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Nucleic Acids Research Advance Access originally published online on February 17, 2009
Nucleic Acids Research 2009 37(7):2153-2163; doi:10.1093/nar/gkp076
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Nucleic Acids Research, 2009, Vol. 37, No. 7 2153-2163
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Structural Biology

Solution structure of DNA containing {alpha}-OH-PdG: the mutagenic adduct produced by acrolein

Tanya Zaliznyak, Rahda Bonala, Sivaprasad Attaluri, Francis Johnson and Carlos de los Santos*

Department of Pharmacological Sciences, Stony Brook University, School of Medicine Stony Brook, NY 11794-8651, USA

*To whom correspondence should be addressed. Tel: +1631 444 3649; Fax: +1 631 444 3218; Email: cds{at}pharm.sunysb.edu

Received November 20, 2008. Revised January 17, 2009. Accepted January 27, 2009.

Acrolein is a cell metabolic product and a main component of cigarette smoke. Its reaction with DNA produces two guanine lesions {gamma}-OH-PdG, a major adduct that is nonmutagenic in mammalian cells, and the positional isomer {alpha}-OH-PdG. We describe here the solution structure of a short DNA duplex containing a single {alpha}-OH-PdG lesion, as determined by solution NMR spectroscopy and restrained molecular dynamics simulations. The spectroscopic data show a mostly regular right-handed helix, locally perturbed at its center by the presence of the lesion. All undamaged residues of the duplex are in anti orientation, forming standard Watson–Crick base-pair alignments. Duplication of proton signals near the damaged site differentiates two enantiomeric duplexes, thus establishing the exocyclic nature of the lesion. At the lesion site, {alpha}-OH-PdG rotates to a syn conformation, pairing to its counter cytosine residue that is protonated at pH 5.9. Three-dimensional models produced by restrained molecular dynamics simulations show different hydrogen-bonding patterns between the lesion and its cytosine partner and identify further stabilization of {alpha}-OH-PdG in a syn conformation by intra-residue hydrogen bonds. We compare the {alpha}-OH-PdG•dC duplex structure with that of duplexes containing the analogous lesion propano-dG and discuss the implications of our findings for the mutagenic bypass of acrolein lesions.


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