The chemical carcinogen, chloroacetaldehyde, modifies a specific site within the regulatory sequence of human cytomegalovirus major immediate early gene in vivo.
The reaction of chemical carcinogens with DNA is well documented, but whether this interaction occurs at specific sites in chromatin is unknown. We have examined in vivo the reaction of a known carcinogen, chloroacetaldehyde, with the active and inactive major immediate early gene of human cytomegalovirus. We found that during active transcription of the gene, this chemical carcinogen reacts with a unique DNA site in the 5' flanking sequence of the major immediate early gene. However, no reaction was detected in infected nonpermissive cells in which the gene was inactive. The chloroacetaldehyde-reactive site is located at -836 +/- 10 bp from the mRNA cap site in the part of the regulatory region that can both negatively and positively affect promoter activity [Nelson et al., Mol Cell Biol 7:4125-4129, 1987]. These results suggest, at least in the case of chloroacetaldehyde, the possibility that the molecular mechanism of chemical carcinogenesis involves a chemical reaction at specific sites in chromatin within the sequences responsible for regulation of gene expression. Such carcinogen-DNA interaction occurs as a consequence of a non-B DNA structure that contains unpaired DNA bases existing at specific sites in chromatin.
Kohwi-Shigematsu
T
T
Cancer Research Center, La Jolla Cancer Research Foundation, California 92037.
Nelson
J A
JA
D000079:Acetaldehyde / Q000031:analogs & derivatives* / Q000494:pharmacology; D000956:Antigens, Viral / Q000096:biosynthesis / Q000235:genetics*; D002843:Chromatin / Q000187:drug effects; D002874:Chromosome Mapping; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics; D004278:DNA, Superhelical / Q000187:drug effects; D004279:DNA, Viral / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins; D015394:Molecular Structure; D010957:Plasmids; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012045:Regulatory Sequences, Nucleic Acid / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000956:Antigens, Viral; D002843:Chromatin; D004278:DNA, Superhelical; D004279:DNA, Viral; D017874:Immediate-Early Proteins; C044582:immediate-early proteins, cytomegalovirus; C004656:chloroacetaldehyde; D000079:Acetaldehyde