Induction of G.C to A.T transitions by the acridine half-mustard ICR-191 supports a mispairing mechanism for mutagenesis by some bulky mutagens.
As the most nucleophilic atom in DNA, the guanine N7 atom is a major site of attack for a large number of chemical mutagens as well as chemotherapeutic agents. Paradoxically, while methylation of guanine N7 is believed to be largely nonmutagenic, aflatoxin B1, among the most potent mutagens, appears to exert its mutagenic activity through adduction at this site. On the basis of an analysis of the specificity of mutations induced by various adduct forms of aflatoxin B1, we have previously proposed mechanisms that can both resolve the paradox and account for the specificity of mutagenesis by aflatoxin B1. The hypothesized mechanisms specify how a bulky guanine N7 lesion can promote G.C to A.T transitions as well as frame-shift mutations. Since the proposed mechanisms are in principle lesion-independent, a simple test of the proposed mechanisms would be to examine the specificity of mutations induced by a structurally different bulky guanine N7 adduct. Toward this goal, M13 replicative form DNA was subjected to in vitro adduction with the acridine mutagen ICR-191 and transfected into Escherichia coli. Mutations in the LacZ(alpha) gene segments were scored and defined at the sequence level. The results show that ICR-191 adduction induces both base substitutions and frame shifts with near-equal efficiency. A clear majority of base substitutions were G.C to A.T transitions. On the other hand, unlike aflatoxin B1 which could induce both -1 and +1 frameshifts, ICR-191 appears to predominantly induce +1 frame shifts. This preference appears to arise by lesion-dependent mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Sahasrabudhe
S R
SR
Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103-2757.
Luo
X
X
Humayun
M Z
MZ
D000585:Aminacrine / Q000031:analogs & derivatives* / Q000737:chemistry; D001483:Base Sequence; D003090:Coliphages / Q000235:genetics; D004249:DNA Damage; D004279:DNA, Viral / Q000737:chemistry / Q000235:genetics; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009153:Mutagens; D009588:Nitrogen Mustard Compounds / Q000737:chemistry*
D004279:DNA, Viral; D009153:Mutagens; D009588:Nitrogen Mustard Compounds; D000585:Aminacrine; C004294:acridine half-mustard