Sulphur 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, CEES) 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 -95% of the oligonucleotides were alkylated at least once using 500 microM HD and 1 mM CEES. Progressive alkylation of the consensus sequence was parallelled by a decrease in transcription factor binding. Under reaction conditions which alkylated approximately 95% of the oligonucleotides at least once, the binding of cloned human AP2 was reduced by 93 and 76% by HD and CEES, 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.
Gray
P J
PJ
Aeronautical and Maritime Research Laboratory, Defence Science and Technology Organisation, Melbourne, Australia.
D000477:Alkylating Agents / Q000494:pharmacology*; D000478:Alkylation; D001483:Base Sequence; D001665:Binding Sites / Q000187:drug effects; D016384:Consensus Sequence; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007509:Irritants / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009151:Mustard Gas / Q000031:analogs & derivatives / Q000494:pharmacology*; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000378:metabolism*
D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D007509:Irritants; D009841:Oligonucleotides; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C031278:2-chloroethyl ethyl sulfide; D009151:Mustard Gas