title: Structural differences in the NOE-derived structure of G-T mismatched DNA relative to normal DNA are correlated with differences in (13)C relaxation-based internal dynamics.
abstract: Detailed description of the characteristics of mismatched DNA that are distinct from normal DNA is vital to the understanding of how mismatch repair proteins are able to recognize and repair these DNA lesions. To this end, we have used nuclear Overhauser effect spectroscopy (NOESY)-based distance restraints and (13)C relaxation measurements to solve the solution structures and measure some of the internal dynamics of the G-T mismatched DNA oligomer d(CCATGCGTGG)(2) (GT) and its parent DNA sequence d(CCACGCGTGG)(2) (GC). In GT, the mismatched G7 is structurally perturbed much more than the mismatched T4 relative to their corresponding bases in GC. The degree of G7 displacement differs from previous high-resolution structures of G-T mismatch-containing B-DNA, suggesting a dependence of G-T mismatch-induced structural perturbation on sequence context. The internal dynamics of GC and GT differ on multiple timescales. The mismatched G7 of GT contains spins that decrease significantly in order in GT compared to GC, while spins in C6, T8, and A3 have significantly higher order in GT compared to GC. Linear correlations between helical parameters of GC and GT and the order of C-1' and aromatic methine carbon atoms relate differences in internal dynamics to the structures quantitatively. The dynamic differences between the normal and mismatched DNA signify changes in local flexibility that may be exploited by the mismatch repair system to bind mismatched DNA preferentially while ignoring normal DNA.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536-0084, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Isaacs
authors.forename: William S
authors.initials: WS
authors.lastname: Rayens
authors.forename: H Peter
authors.initials: HP
authors.lastname: Spielmann
mesh_terms: D020137:Base Pair Mismatch / Q000235:genetics*; D001483:Base Sequence; D002247:Carbon Isotopes; D003596:Cytosine / Q000737:chemistry; D004247:DNA / Q000138:chemical synthesis / Q000737:chemistry* / Q000235:genetics*; D004260:DNA Repair; D006147:Guanine / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D013941:Thymine / Q000737:chemistry
chemical_list: D002247:Carbon Isotopes; D006147:Guanine; D003596:Cytosine; D004247:DNA; D013941:Thymine