CHEMICAL SYNTHESIS AND BIOLOGICAL APPLICATIONS OF OL IGODEOXYNUCLEOTIDES CONTAINING CARCINOGEN-DNA ADDUCTS: O6-METHYLGUANINE AND N-(GUAN-8-YL)- 4-AMINOBIPHENYL

Abstract

Tetranucleotides containing the carcinogen-DNA adducts 06-methylguanine and N-(guan-8-yl )-4-aminobiphenyl were synthesized and the structures of these adducted oligomers were characterized. Both tetramers were efficiently incorporated into E. coli bacteriophage M13 DNA containing a four-base gap in the unique recognition site for the restriction endonuclease PstI. Each lesion inhibited cleavage of the respective adducted genome by PstI. After introduction into E. coli, 06-methylguanine induced mutations at the PstI site. In cells with normal 06-methylguanine DNA repair capability, the frequency of mutant phage was 0.4%. When cells were depleted in their ability to repair this lesion, the mutation frequency increased. The highest mutation frequency attained was 20%. In both repair competent and repair depleted cells, the mutants induced by 06-methylguanine were exclusively G to A transitions.