Base sequence effects on interactions of aromatic mutagens with DNA
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; USDOE, Washington, DC (United States)
- DOE Contract Number:
- FG02-88ER60674
- OSTI ID:
- 7198706
- Report Number(s):
- DOE/ER/60674-5; ON: DE93001568
- Country of Publication:
- United States
- Language:
- English
Similar Records
Base sequence effects on interactions of aromatic mutagens with DNA
Direct synthesis and indentification of benzo[a]pyrene diol epoxide-deoxyguanosine binding sites in modified oligodeoxynucleotides
Related Subjects
59 BASIC BIOLOGICAL SCIENCES
OLIGONUCLEOTIDES
STRUCTURE-ACTIVITY RELATIONSHIPS
POLYCYCLIC AROMATIC HYDROCARBONS
MUTAGENESIS
DNA SEQUENCING
PROGRESS REPORT
AROMATICS
DOCUMENT TYPES
HYDROCARBONS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
STRUCTURAL CHEMICAL ANALYSIS
560300* - Chemicals Metabolism & Toxicology
550200 - Biochemistry