Thermodynamic profiles and nuclear magnetic resonance studies of oligonucleotide duplexes containing single diastereomeric spiroiminodihydantoin lesions.
Thermodynamic profiles and nuclear magnetic resonance studies of oligonucleotide duplexes containing single diastereomeric spiroiminodihydantoin lesions.
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DOI：
10.1021/bi301566v
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发表时间：
2013-02-26
期刊：
影响因子：
2.9
通讯作者：
Shafirovich V
中科院分区：
文献类型：
--
作者：
Khutsishvili I;Zhang N;Marky LA;Crean C;Patel DJ;Geacintov NE;Shafirovich V
The spiroiminodihydantoins (Sp) are highly mutagenic oxidation products of guanine and 8-oxo-7,8-dihydroguanine in DNA. The Sp lesions have been recently detected in the liver and colon of mice infected with H. hepaticus that induces inflammation and development of liver and colon cancers in murine model systems [Mangerich, A., et al. (2012) Proc. Natl. Acad. Sci. U.S.A. 109, E1820–E1829]. The impact of Sp lesions on the thermodynamic characteristics and the effects of the diastereomeric Sp-R and Sp-S lesions on the conformational features of double-stranded 11-mer oligonucleotide duplexes have been studied by a combination of microcalorimetric, analysis of DNA melting curves, and two-dimensional NMR methods. The non-planar, propeller-like shapes of the Sp residues strongly diminish the local base stacking interactions that destabilize the DNA duplexes characterized by unfavorable enthalpy contributions. Relative to an unmodified duplex, the thermally induced unfolding of the duplexes with centrally positioned Sp-R and Sp-S lesions into single strands is accompanied by a smaller release of cationic counterions (ΔnNa+ = 0.6 mol Na+ per mol duplex) and water molecules (Δnw = 17 mol H2O per mol duplex). The unfolding parameters are similar for the Sp-R and Sp-S lesions although their orientations in the duplexes are different. The structural disturbances radiate one base pair beyond the flanking C:G pair, although Watson-Crick hydrogen bonding is maintained at all flanking base pairs. The observed relatively strong destabilization of B-form DNA by the physically small Sp lesions are expected to have a significant impact on the processing of these lesions in biological environments.
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