Impact of alpha-hydroxy-propanodeoxyguanine adducts on DNA duplex energetics: opposite base modulation and implications for mutagenicity and genotoxicity.
Acrolein is an alpha,beta-unsaturated aldehyde that is a major environmental pollutant, as well as a product of cellular metabolism. DNA bases react with acrolein to form two regioisomeric exocyclic guanine adducts, namely gamma-hydroxy-propanodeoxyguanosine (gamma-OH-PdG) and its positional isomer alpha-hydroxy-propanodeoxyguanosine (alpha-OH-PdG). The gamma-OH-PdG isomer adopts a ring-opened conformation with minimal structural perturbation of the DNA host duplex. Conversely, the alpha-OH-PdG isomer assumes a ring-closed conformation that significantly disrupts Watson-Crick base-pair alignments within the immediate vicinity of the damaged site. We have employed a combination of calorimetric and spectroscopic techniques to characterize the thermodynamic origins of these lesion-induced structural alterations. Specifically, we have assessed the energetic impact of alpha-OH-PdG centered within an 11-mer duplex by hybridizing the adduct-containing oligonucleotide with its complementary strand harboring a central base N [where N = C or A], yielding a pair of duplexes containing the nascent lesion (alpha-OH-PdG.C) or mismatched adduct (alpha-OH-PdG.A), respectively. Our data reveal that the nascent lesion is highly destabilizing, whereas its mismatched counterpart partially ameliorates alpha-OH-PdG-induced destabilization. Collectively, our data provide energetic characterizations of the driving forces that modulate error-free versus error-prone DNA translesion synthesis. The biological implications of our findings are discussed in terms of energetically probing acrolein-mediated mutagenicity versus adduct-induced genotoxicity.
Minetti
Conceição A S A
CA
Department of Chemistry and Chemical Biology, Rutgers-The State University of New Jersey, Piscataway, NJ 08854, USA.
Remeta
David P
DP
Johnson
Francis
F
Iden
Charles R
CR
Breslauer
Kenneth J
KJ
D000171:Acrolein / Q000737:chemistry / Q000633:toxicity; D002152:Calorimetry, Differential Scanning; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D004249:DNA Damage; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D016296:Mutagenesis; D009841:Oligonucleotides / Q000737:chemistry; D013816:Thermodynamics
D018736:DNA Adducts; D009841:Oligonucleotides; D006147:Guanine; D000171:Acrolein; D004247:DNA