title: Base and Nucleotide Excision Repair of Oxidatively Generated Guanine Lesions in DNA.
abstract: The well known biomarker of oxidative stress, 8-oxo-7,8-dihydroguanine, is more susceptible to further oxidation than the parent guanine base and can be oxidatively transformed to the genotoxic spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh) lesions. Incubation of 135-mer duplexes with single Sp or Gh lesions in human cell extracts yields a characteristic nucleotide excision repair (NER)-induced ladder of short dual incision oligonucleotide fragments in addition to base excision repair (BER) incision products. The ladders were not observed when NER was inhibited either by mouse monoclonal antibody (5F12) to human XPA or in XPC(-/-) fibroblast cell extracts. However, normal NER activity appeared when the XPC(-/-) cell extracts were complemented with XPC-RAD23B proteins. The Sp and Gh lesions are excellent substrates of both BER and NER. In contrast, 5-guanidino-4-nitroimidazole, a product of the oxidation of guanine in DNA by peroxynitrite, is an excellent substrate of BER only. In the case of mouse embryonic fibroblasts, BER of the Sp lesion is strongly reduced in NEIL1(-/-) relative to NEIL1(+/+) extracts. In summary, in human cell extracts, BER and NER activities co-exist and excise Gh and Sp DNA lesions, suggesting that the relative NER/BER product ratios may depend on competitive BER and NER protein binding to these lesions.
authors.affiliation: From the Department of Chemistry, New York University, New York, New York 10003, vs5@nyu.edu.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Shafirovich
authors.affiliation: From the Department of Chemistry, New York University, New York, New York 10003.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Kropachev
authors.affiliation: From the Department of Chemistry, New York University, New York, New York 10003.
authors.forename: Thomas
authors.initials: T
authors.lastname: Anderson
authors.affiliation: From the Department of Chemistry, New York University, New York, New York 10003.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: From the Department of Chemistry, New York University, New York, New York 10003.
authors.forename: Marina
authors.initials: M
authors.lastname: Kolbanovskiy
authors.affiliation: Department of Chemistry, University of Montana, Missoula, Montana 59812, and.
authors.forename: Brooke D
authors.initials: BD
authors.lastname: Martin
authors.affiliation: Department of Chemistry, University of Montana, Missoula, Montana 59812, and.
authors.forename: Kent
authors.initials: K
authors.lastname: Sugden
authors.affiliation: Department of Chemistry, University of Illinois, Chicago, Illinois 60607.
authors.forename: Yoonjung
authors.initials: Y
authors.lastname: Shim
authors.affiliation: Department of Chemistry, University of Illinois, Chicago, Illinois 60607.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Illinois, Chicago, Illinois 60607.
authors.forename: Jung-Hyun
authors.initials: JH
authors.lastname: Min
authors.affiliation: From the Department of Chemistry, New York University, New York, New York 10003, ng1@nyu.edu.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Geacintov
mesh_terms: D000818:Animals; D002460:Cell Line; D002477:Cells; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018384:Oxidative Stress
chemical_list: D004268:DNA-Binding Proteins; C086984:XPC protein, human; C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C473634:NEIL1 protein, human
keywords: DNA damage; DNA repair; base excision repair (BER); nucleotide excision repair; oxidative stress