Impact of α‐hydroxy‐propanodeoxyguanine adducts on DNA duplex energetics: Opposite base modulation and implications for mutagenicity and genotoxicity |
| |
| Authors: | Conceição A S A Minetti David P Remeta Francis Johnson Charles R Iden Kenneth J Breslauer |
| |
| Institution: | 1. Department of Chemistry and Chemical Biology, Rutgers—The State University of New Jersey, Piscataway, NJ 08854;2. Department of Pharmacological Sciences, School of Medicine, Stony Brook University, Stony Brook, NY 11794‐8651;3. The Cancer Institute of New Jersey, New Brunswick, NJ 08901 |
| |
| Abstract: | Acrolein is an α,β‐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 γ‐hydroxy‐propanodeoxyguanosine (γ‐OH‐PdG) and its positional isomer α‐hydroxy‐propanodeoxyguanosine (α‐OH‐PdG). The γ‐OH‐PdG isomer adopts a ring‐opened conformation with minimal structural perturbation of the DNA host duplex. Conversely, the α‐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 α‐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 (α‐OH‐PdG·C) or mismatched adduct (α‐OH‐PdG·A), respectively. Our data reveal that the nascent lesion is highly destabilizing, whereas its mismatched counterpart partially ameliorates α‐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. © 2009 Wiley Periodicals, Inc. Biopolymers 93: 370–382, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com |
| |
| Keywords: | acrolein adducts thermodynamic stability calorimetry mutagenicity genotoxicity |
|
|
