Distortion in stereospecific and site-specific BPDE-DNA
- New York Univ., NY (United States)
- American Health Foundation, Valhalla, NY (United States)
The mutagenic and tumorigenic characteristics of the (+)- and (-)- enantiomers of trans-7.8-dihydroxy-anti-9, 10-epoxy-7,8,9,10- tetrahydrobenzo (a)pyrene (anti-BPDE) are strikingly different from one another. Deformations of DNA by anti-BPDE bound covalently to the exocyclic amino group of guanosine residues in DNA may have a strong impact on DNA replication fidelity, inhibition of DNA synthesis, and recognition of the damaged DNA by repair enzymes. In order to gain an understanding of the role of BPDE-N{sup 2}-dG adduct stereochemistry and the influence of base sequence contexts on these phenomena, we are investigating distortions of the local DNA structure associated with the formation of these lesions by gel electrophoresis. Oligonucleotides 11-22 bases long with a single, site-specifically positioned, stereochemically defined BPDE-N{sup 2}-dG lesion in two different sequence contexts (5{prime}...TG{sup BPDE}T...3{prime} and 5..CG{sup BPDE}C...3{prime}) were synthesized. Local DNA distortions at the site of the lesions were amplified by ligation to multimers and their electrophoretic mobilities relative to similar unmodified oligonucleotides were evaluated. The degrees of structural distortion induced by the BPDE residues exhibit stereochemistry-dependent and base sequence-dependent effects. Prominent hinge joints at the site of the BPDE lesions are observed in the (+)-trans, but not in the (-)-trans, (+) and (-)-cis adducts in ...TG{sup BPDE}T...sequences. In ..CG{sup BPDE}C... sequences on the other hand, the (+) trans adducts are characterized by physical bends rather than hinge joints. These results suggest that chemically identical BPDE adducts, but with different stereochemical properties and situated in different base sequences, may exhibit different biological endpoints.
- DOE Contract Number:
- FG02-86ER60405
- OSTI ID:
- 88933
- Report Number(s):
- CONF-9405324--
- Journal Information:
- Environmental and Molecular Mutagenesis, Journal Name: Environmental and Molecular Mutagenesis Journal Issue: Suppl.23 Vol. 23; ISSN EMMUEG; ISSN 0893-6692
- Country of Publication:
- United States
- Language:
- English
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