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  • Title: Mechanism of inhibition of enzymatic deoxyribonucleic acid methylation by 2-(acetylamino)fluorene bound to deoxyribonucleic acid.
    Author: Pfohl-Leszkowicz A, Salas C, Fuchs RP, Dirheimer G.
    Journal: Biochemistry; 1981 May 26; 20(11):3020-4. PubMed ID: 7248263.
    Abstract:
    Binding of 2-(acetylamino)fluorene (AAF) to C-8 of guanine induces a local destabilization of the DNA helix. A relationship was observed where the degree of DNA modification by AAF was inversely proportional to its methyl acceptor capacity from S-adenosyl-L-methionine in the presence of rat brain DNA cytosine 5-methyltransferase. Moreover, substituted DNA (DNA-AAF) behaves as a methylation inhibitor of native DNA. This inhibition is of the mixed type. The substituted DNAs have higher affinities for the enzyme than native DNA. The inhibition is irreversible. Addition of DNA-AAF to the enzyme preincubated with native DNA inhibits methylation, but only after a lag period. This agrees with the model in which the methylase "walks" along the strand to methylate cytosine residues before being detached from the DNA. AAF bound to guanine residues may block the movement of the enzyme along the helix. Single-stranded DNA has an affinity for the methylase 1.6 times lower than that of native double-stranded DNA. On the other hand, single-stranded DNA-AAF is more methylated than double-stranded DNA-AAF. A tentative model taking into account these observations is presented under Discussion. The in vitro hypomethylation of DNA-AAF could explain the in vivo observations made by several authors.
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