1. The activity of the DNA-dependent protein kinase (DNA-PK) complex is determinant in the cellular response to nitrogen mustards.
- Author
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Muller C, Calsou P, and Salles B
- Subjects
- Animals, Antibiotics, Antineoplastic pharmacology, Bleomycin pharmacology, Cell Line drug effects, Cell Survival drug effects, Cross-Linking Reagents pharmacology, DNA drug effects, DNA Damage drug effects, DNA-Activated Protein Kinase, DNA-Binding Proteins drug effects, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Humans, Ku Autoantigen, Mechlorethamine pharmacology, Melphalan pharmacology, Mice, Mice, SCID, Mutation, Nuclear Proteins drug effects, Nuclear Proteins genetics, Nuclear Proteins metabolism, Protein Serine-Threonine Kinases genetics, Transfection, Zinostatin pharmacology, Antigens, Nuclear, DNA Helicases, Nitrogen Mustard Compounds pharmacology, Protein Serine-Threonine Kinases drug effects, Protein Serine-Threonine Kinases metabolism
- Abstract
The DNA-dependent protein kinase plays a critical role in mammalian DNA double strand break (DSB) repair and in specialized recombination, such as lymphoid V(D)J recombination. Its regulatory subunit Ku (dimer of the Ku70 and Ku80 protein) binds to DNA and recruits the kinase catalytic sub-unit, DNA-PKcs. We show here that three different strains deficient in either the Ku80 (xrs-6) or DNA-PKcs (V-3, scid) component of DNA-PK are markedly sensitive (3.5- to 5-fold) to a group of DNA cross-linking agents, the nitrogen mustards (NMs) (melphalan and mechlorethamine) as compared to their parental cell line. Importantly, the level of hypersensitivity to these drugs was close to the level of hypersensitivity observed for radiomimetic agents that create DSBs in DNA (bleomycin and neocarzinostatin). In addition, sensitivity to NMs was restored to the parental level in the xrs-6 cell line stably transfected with the human Ku80 gene (xrs-6/Ku80), showing unequivocally that DNA-PK is involved in this phenotype. These results indicate that a function of the whole DNA-PK protein complex is involved in the cellular response to NMs and suggest that the repair of DNA interstrand cross-links induced in DNA by NMs involved a DNA-PK dependent pathway that shares common features with DNA DSBs repair.
- Published
- 2000
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