Mechanisms of mutagenesis by chloroacetaldehyde.
A number of bifunctional chemical mutagens induce exocyclic DNA lesions. For example, 2-chloroacetaldehyde (CAA), a metabolite of vinyl chloride, readily reacts with single-stranded DNA to predominantly form etheno lesions. Here, we report on in vivo mutagenesis caused by CAA treatment of DNA in vitro. These experiments used partially duplex phage M13AB28 replicative form DNA in which a part of the lacZ gene sequence was held in single-stranded form to direct reaction with CAA. CAA-treated partial duplex DNA was transfected into Escherichia coli, and the induced base changes were defined by DNA sequencing. These experiments suggested that CAA treatment induced mutations at cytosines, much less efficiently at adenines, but not at guanines or thymines. Among mutations targeted to cytosine, 80% were C-to-T transitions and 20% were C-to-A transversions. Application of a post-labeling method detected dose-dependent formation of ethenoadenine and ethenocytosine in CAA treated DNA. These data indicate that ethenocytosine is a highly efficient mutagen with properties suggestive of a non-instructional DNA lesion in vivo. Paradoxically, ethenoadenines are efficiently bypassed by a mechanism which appears to be largely nonmutagenic.
Jacobsen
J S
JS
Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey, Newark 07103.
Perkins
C P
CP
Callahan
J T
JT
Sambamurti
K
K
Humayun
M Z
MZ
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000633:toxicity; D001483:Base Sequence; D002470:Cell Survival; D003090:Coliphages / Q000235:genetics; D003597:Cytosine Nucleotides / Q000235:genetics; D004247:DNA / Q000032:analysis; D004279:DNA, Viral / Q000187:drug effects; D004926:Escherichia coli / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D014162:Transfection
D003597:Cytosine Nucleotides; D004279:DNA, Viral; D004247:DNA; C004656:chloroacetaldehyde; D000079:Acetaldehyde