title: Base Excision Repair of N6-Deoxyadenosine Adducts of 1,3-Butadiene.
abstract: The important industrial and environmental carcinogen 1,3-butadiene (BD) forms a range of adenine adducts in DNA, including N6-(2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine (N6-HB-dA), 1,N6-(2-hydroxy-3-hydroxymethylpropan-1,3-diyl)-2'-deoxyadenosine (1,N6-HMHP-dA), and N6,N6-(2,3-dihydroxybutan-1,4-diyl)-2'-deoxyadenosine (N6,N6-DHB-dA). If not removed prior to DNA replication, these lesions can contribute to A → T and A → G mutations commonly observed following exposure to BD and its metabolites. In this study, base excision repair of BD-induced 2'-deoxyadenosine (BD-dA) lesions was investigated. Synthetic DNA duplexes containing site-specific and stereospecific (S)-N6-HB-dA, (R,S)-1,N6-HMHP-dA, and (R,R)-N6,N6-DHB-dA adducts were prepared by a postoligomerization strategy. Incision assays with nuclear extracts from human fibrosarcoma (HT1080) cells have revealed that BD-dA adducts were recognized and cleaved by a BER mechanism, with the relative excision efficiency decreasing in the following order: (S)-N6-HB-dA > (R,R)-N6,N6-DHB-dA > (R,S)-1,N6-HMHP-dA. The extent of strand cleavage at the adduct site was decreased in the presence of BER inhibitor methoxyamine and by competitor duplexes containing known BER substrates. Similar strand cleavage assays conducted using several eukaryotic DNA glycosylases/lyases (AAG, Mutyh, hNEIL1, and hOGG1) have failed to observe correct incision products at the BD-dA lesion sites, suggesting that a different BER enzyme may be involved in the removal of BD-dA adducts in human cells.
authors.affiliation: Masonic Cancer Center and Departments of Chemistry and Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Susith
authors.initials: S
authors.lastname: Wickramaratne
authors.affiliation: Department of Chemistry, University of California , Davis, California 95616, United States.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Banda
authors.affiliation: Masonic Cancer Center and Departments of Chemistry and Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Shaofei
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Chemistry, University of California , Davis, California 95616, United States.
authors.forename: Amelia H
authors.initials: AH
authors.lastname: Manlove
authors.affiliation: Masonic Cancer Center and Departments of Chemistry and Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Malayappan
authors.affiliation: Department of Chemistry, University of California , Davis, California 95616, United States.
authors.forename: Nicole N
authors.initials: NN
authors.lastname: Nuñez
authors.affiliation: Division of Biological Engineering, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Leona
authors.initials: L
authors.lastname: Samson
authors.affiliation: Department of Pharmacology, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Colin
authors.initials: C
authors.lastname: Campbell
authors.affiliation: Department of Chemistry, University of California , Davis, California 95616, United States.
authors.forename: Sheila S
authors.initials: SS
authors.lastname: David
authors.affiliation: Masonic Cancer Center and Departments of Chemistry and Medicinal Chemistry, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors.forename: Natalia
authors.initials: N
authors.lastname: Tretyakova
mesh_terms: D000818:Animals; D002070:Butadienes / Q000737:chemistry*; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004260:DNA Repair; D003839:Deoxyadenosines / Q000737:chemistry*; D006801:Humans
chemical_list: D002070:Butadienes; D003839:Deoxyadenosines; C031763:1,3-butadiene