Send to:

Choose Destination
See comment in PubMed Commons below
Environ Mol Mutagen. 2010 Jul;51(6):625-34. doi: 10.1002/em.20599.

DNA cross-link induced by trans-4-hydroxynonenal.

Author information

  • 1Department of Chemistry, Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37235, USA.


Trans-4-Hydroxynonenal (HNE) is a peroxidation product of omega-6 polyunsaturated fatty acids. Michael addition of HNE to deoxyguanosine yields four diastereomeric 1,N(2)-dG adducts. The adduct of (6S,8R,11S) stereochemistry forms interstrand N(2)-dG:N(2)-dG cross-links in the 5'-CpG-3' sequence. It has been compared with the (6R,8S,11R) adduct, incorporated into 5'-d(GCTAGCXAGTCC)-3' . 5'-d(GGACTCGCTAGC)-3', containing the 5'-CpG-3' sequence (X = HNE-dG). Both adducts rearrange in DNA to N(2)-dG aldehydes. These aldehydes exist in equilibrium with diastereomeric cyclic hemiacetals, in which the latter predominate at equilibrium. These cyclic hemiacetals mask the aldehydes, explaining why DNA cross-linking is slow compared to related 1,N(2)-dG adducts formed by acrolein and crotonaldehyde. Both the (6S,8R,11S) and (6R,8S,11R) cyclic hemiacetals are located within the minor groove. However, the (6S,8R,11S) cyclic hemiacetal orients in the 5'-direction, while the (6R,8S,11R) cyclic hemiacetal orients in the 3'-direction. The conformations of the diastereomeric N(2)-dG aldehydes, which are the reactive species involved in DNA cross-link formation, have been calculated using molecular mechanics methods. The (6S,8R,11S) aldehyde orients in the 5'-direction, while the (6R,8S,11R) aldehyde orients in the 3'-direction. This suggests a kinetic basis to explain, in part, why the (6S,8R,11S) HNE adduct forms interchain cross-links in the 5'-CpG-3' sequence, whereas (6R,8S,11R) HNE adduct does not. 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.

Environ. Mol. Mutagen., 2010. (c) 2010 Wiley-Liss, Inc.

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Wiley Icon for PubMed Central
    Loading ...
    Write to the Help Desk