Thermodynamic profiles and nuclear magnetic resonance studies of oligonucleotide duplexes containing single diastereomeric spiroiminodihydantoin lesions Journal Article


Authors: Khutsishvili, I.; Zhang, N.; Marky, L. A.; Crean, C.; Patel, D. J.; Geacintov, N. E.; Shafirovich, V.
Article Title: Thermodynamic profiles and nuclear magnetic resonance studies of oligonucleotide duplexes containing single diastereomeric spiroiminodihydantoin lesions
Abstract: The spiroiminodihydantoins (Sp) are highly mutagenic oxidation products of guanine and 8-oxo-7,8-dihydroguanine in DNA. The Sp lesions have recently been detected in the liver and colon of mice infected with Helicobacter hepaticus that induces inflammation and the 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 methods, analysis of DNA melting curves, and two-dimensional nuclear magnetic resonance methods. The nonplanar, propeller-like shapes of the Sp residues strongly diminish the extent of local base stacking interactions that destabilize the DNA duplexes characterized by unfavorable enthalpy contributions. Relative to that of 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 of Na+/mol of duplex) and water molecules (Δnw = 17 mol of H2O/mol of 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 is expected to have a significant impact on the processing of these lesions in biological environments. © 2013 American Chemical Society.
Keywords: controlled study; unclassified drug; inflammation; dna; double stranded dna; colon cancer; double stranded dna break; liver cancer; base pairing; dna structure; hydrogen bond; thermodynamics; water; single stranded dna; oligonucleotide; dna determination; nuclear magnetic resonance; murine model; stereochemistry; guanine derivative; oligonucleotides; single stranded dna break; hydrogen bonds; diastereomeric; dna duplexes; oligonucleotide duplexes; diastereoisomer; dna strand; differential scanning calorimetry; base pairs; enthalpy; helicobacter hepaticus; helicobacter; 8-oxo-7 ,8-dihydroguanine; base stacking; biological environments; counterions; dna melting; microcalorimetric methods; nuclear magnetic resonance studies; oxidation products of guanines; significant impacts; spiroiminodihydantoin; structural disturbances; thermally induced; thermodynamic characteristics; thermodynamic profiles; two-dimensional nuclear magnetic resonance; water molecule; watson-crick hydrogen bonding; microcalorimetry
Journal Title: Biochemistry
Volume: 52
Issue: 8
ISSN: 0006-2960
Publisher: American Chemical Society  
Date Published: 2013-02-26
Start Page: 1354
End Page: 1363
Language: English
DOI: 10.1021/bi301566v
PROVIDER: scopus
PMCID: PMC3588586
PUBMED: 23360616
DOI/URL:
Notes: --- - "Export Date: 1 April 2013" - "CODEN: BICHA" - "Source: Scopus"
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  1. Dinshaw J Patel
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  2. Na Zhang
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