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Repair of 4-nitroquinoline-1-oxide-induced DNA damage in normal human cells and cells from classical and variant

A A Dollery, W T Melvin, H M Keir

    Mutation Research
    |February 1, 1983
    PubMed

    Insights

    Xeroderma pigmentosum (XP) cells show increased sensitivity to 4-nitroquinoline-1-oxide (4NQO). DNA replication and repair mechanisms are impaired in XP variants, affecting DNA fragment size after 4NQO exposure.

    Area of Science:

    • Cell Biology
    • Genetics
    • Molecular Biology

    Background:

    • Xeroderma pigmentosum (XP) is a genetic disorder characterized by defective DNA repair.
    • 4-nitroquinoline-1-oxide (4NQO) is a chemical mutagen used to study DNA damage and repair.
    • Fibroblast cell lines from normal and XP subjects provide a model for investigating DNA repair pathways.

    Purpose of the Study:

    • To compare the effects of 4NQO on normal and XP fibroblast cell lines.
    • To investigate the relationship between 4NQO cytotoxicity, DNA synthesis, and DNA repair.
    • To elucidate the role of DNA repair mechanisms in mitigating 4NQO-induced DNA damage.

    Main Methods:

    • Culturing of three fibroblast cell lines: normal, XP variant (XP7TA), and excision-deficient XP (XP2BI).
    • Treatment with varying doses of 4NQO.
    • Measurement of cell viability (cytotoxicity).
    • Assessment of unscheduled DNA synthesis (UDS) as a measure of DNA repair.
    • Analysis of newly synthesized DNA fragment sizes post-4NQO treatment.

    Main Results:

    • Excision-deficient XP2BI cells were ~200-fold more sensitive to 4NQO than normal cells.
    • XP variant XP7TA cells were ~2-fold more sensitive to 4NQO than normal cells.
    • Cytotoxicity correlated with UDS levels, indicating impaired DNA repair in XP cells.
    • 4NQO inhibited DNA replication in a dose-dependent manner across all cell lines.
    • Newly replicated DNA fragments were smaller in XP7TA and significantly smaller (50%) in XP2BI cells compared to normal cells.

    Conclusions:

    • XP cells exhibit differential sensitivity to 4NQO, with excision-deficient cells being most sensitive.
    • 4NQO-induced DNA damage impacts DNA replication and repair processes.
    • Smaller DNA fragment sizes in XP cells suggest defective repair of 4NQO lesions, potentially involving a short-patch repair pathway.
    • These findings highlight the critical role of DNA excision repair in cellular resistance to chemical mutagens like 4NQO.

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