title: Solution structure of an 11-mer duplex containing the 3, N(4)-ethenocytosine adduct opposite 2'-deoxycytidine: implications for the recognition of exocyclic lesions by DNA glycosylases.
abstract: Lipid peroxidation products, as well as the metabolic products of vinyl chloride, react with cellular DNA producing the mutagenic adduct 3,N(4)-etheno-2'-deoxycytidine (epsilondC), along with several other exocyclic derivatives. High-resolution NMR spectroscopy and restrained molecular dynamics simulations were used to establish the solution structure of an 11-mer duplex containing an epsilondC.dC base-pair at its center. The NMR data suggested a regular right-handed helical structure having all residues in the anti orientation around the glycosydic torsion angle and Watson-Crick alignments for all canonical base-pairs of the duplex. Restrained molecular dynamics generated a three-dimensional model in excellent agreement with the spectroscopic data. The (epsilondC. dC)-duplex structure is a regular right-handed helix with a slight bend at the lesion site and no severe distortions of the sugar-phosphate backbone. The epsilondC adduct and its partner dC were displaced towards opposite grooves of the helix, resulting in a lesion-containing base-pair that was highly sheared but stabilized to some degree by the formation of a single hydrogen bond. Such a sheared base-pair alignment at the lesion site was previously observed for epsilondC.dG and epsilondC.T duplexes, and was also present in the crystal structures of duplexes containing dG.T and dG. U mismatches. These observations suggest the existence of a substrate structural motif that may be recognized by specific DNA glycosylases during the process of base excision repair.
authors.affiliation: Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY, 11794-8651, USA.
authors.forename: D
authors.initials: D
authors.lastname: Cullinan
authors.forename: F
authors.initials: F
authors.lastname: Johnson
authors.forename: C
authors.initials: C
authors.lastname: de los Santos
mesh_terms: D000595:Amino Acid Sequence; D020029:Base Pairing; D001665:Binding Sites; D003198:Computer Simulation; D018736:DNA Adducts / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D010710:Phosphates / Q000378:metabolism; D012996:Solutions
chemical_list: D018736:DNA Adducts; D010710:Phosphates; D012996:Solutions; D003841:Deoxycytidine; C032222:3,N(4)-ethenodeoxycytidine; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases