How are potent bulky carcinogens able to induce such a diverse array of mutations?
Mutations induced by activated benzo[a]pyrene ((+)-anti-B[a]PDE) in Escherichia coli are being investigated, by using both random and adduct-site-specific mutagenesis approaches. A working hypothesis was proposed that the major adduct of (+)-anti-B[a]PDE (formed at N2-Gua) is able to induce different base-substitution mutations (e.g., GC-->TA vs. GC-->AT) depending upon its conformation in DNA, which can be influenced by various factors, notably DNA sequence context. Frameshift mutations are also common with (+)-anti-B[a]PDE, and other work suggested that the frameshift and base-substitution mutagenesis pathways are coupled. The simplest hypothesis to rationalize this interrelationship is that a single (+)-anti-B[a]PDE adduct in a single conformation can be bypassed via either a frameshift or a base-substitution pathway. This counterintuitive notion can be reconciled if there are two different kinds of conformations on the pathway to mutagenesis: a class I conformation, which is the initial conformation of a DNA adduct in double-stranded DNA before its encounter with a DNA polymerase, and a class II conformation, which is the conformation that forms at a single-strand/double-strand DNA junction during replication by a DNA polymerase. Thus, GC-->TA and GC-->AT mutations may be induced by different class I conformations, whereas base substitution and frameshift mutations may be induced by the same class I conformation but by different class II conformations. The pathway of mutagenesis would be dictated by the relevant class I and II conformations, which in turn would be controlled by various factors, notably DNA sequence context.
Loechler
E L
EL
Department of Biology, Boston University, Massachusetts 02215, USA.
D001580:Benzopyrenes / Q000737:chemistry*; D002273:Carcinogens / Q000737:chemistry*; D018736:DNA Adducts; D004269:DNA, Bacterial / Q000737:chemistry; D004852:Epoxy Compounds; D004926:Escherichia coli; D006147:Guanine / Q000737:chemistry; D016296:Mutagenesis; D009153:Mutagens / Q000737:chemistry*; D009690:Nucleic Acid Conformation
D001580:Benzopyrenes; D002273:Carcinogens; D018736:DNA Adducts; D004269:DNA, Bacterial; D004852:Epoxy Compounds; D009153:Mutagens; D006147:Guanine