Solution structure of DNA containing alpha-OH-PdG: the mutagenic adduct produced by acrolein.
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.
Zaliznyak
Tanya
T
Department of Pharmacological Sciences, Stony Brook University, School of Medicine Stony Brook, NY 11794-8651, USA.
Bonala
Rahda
R
Attaluri
Sivaprasad
S
Johnson
Francis
F
de los Santos
Carlos
C
D000171:Acrolein / Q000633:toxicity*; D018736:DNA Adducts / Q000737:chemistry*; D003841:Deoxycytidine / Q000737:chemistry; D004785:Environmental Pollutants / Q000633:toxicity*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D016296:Mutagenesis; D019906:Nuclear Magnetic Resonance, Biomolecular; D011522:Protons; D012996:Solutions
D018736:DNA Adducts; D004785:Environmental Pollutants; D011522:Protons; D012996:Solutions; D003841:Deoxycytidine; D006151:Guanosine; D000171:Acrolein