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

Irine Khutsishvili, Na Zhang, Luis A. Marky, Conor Crean, Dinshaw J. Patel, Nicholas Geacintov, Vladimir Shafirovich

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1354-1363
Number of pages10
JournalBiochemistry
Volume52
Issue number8
DOIs
StatePublished - Feb 26 2013

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Thermodynamics
Oligonucleotides
Magnetic Resonance Spectroscopy
Nuclear magnetic resonance
Base Pairing
Liver
DNA
Helicobacter hepaticus
spiroiminodihydantoin
B-Form DNA
Nucleic Acid Denaturation
Guanine
Propellers
Hydrogen Bonding
Liver Neoplasms
Colonic Neoplasms
Enthalpy
Hydrogen bonds
Colon
Melting

ASJC Scopus subject areas

  • Biochemistry

Cite this

Thermodynamic profiles and nuclear magnetic resonance studies of oligonucleotide duplexes containing single diastereomeric spiroiminodihydantoin lesions. / Khutsishvili, Irine; Zhang, Na; Marky, Luis A.; Crean, Conor; Patel, Dinshaw J.; Geacintov, Nicholas; Shafirovich, Vladimir.

In: Biochemistry, Vol. 52, No. 8, 26.02.2013, p. 1354-1363.

Research output: Contribution to journalArticle

Khutsishvili, Irine ; Zhang, Na ; Marky, Luis A. ; Crean, Conor ; Patel, Dinshaw J. ; Geacintov, Nicholas ; Shafirovich, Vladimir. / Thermodynamic profiles and nuclear magnetic resonance studies of oligonucleotide duplexes containing single diastereomeric spiroiminodihydantoin lesions. In: Biochemistry. 2013 ; Vol. 52, No. 8. pp. 1354-1363.
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