Source:http://linkedlifedata.com/resource/pubmed/id/10626224
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
150
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| pubmed:dateCreated |
2000-2-17
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| pubmed:abstractText |
Two human carcinogens that have been extensively studied are vinyl chloride and benzene. The active metabolites used in this study are chloroacetaldehyde (CAA) and para-benzoquinone (pBQ). Each forms exocyclic adducts between the N1 and N6 of A, the N3 and N4 of C and the N1 and N2 of G. Only CAA has been found to form the N2,3 adduct of G. CAA and pBQ adducts differ structurally in size and in the number of added rings, pBQ adding two rings to the base, while etheno bases have a single five-membered ring. The mechanism of repair of these two types of adducts by human enzymes has been studied in our laboratory with defined oligodeoxynucleotides and a site-specific adduct. The etheno derivatives are repaired by DNA glycosylase activity; two mammalian glycosylases are responsible: alkylpurine-DNA-N-glycosylase (APNG) and mismatch-specific thymine-DNA glycosylase. The former repairs 1,N6-ethenoA (epsilon A) as rapidly as the original substrate, 3-methyladenine, while the latter repairs 3,N4-ethenoC (epsilon C) more efficiently than the G/T mismatch. Our finding that there are separate enzymes for epsilon A and epsilon C has been confirmed by the use of tissue extracts from an APNG knockout mouse. As pBQ is much less efficient than CAA in modifying bases, the biochemical studies required total synthesis of the nucleosides. Furthermore, the pBQ adduct-containing oligomers are cleaved, to various extents by a different class of enzyme: human and bacterial N-5'-alkylpurine (AP) endonucleases. The enzyme incises such oligomers 5' to the adduct and generates 3'-hydroxyl and 5'-phosphoryl termini but leaves the modified base on the 5'-terminus of the 3' cleavage fragment ('dangling base'). Using active-site mutants of the human AP endonuclease, we found that the active site for the primary substrate, abasic (AP) site, is the same as that for the bulky pBQ adducts. There appears to be no clear rationale for the widely differing recognition and repair mechanisms for these exocyclic adducts, as shown for the repair of the same types of modification on different bases (e.g. epsilon A and epsilon C) and for completely unrelated lesions (e.g. AP site and pBQ adducts). Another important variable that affects the rate and extent of repair is the effect of neighbouring bases. In the case of epsilon A, this sequence-dependent repair correlates with the extent of double-strandedness of the substrate, as demonstrated by thermal stability studies.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/1,N(6)-ethenoadenine,
http://linkedlifedata.com/resource/pubmed/chemical/3,N(4)-ethenocytosine,
http://linkedlifedata.com/resource/pubmed/chemical/Adenine,
http://linkedlifedata.com/resource/pubmed/chemical/Benzene,
http://linkedlifedata.com/resource/pubmed/chemical/Benzoquinones,
http://linkedlifedata.com/resource/pubmed/chemical/Carcinogens,
http://linkedlifedata.com/resource/pubmed/chemical/Cytosine,
http://linkedlifedata.com/resource/pubmed/chemical/DNA Adducts,
http://linkedlifedata.com/resource/pubmed/chemical/N-Glycosyl Hydrolases,
http://linkedlifedata.com/resource/pubmed/chemical/Thymine DNA Glycosylase,
http://linkedlifedata.com/resource/pubmed/chemical/Vinyl Chloride,
http://linkedlifedata.com/resource/pubmed/chemical/benzoquinone,
http://linkedlifedata.com/resource/pubmed/chemical/mismatch-specific thymine...
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| pubmed:status |
MEDLINE
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| pubmed:issn |
0300-5038
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
233-47
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| pubmed:dateRevised |
2004-11-17
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| pubmed:meshHeading |
pubmed-meshheading:10626224-Adenine,
pubmed-meshheading:10626224-Animals,
pubmed-meshheading:10626224-Base Sequence,
pubmed-meshheading:10626224-Benzene,
pubmed-meshheading:10626224-Benzoquinones,
pubmed-meshheading:10626224-Carcinogens,
pubmed-meshheading:10626224-Crystallography, X-Ray,
pubmed-meshheading:10626224-Cytosine,
pubmed-meshheading:10626224-DNA Adducts,
pubmed-meshheading:10626224-DNA Repair,
pubmed-meshheading:10626224-Dose-Response Relationship, Drug,
pubmed-meshheading:10626224-HeLa Cells,
pubmed-meshheading:10626224-Humans,
pubmed-meshheading:10626224-Magnetic Resonance Spectroscopy,
pubmed-meshheading:10626224-Male,
pubmed-meshheading:10626224-Mice,
pubmed-meshheading:10626224-Mice, Knockout,
pubmed-meshheading:10626224-Models, Chemical,
pubmed-meshheading:10626224-Molecular Sequence Data,
pubmed-meshheading:10626224-N-Glycosyl Hydrolases,
pubmed-meshheading:10626224-Structure-Activity Relationship,
pubmed-meshheading:10626224-Substrate Specificity,
pubmed-meshheading:10626224-Temperature,
pubmed-meshheading:10626224-Testis,
pubmed-meshheading:10626224-Thymine DNA Glycosylase,
pubmed-meshheading:10626224-Vinyl Chloride
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| pubmed:year |
1999
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| pubmed:articleTitle |
Mammalian enzymatic repair of etheno and para-benzoquinone exocyclic adducts derived from the carcinogens vinyl chloride and benzene.
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| pubmed:affiliation |
Donner Laboratory, Lawrence Berkeley National Laboratory, University of California, Berkeley 94720, USA.
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| pubmed:publicationType |
Journal Article
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