Base sequence effects on interactions of aromatic mutagens with DNA. Progress report, September 1, 1991--August 31, 1992
The chemical binding of bulky, mutagenic and carcinogenic polynuclear aromatic compounds to certain base-sequences in genomic DNA is known to inhibit DNA replication, and to induce mutations and cancer. In particular, sequences that contain multiple consecutive guanines appear to be hot spots of mutation. The objectives of this research are to determine how the base sequence around the mutagen-modified target bases influences the local DNA conformation and gives rise to mispairing of bases, or deletions, near the lesion. Oligonucleotides containing one, two, or three guanines were synthesized and chemically reacted with the mutagen anti-7,8-dihydroxy-9,10-epoxy-benzo[a]pyrene (BPDE), one of the most mutagenic and tumorigenic metabolites of benzo[a]pyrene. Adducts are formed in which only one of the guanines is modified by trans or cis addition to the exocyclic amino group. The BPDE-oligonucleotides are separated chromatographically, and the site of modification is established by Maxam-Gilbert high resolution gel electrophoresis techniques. The thermodynamic properties of duplexes using complementary, or partially complementary strands were examined. In the latter, the base opposite the modified guanine was varied in order to investigate the probability of mispairing of the modified G with A,T and G. The successful synthesis of stereospecific and site-specific mutagen-oligonucleotide adducts opens new possibilities for correlating adduct structure-biological activity relationships, and thus lead to a better understanding of base-sequence effects in mutagenesis induced by energy-related bulky polynuclear aromatic chemicals.
- Research Organization:
- New York Univ., NY (United States). Dept. of Chemistry
- Sponsoring Organization:
- USDOE, Washington, DC (United States)
- DOE Contract Number:
- FG02-88ER60674
- OSTI ID:
- 10183016
- Report Number(s):
- DOE/ER/60674-5; ON: DE93001568
- Resource Relation:
- Other Information: PBD: 30 Sep 1992
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
59 BASIC BIOLOGICAL SCIENCES
POLYCYCLIC AROMATIC HYDROCARBONS
MUTAGENESIS
OLIGONUCLEOTIDES
STRUCTURE-ACTIVITY RELATIONSHIPS
PROGRESS REPORT
DNA SEQUENCING
560300
550200
CHEMICALS METABOLISM AND TOXICOLOGY
BIOCHEMISTRY