Inhibition of enzymic incision of thymine dimers by covalently bound guanine adducts of 4-nitroquinoline-1-oxide in DNA

The effects of the presence in DNA of covalently bound guanine adducts of the carcinogen 4-nitroquinoline-1-oxide on the pyrimidine dimer-DNA glycosylase, purified from bacteriophage T4-infected Escherichia coli, were investigated. E. coli DNA, labeled in thymine, photosensitized by silver nitrate,...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1986-05, Vol.46 (5), p.2374
Main Authors: Duker, N J, Merkel, G W
Format: Article
Language:English
Subjects:
4-Nitroquinoline-1-oxide - metabolism
DNA Glycosylases
DNA Repair - drug effects
DNA, Bacterial - metabolism
Escherichia coli
N-Glycosyl Hydrolases - pharmacology
Nitroquinolines - metabolism
Pyrimidine Dimers - metabolism
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Summary:The effects of the presence in DNA of covalently bound guanine adducts of the carcinogen 4-nitroquinoline-1-oxide on the pyrimidine dimer-DNA glycosylase, purified from bacteriophage T4-infected Escherichia coli, were investigated. E. coli DNA, labeled in thymine, photosensitized by silver nitrate, and irradiated by 254 nm monochromatic light, was the substrate. 4-Nitroquinoline-1-oxide was reduced to 4-hydroxyaminoquinoline-1-oxide and then reacted with irradiated DNA in the presence of seryl-AMP, yielding covalently bound adducts in DNA. These were assayed by high performance liquid chromatography. Enzyme activity was assayed by measuring release of labeled free thymine from directly photoreversed DNA after the reaction. Glycosylase activity was reduced against carcinogen-modified DNA, with the Vmax 38% of that against the control DNA; the Km was unaffected. Therefore, as with other modified purines, 4-nitroquinoline-1-oxide guanine modifications can reduce enzymic incision at thymine dimers. Left unrepaired, pyrimidine dimers are both mutagenic and carcinogenic. This is consistent with the possibility that interference with enzymic initiation of DNA excision repair of UV damage may be an indirect mechanism of mutagenesis by stable carcinogen-DNA adducts.
ISSN:0008-5472