title: Interstrand DNA cross-links induced by alpha,beta-unsaturated aldehydes derived from lipid peroxidation and environmental sources.
abstract: Significant levels of the 1, N(2)-gamma-hydroxypropano-dG adducts of the alpha,beta-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxy-2E-nonenal (HNE) have been identified in human DNA, arising from both exogenous and endogenous exposures. They yield interstrand DNA cross-links between guanines in the neighboring C.G and G.C base pairs located in 5'-CpG-3' sequences, as a result of opening of the 1,N(2)-gamma-hydroxypropano-dG adducts to form reactive aldehydes that are positioned within the minor groove of duplex DNA. Using a combination of chemical, spectroscopic, and computational methods, we have elucidated the chemistry of cross-link formation in duplex DNA. NMR spectroscopy revealed that, at equilibrium, the acrolein and crotonaldehyde cross-links consist primarily of interstrand carbinolamine linkages between the exocyclic amines of the two guanines located in the neighboring C.G and G.C base pairs located in 5'-CpG-3' sequences, that maintain the Watson-Crick hydrogen bonding of the cross-linked base pairs. The ability of crotonaldehyde and HNE to form interstrand cross-links depends upon their common relative stereochemistry at the C6 position of the 1,N(2)-gamma-hydroxypropano-dG adduct. The stereochemistry at this center modulates the orientation of the reactive aldehyde within the minor groove of the double-stranded DNA, either facilitating or hindering the cross-linking reactions; it also affects the stabilities of the resulting diastereoisomeric cross-links. The presence of these cross-links in vivo is anticipated to interfere with DNA replication and transcription, thereby contributing to the etiology of human disease. Reduced derivatives of these cross-links are useful tools for studying their biological processing.
authors.affiliation: Department of Chemistry, Center in Molecular Toxicology, and Vanderbilt Institute for Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, USA. michael.p.stone@vanderbilt.edu
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stone
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Cho
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Kozekov
authors.forename: Albena
authors.initials: A
authors.lastname: Kozekova
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Irina G
authors.initials: IG
authors.lastname: Minko
authors.forename: R Stephen
authors.initials: RS
authors.lastname: Lloyd
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Harris
authors.forename: Carmelo J
authors.initials: CJ
authors.lastname: Rizzo
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D000605:Amino Alcohols / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D004777:Environment; D015227:Lipid Peroxidation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009841:Oligonucleotides / Q000737:chemistry; D044366:Transition Temperature
chemical_list: D000447:Aldehydes; D000605:Amino Alcohols; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D009841:Oligonucleotides