A general role for c-Fos in cellular protection against DNA-damaging carcinogens and cytostatic drugs.

One of the earliest responses of cells upon exposure to DNA-damaging agents is the induction of c-fos. To elucidate the biological role of Fos expression, we analyzed cells deficient in c-Fos upon treatment with different DNA-damaging agents, including carcinogens and antineoplastic drugs. We show that cells lacking c-Fos are hypersensitive with regard to reproductive cell death, apoptosis, and chromosomal breakage after treatment with agents inducing methylation lesions, bulky adducts, or crosslinks in DNA. They were not significantly hypersensitive to ionizing radiation. The activities of various repair enzymes and glutathione S-transferase and the level of proliferating cell nuclear antigen were not altered in c-fos-/- fibroblasts. Furthermore, the cells were able to remove the main methylation lesions from DNA. c-Fos-deficient cells exhibited a more severe mutagen-induced block to DNA replication and were compromised in the abolition of replication blockage. The data provide compelling evidence that c-Fos/activator protein-1 plays a decisive and general role in cellular defense against genotoxic agents, which require DNA replication to induce chromosomal instability. They are consistent with the hypothesis that impaired recovery from DNA replication inhibition upon mutagen exposure is causally involved in c-fos-/- hypersensitivity.