TY - JOUR
T1 - 1,N2-deoxyguanosine adducts of acrolein, crotonaldehyde, and trans-4-hydroxynonenal cross-link to peptides via Schiff base linkage
AU - Kurtz, Andrew J.
AU - Lloyd, R. Stephen
PY - 2003/2/21
Y1 - 2003/2/21
N2 - DNA-protein cross-links (DPCs) are formed upon exposure to a variety of chemical and physical agents and pose a threat to genomic integrity. In particular, acrolein and related aldehydes produce DPCs, although the chemical linkages for such cross-links have not been identified. Here, we report that oligodeoxynucleotides containing 1,N2-deoxyguanosine adducts of acrolein, crotonaldehyde, and trans-4-hydroxynonenal can form cross-links with the tetrapeptide Lys-Trp-Lys-Lys. We concluded that complex formation is mediated by a Schiff base linkage because DNA-peptide complexes were covalently trapped following reduction with sodium cyanoborohydride, and pre-reduction of adducted DNAs inhibited complex formation. A previous NMR study demonstrated that duplex DNA catalyzes ring opening for the acrolein-derived γ-hydroxy-1,N2-propanodeoxyguanosine adduct to yield an aldehydic function (de los Santos, C., Zaliznyak, T., and Johnson, F. (2001) J. Biol. Chem. 276, 9077-9082). Consistent with this earlier observation, the adducts under investigation were more reactive in duplex DNA than in single-stranded DNA, and we concluded that the ring-open aldehydic moiety is the induced tautomer in duplex DNA for adducts exhibiting high relative reactivity. Adducted DNA cross-linked to Arg-Trp-Arg-Arg and Lys-Trp-Lys-Lys with comparable efficiency, and Nα-acetylation of peptides dramatically inhibited trapping; thus, the reactive nucleophile is located at the N-terminal α-amine of the peptide. These data suggest that Schiff base chemistry can mediate DPC formation in vivo following the formation of stable aldehyde-derived DNA adducts.
AB - DNA-protein cross-links (DPCs) are formed upon exposure to a variety of chemical and physical agents and pose a threat to genomic integrity. In particular, acrolein and related aldehydes produce DPCs, although the chemical linkages for such cross-links have not been identified. Here, we report that oligodeoxynucleotides containing 1,N2-deoxyguanosine adducts of acrolein, crotonaldehyde, and trans-4-hydroxynonenal can form cross-links with the tetrapeptide Lys-Trp-Lys-Lys. We concluded that complex formation is mediated by a Schiff base linkage because DNA-peptide complexes were covalently trapped following reduction with sodium cyanoborohydride, and pre-reduction of adducted DNAs inhibited complex formation. A previous NMR study demonstrated that duplex DNA catalyzes ring opening for the acrolein-derived γ-hydroxy-1,N2-propanodeoxyguanosine adduct to yield an aldehydic function (de los Santos, C., Zaliznyak, T., and Johnson, F. (2001) J. Biol. Chem. 276, 9077-9082). Consistent with this earlier observation, the adducts under investigation were more reactive in duplex DNA than in single-stranded DNA, and we concluded that the ring-open aldehydic moiety is the induced tautomer in duplex DNA for adducts exhibiting high relative reactivity. Adducted DNA cross-linked to Arg-Trp-Arg-Arg and Lys-Trp-Lys-Lys with comparable efficiency, and Nα-acetylation of peptides dramatically inhibited trapping; thus, the reactive nucleophile is located at the N-terminal α-amine of the peptide. These data suggest that Schiff base chemistry can mediate DPC formation in vivo following the formation of stable aldehyde-derived DNA adducts.
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U2 - 10.1074/jbc.M212012200
DO - 10.1074/jbc.M212012200
M3 - Article
C2 - 12502710
AN - SCOPUS:0037458649
SN - 0021-9258
VL - 278
SP - 5970
EP - 5976
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 8
ER -