title: Recognition of platinum-DNA adducts by HMGB1a.
abstract: Cisplatin (CP) and oxaliplatin (OX), platinum-based drugs used widely in chemotherapy, form adducts on intrastrand guanines (5'GG) in genomic DNA. DNA damage recognition proteins, transcription factors, mismatch repair proteins, and DNA polymerases discriminate between CP- and OX-GG DNA adducts, which could partly account for differences in the efficacy, toxicity, and mutagenicity of CP and OX. In addition, differential recognition of CP- and OX-GG adducts is highly dependent on the sequence context of the Pt-GG adduct. In particular, DNA binding protein domain HMGB1a binds to CP-GG DNA adducts with up to 53-fold greater affinity than to OX-GG adducts in the TGGA sequence context but shows much smaller differences in binding in the AGGC or TGGT sequence contexts. Here, simulations of the HMGB1a-Pt-DNA complex in the three sequence contexts revealed a higher number of interface contacts for the CP-DNA complex in the TGGA sequence context than in the OX-DNA complex. However, the number of interface contacts was similar in the TGGT and AGGC sequence contexts. The higher number of interface contacts in the CP-TGGA sequence context corresponded to a larger roll of the Pt-GG base pair step. Furthermore, geometric analysis of stacking of phenylalanine 37 in HMGB1a (Phe37) with the platinated guanines revealed more favorable stacking modes correlated with a larger roll of the Pt-GG base pair step in the TGGA sequence context. These data are consistent with our previous molecular dynamics simulations showing that the CP-TGGA complex was able to sample larger roll angles than the OX-TGGA complex or either CP- or OX-DNA complexes in the AGGC or TGGT sequences. We infer that the high binding affinity of HMGB1a for CP-TGGA is due to the greater flexibility of CP-TGGA compared to OX-TGGA and other Pt-DNA adducts. This increased flexibility is reflected in the ability of CP-TGGA to sample larger roll angles, which allows for a higher number of interface contacts between the Pt-DNA adduct and HMGB1a.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ramachandran
authors.forename: Brenda
authors.initials: B
authors.lastname: Temple
authors.forename: Anastassia N
authors.initials: AN
authors.lastname: Alexandrova
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Chaney
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002945:Cisplatin / Q000378:metabolism*; D018736:DNA Adducts / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009944:Organoplatinum Compounds / Q000378:metabolism*; D000077150:Oxaliplatin; D051381:Rats
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin