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Excision of Oxidatively Generated Guanine Lesions by Competing Base and Nucleotide Excision Repair Mechanisms in Human Cells.
- Source :
-
Chemical research in toxicology [Chem Res Toxicol] 2019 Apr 15; Vol. 32 (4), pp. 753-761. Date of Electronic Publication: 2019 Feb 08. - Publication Year :
- 2019
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Abstract
- The interchange between different repair mechanisms in human cells has long been a subject of interest. Here, we provide a direct demonstration that the oxidatively generated guanine lesions spiroiminodihydantoin (Sp) and 5-guanidinohydantoin (Gh) embedded in double-stranded DNA are substrates of both base excision repair (BER) and nucleotide excision repair (NER) mechanisms in intact human cells. Site-specifically modified, <superscript>32</superscript> P-internally labeled double-stranded DNA substrates were transfected into fibroblasts or HeLa cells, and the BER and/or NER mono- and dual incision products were quantitatively recovered after 2-8 h incubation periods and lysis of the cells. DNA duplexes bearing single benzo[ a]pyrene-derived guanine adduct were employed as positive controls of NER. The NER activities, but not the BER activities, were abolished in XPA <superscript>-/-</superscript> cells, while the BER yields were strongly reduced in NEIL1 <superscript>-/-</superscript> cells. Co-transfecting different concentrations of analogous DNA sequences bearing the BER substrates 5-hydroxyuracil diminish the BER yields of Sp lesions and enhance the yields of NER products. These results are consistent with a model based on the local availability of BER and NER factors in human cells and their competitive binding to the same Sp or Gh BER/NER substrates.
Details
- Language :
- English
- ISSN :
- 1520-5010
- Volume :
- 32
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Chemical research in toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 30688445
- Full Text :
- https://doi.org/10.1021/acs.chemrestox.8b00411