Base Excision Repair of N6-Deoxyadenosine Adducts of 1,3-Butadiene

Susith Wickramaratne, Douglas M. Banda, Shaofei Ji, Amelia H. Manlove, Bhaskar Malayappan, Nicole N. Nuñez, Leona Samson, Colin Campbell, Sheila S. David, Natalia Tretyakova

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6070-6081
Number of pages12
JournalBiochemistry
Volume55
Issue number43
DOIs
StatePublished - Nov 1 2016

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DNA Repair
Repair
Assays
DNA
Environmental Carcinogens
DNA Glycosylases
Lyases
DNA Adducts
Fibrosarcoma
Adenine
Metabolites
DNA Replication
1,3-butadiene
2'-deoxyadenosine
Cells
Mutation
Substrates
Enzymes
N6-(2-hydroxy-3-buten-1-yl)-2'-deoxyadenosine

ASJC Scopus subject areas

  • Biochemistry

Cite this

Wickramaratne, S., Banda, D. M., Ji, S., Manlove, A. H., Malayappan, B., Nuñez, N. N., ... Tretyakova, N. (2016). Base Excision Repair of N6-Deoxyadenosine Adducts of 1,3-Butadiene. Biochemistry, 55(43), 6070-6081. https://doi.org/10.1021/acs.biochem.6b00553

Base Excision Repair of N6-Deoxyadenosine Adducts of 1,3-Butadiene. / Wickramaratne, Susith; Banda, Douglas M.; Ji, Shaofei; Manlove, Amelia H.; Malayappan, Bhaskar; Nuñez, Nicole N.; Samson, Leona; Campbell, Colin; David, Sheila S.; Tretyakova, Natalia.

In: Biochemistry, Vol. 55, No. 43, 01.11.2016, p. 6070-6081.

Research output: Contribution to journalArticle

Wickramaratne, S, Banda, DM, Ji, S, Manlove, AH, Malayappan, B, Nuñez, NN, Samson, L, Campbell, C, David, SS & Tretyakova, N 2016, 'Base Excision Repair of N6-Deoxyadenosine Adducts of 1,3-Butadiene', Biochemistry, vol. 55, no. 43, pp. 6070-6081. https://doi.org/10.1021/acs.biochem.6b00553
Wickramaratne S, Banda DM, Ji S, Manlove AH, Malayappan B, Nuñez NN et al. Base Excision Repair of N6-Deoxyadenosine Adducts of 1,3-Butadiene. Biochemistry. 2016 Nov 1;55(43):6070-6081. https://doi.org/10.1021/acs.biochem.6b00553
Wickramaratne, Susith ; Banda, Douglas M. ; Ji, Shaofei ; Manlove, Amelia H. ; Malayappan, Bhaskar ; Nuñez, Nicole N. ; Samson, Leona ; Campbell, Colin ; David, Sheila S. ; Tretyakova, Natalia. / Base Excision Repair of N6-Deoxyadenosine Adducts of 1,3-Butadiene. In: Biochemistry. 2016 ; Vol. 55, No. 43. pp. 6070-6081.
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AB - 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.

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