SULFUR MUSTARDS INHIBIT BINDING OF TRANSCRIPTION FACTOR AP2 IN-VITRO

The bifunctional sulphur mustard (bis-(2-chloroethyl)sulphide, HD) and its monofunctional analogue (2-chloroethyl ethyl sulphide, GEES) are both vesicants, In this study, both mustards were shown to rapidly alkylate the AP2 consensus binding sequence incorporated in a 26mer oligonucleotide, The reaction was essentially complete within 10 min under the conditions employed in this study and similar to 95% of the oligonucleotides were alkylated at least once using 500 mu M HD and 1 mM GEES, Progressive alkylation of the consensus sequence was parallelled by a decrease in transcription factor binding, Under reaction conditions which alkylated similar to 95% of the oligonucleotides at least once, the binding of cloned human AP2 was reduced by 93 and 76% by HD and GEES, respectively, compared with control values, The interference with binding is a result of alkylation of the DNA and not damage to the transcription factor by mustard or its hydrolysis products, Interference with transcription factor binding would be expected to have a profound influence on the ability of the cell to function normally and to respond to DNA damage and may contribute significantly to the skin damage produced by these compounds.