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Irreparable DNA cross-links and mammalian cell lethality with bifunctional alkylating agents

J P Murnane, J E Byfield

    Chemico-Biological Interactions
    |December 1, 1981
    PubMed

    Insights

    Residual DNA cross-links, including interstrand and DNA-protein types, persist after repair in C3H10T1/2 cells. These persistent DNA cross-links correlate with cell transformation and lethality following exposure to alkylating agents.

    Area of Science:

    • Molecular Biology
    • Cell Biology
    • Toxicology

    Background:

    • Bifunctional alkylating agents induce DNA cross-links.
    • Repair mechanisms exist for DNA damage.
    • Cellular response to DNA damage is critical.

    Purpose of the Study:

    • Investigate DNA cross-link formation and removal in C3H10T1/2 cells.
    • Correlate residual DNA cross-links with cell lethality and transformation.
    • Examine the role of different alkylating agents' kinetics.

    Main Methods:

    • Exposure of C3H10T1/2 cells to nitrogen mustard, phosphoramide mustard, and melphalan.
    • Quantification of DNA cross-links (interstrand and DNA-protein).
    • Assessment of cell lethality, colony formation, and transformation.

    Main Results:

    • Equivalent cell lethality observed across different alkylating agents.
    • Residual DNA cross-links remain 24 hours post-treatment, even after apparent repair.
    • DNA-protein cross-links significantly outnumber interstrand cross-links.
    • Correlation found between residual DNA cross-links, transformation, and loss of colony formation.

    Conclusions:

    • Residual DNA cross-links, particularly DNA-protein types, are present post-repair and linked to cell death.
    • These adducts may impede DNA replication, contributing to lethality.
    • Specific DNA damage types, like phosphotriester adducts, might play a role.

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