Repair of hydantoin lesions and their amine adducts in DNA by base and nucleotide excision repair

Paige L. McKibbin, Aaron M. Fleming, Mohammad Atif Towheed, Bennett Van Houten, Cynthia J. Burrows, Sheila S. David

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

An important feature of the common DNA oxidation product 8-oxo-7,8-dihydroguanine (OG) is its susceptibility to further oxidation that produces guanidinohydantoin (Gh) and spiroiminodihydantoin (Sp) lesions. In the presence of amines, G or OG oxidation produces hydantoin amine adducts. Such adducts may form in cells via interception of oxidized intermediates by protein-derived nucleophiles or naturally occurring amines that are tightly associated with DNA. Gh and Sp are known to be substrates for base excision repair (BER) glycosylases; however, large Sp-amine adducts would be expected to be more readily repaired by nucleotide excision repair (NER). A series of Sp adducts differing in the size of the attached amine were synthesized to evaluate the relative processing by NER and BER. The UvrABC complex excised Gh, Sp, and the Sp-amine adducts from duplex DNA, with the greatest efficiency for the largest Sp-amine adducts. The affinity of UvrA for all of the lesion duplexes was found to be similar, whereas the efficiency of UvrB loading tracked with the efficiency of UvrABC excision. In contrast, the human BER glycosylase NEIL1 exhibited robust activity for all Sp-amine adducts irrespective of size. These studies suggest that both NER and BER pathways mediate repair of a diverse set of hydantoin lesions in cells.

Original languageEnglish (US)
Pages (from-to)13851-13861
Number of pages11
JournalJournal of the American Chemical Society
Volume135
Issue number37
DOIs
StatePublished - Sep 18 2013

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

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    McKibbin, P. L., Fleming, A. M., Towheed, M. A., Van Houten, B., Burrows, C. J., & David, S. S. (2013). Repair of hydantoin lesions and their amine adducts in DNA by base and nucleotide excision repair. Journal of the American Chemical Society, 135(37), 13851-13861. https://doi.org/10.1021/ja4059469