond formation between Pt-amine-hydrogens and surrounding bases of the DNA were different for CP- and OX-GG adducts; (b) patterns of hydrogen bond formation were also influenced by the DNA sequence context of the Pt-GG adducts, and (c) differences in patterns of hydrogen bond formation were highly correlated with differences in the conformational dynamics of the adduct. Thus, we postulate that patterns of hydrogen bond formation between Pt-amine hydrogens and surrounding DNA bases are different for CP- and OX-GG adducts, and that those differences in hydrogen bond patterns result in DNA conformational differences that allow selective recognition of CP- and OX-GG adducts by a number of proteins that determine the relative cytotoxiCity and mutageniCity of those adducts.
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Chaney, S.G. et al. (2009). Differences in Conformation and Conformational Dynamics Between Cisplatin and Oxaliplatin DNA Adducts. In: Bonetti, A., Leone, R., Muggia, F.M., Howell, S.B. (eds) Platinum and Other Heavy Metal Compounds in Cancer Chemotherapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60327-459-3_20
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DOI: https://doi.org/10.1007/978-1-60327-459-3_20
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