Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
Chem Res Toxicol. 2009 May;22(5):759-78. doi: 10.1021/tx9000489.

Chemistry and biology of DNA containing 1,N(2)-deoxyguanosine adducts of the alpha,beta-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal.

Author information

  • 1Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, Oregon 97239, USA.

Abstract

The alpha,beta-unsaturated aldehydes (enals) acrolein, crotonaldehyde, and trans-4-hydroxynonenal (4-HNE) are products of endogenous lipid peroxidation, arising as a consequence of oxidative stress. The addition of enals to dG involves Michael addition of the N(2)-amine to give N(2)-(3-oxopropyl)-dG adducts, followed by reversible cyclization of N1 with the aldehyde, yielding 1,N(2)-dG exocyclic products. The 1,N(2)-dG exocyclic adducts from acrolein, crotonaldehyde, and 4-HNE exist in human and rodent DNA. The enal-induced 1,N(2)-dG lesions are repaired by the nucleotide excision repair pathway in both Escherichia coli and mammalian cells. Oligodeoxynucleotides containing structurally defined 1,N(2)-dG adducts of acrolein, crotonaldehyde, and 4-HNE were synthesized via a postsynthetic modification strategy. Site-specific mutagenesis of enal adducts has been carried out in E. coli and various mammalian cells. In all cases, the predominant mutations observed are G-->T transversions, but these adducts are not strongly miscoding. When placed into duplex DNA opposite dC, the 1,N(2)-dG exocyclic lesions undergo ring opening to the corresponding N(2)-(3-oxopropyl)-dG derivatives. Significantly, this places a reactive aldehyde in the minor groove of DNA, and the adducted base possesses a modestly perturbed Watson-Crick face. Replication bypass studies in vitro indicate that DNA synthesis past the ring-opened lesions can be catalyzed by pol eta, pol iota, and pol kappa. It also can be accomplished by a combination of Rev1 and pol zeta acting sequentially. However, efficient nucleotide insertion opposite the 1,N(2)-dG ring-closed adducts can be carried out only by pol iota and Rev1, two DNA polymerases that do not rely on the Watson-Crick pairing to recognize the template base. The N(2)-(3-oxopropyl)-dG adducts can undergo further chemistry, forming interstrand DNA cross-links in the 5'-CpG-3' sequence, intrastrand DNA cross-links, or DNA-protein conjugates. NMR and mass spectrometric analyses indicate that the DNA interstand cross-links contain a mixture of carbinolamine and Schiff base, with the carbinolamine forms of the linkages predominating in duplex DNA. The reduced derivatives of the enal-mediated N(2)-dG:N(2)-dG interstrand cross-links can be processed in mammalian cells by a mechanism not requiring homologous recombination. Mutations are rarely generated during processing of these cross-links. In contrast, the reduced acrolein-mediated N(2)-dG peptide conjugates can be more mutagenic than the corresponding monoadduct. DNA polymerases of the DinB family, pol IV in E. coli and pol kappa in human, are implicated in error-free bypass of model acrolein-mediated N(2)-dG secondary adducts, the interstrand cross-links, and the peptide conjugates.

PMID:
19397281
[PubMed - indexed for MEDLINE]
PMCID:
PMC2685875
Free PMC Article

Images from this publication.See all images (8)Free text

Figure 1
Scheme 1
Scheme 2
Figure 2
Scheme 3
Scheme 4
Scheme 5
Figure 3
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for American Chemical Society Icon for PubMed Central
    Loading ...
    Write to the Help Desk