Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XII mutational and non-mutational mechanism as subsets of a more general mechanism. Part A--Ethionine.
The ethionine-induced genic derepression mechanism is visualized as a secondary process that occurs after the S-adenosyl-L methionine pool concentrations are lowered to critical levels. Although DNA methylation has been shown to be correlated with genic activity, the times observed for inducement (3 days) of the alpha-fetoprotein gene and its reversibility (within 7 days) does not make it likely that alterations in the methylated status of DNA is involved. The specific mechanism is theorized to be as follows: the adenine moiety of S-adenosyl-L-methionine base-pairs with thymine of a specific structural area of the alpha-fetoprotein gene. The process is visualized as a frequent event during moments of structural relaxation of an otherwise hyperspiralized condition of the chromatin. This weak hydrogen bonding situation allows the methylation by protein methylases of a precursor chromatin protein that after methylation by the S-adenosyl-L-methionine which is base-paired to the specific DNA site, conformationally is set or locked into place and acts as a specific repressor for the alpha-fetoprotein gene. This subsequently disallows RNA polymerase activity of the region. During turnover of this chromatin protein the replacement of the methylated repressor is normally maintained. But if the S-adenosyl-L-methionine pool concentration is lowered to a level below that required for base-pairing by the adenine moiety, then the repressed conformational condition of the alpha-fetoprotein gene is altered allowing transcription. In this manner the correlation between low S-adenosyl-L-methionine and alpha-fetoprotein synthesis can be made.
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000235:genetics; D004622:Embryo, Mammalian / Q000502:physiology; D005001:Ethionine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008745:Methylation; D009363:Neoplasm Proteins / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D012436:S-Adenosylmethionine / Q000235:genetics; D000509:alpha-Fetoproteins / Q000235:genetics*
D002273:Carcinogens; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D000509:alpha-Fetoproteins; D012436:S-Adenosylmethionine; D005001:Ethionine