Specificity of mutagenesis by 4-aminobiphenyl: mutations at G residues in bacteriophage M13 DNA and G-->C transversions at a unique dG(8-ABP) lesion in single-stranded DNA.
Mutagenesis by the human bladder carcinogen 4-aminobiphenyl (ABP) was studied in single-stranded DNA from a bacteriophage M13 cloning vector. In comparison to ABP lesions in double-stranded DNA, lesions in single-stranded DNA were approximately 70-fold more mutagenic and 50-fold more genotoxic. Sequencing analysis of ABP-induced mutations in the lacZ gene revealed exclusively base-pair substitutions, with over 80% of the mutations occurring at G sites; the G at position 6310 accounted for 25% of the observed mutations. Among the sequence changes at G sites, G-->T transversions predominated, followed by G-->C transversions and G-->A transitions. In order to further elucidate the mutagenic mechanism of ABP, an oligonucleotide containing the major DNA adduct, N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG(8-ABP)), was situated within the PstI site of a single-stranded M13 genome. After in vivo replication of the adduct containing ABP-modified and control (unadducted) genomes, the mutational frequency and mutational specificity of the dG(8-ABP) lesion were determined. The targeted mutational efficiency was approximately 0.01%, and the primary mutation observed was the G-->C transversion. Thus dG(8-ABP), albeit weakly mutagenic at the PstI site, can contribute to the mutational spectrum of ABP lesions.
Verghis
S B
SB
Department of Chemistry, Whitaker College of Health Sciences, Massachusetts Institute of Technology, Cambridge 02139, USA.
Essigmann
J M
JM
Kadlubar
F F
FF
Morningstar
M L
ML
Lasko
D D
DD
D000595:Amino Acid Sequence; D000611:Aminobiphenyl Compounds / Q000737:chemistry*; D017104:Bacteriophage M13; D001483:Base Sequence; D018736:DNA Adducts / Q000737:chemistry*; D004277:DNA, Single-Stranded / Q000235:genetics*; D004279:DNA, Viral / Q000737:chemistry; D015252:Deoxyribonucleases, Type II Site-Specific; D006150:Guanine Nucleotides / Q000737:chemistry*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016297:Mutagenesis, Site-Directed
D000611:Aminobiphenyl Compounds; D018736:DNA Adducts; D004277:DNA, Single-Stranded; D004279:DNA, Viral; D006150:Guanine Nucleotides; C006757:4-biphenylamine; C024388:CTGCAG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific