Chloroethylnitrosourea-derived ethano cytosine and adenine adducts are substrates for Escherichia coli glycosylases excising analogous etheno adducts

DNA Repair
Anton B GuliaevB Hang

Abstract

Exocyclic ethano DNA adducts are saturated etheno ring derivatives formed mainly by therapeutic chloroethylnitrosoureas (CNUs), which are also mutagenic and carcinogenic. In this work, we report that two of the ethano adducts, 3,N4-ethanocytosine (EC) and 1,N6-ethanoadenine (EA), are novel substrates for the Escherichia coli mismatch-specific uracil-DNA glycosylase (Mug) and 3-methyladenine DNA glycosylase II (AlkA), respectively. It has been shown previously that Mug excises 3,N4-ethenocytosine (epsilonC) and AlkA releases 1,N6-ethenoadenine (epsilonA). Using synthetic oligonucleotides containing a single ethano or etheno adduct, we found that both glycosylases had a approximately 20-fold lower excision activity toward EC or EA than that toward their structurally analogous epsilonC or epsilonA adduct. Both enzymes were capable of excising the ethano base paired with any of the four natural bases, but with varying efficiencies. The Mug activity toward EC could be stimulated by E. coli endonuclease IV and, more efficiently, by exonuclease III. Molecular dynamics (MD) simulations showed similar structural features of the etheno and ethano derivatives when present in DNA duplexes. However, also as shown by MD, the stacking interac...Continue Reading

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Citations

Jul 31, 2007·Chemical Research in Toxicology·Min Young KimGerald N Wogan
Oct 31, 2009·Carcinogenesis·Nidhi ShrivastavJohn M Essigmann
Apr 17, 2012·Journal of Drug Delivery·Sarah Brown, David R Khan
Feb 3, 2007·Chemico-biological Interactions·Bo Hang, Anton B Guliaev
Oct 23, 2004·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Bo Hang
Jan 11, 2007·Proceedings of the National Academy of Sciences of the United States of America·Lauren E FrickJohn M Essigmann
May 5, 2012·Journal of the American Chemical Society·Anna Zhachkina MichelsonJeehiun K Lee
Jun 28, 2011·Parasitology International·Puangrat YongvanitHelmut Bartsch
Jun 17, 2021·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·F Peter Guengerich, Pratibha P Ghodke

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