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Fos is an essential component of the mammalian UV response
M Schreiber1, B Baumann, M Cotten
1Research Institute of Molecular Pathology (IMP), Vienna, Austria.
Abstract:
Mouse 3T3 fibroblasts lacking c-fos were employed to demonstrate an essential function of the UV-inducible transcription factor AP-1 (Fos/Jun) in the response to the cytotoxic effects of short-wavelength ultraviolet (UVC) radiation. Clonogenic survival and proliferation of cells lacking c-fos were drastically reduced following UV irradiation. This UV hypersensitivity manifests itself primarily in increased cell death, partly by apoptosis, and prolonged recovery time from UV-induced cell cycle arrest. Co-culture with wild-type cells did not ameliorate the hypersensitivity of mutant cells. Transcriptional induction of the c-Fos target genes collagenase I, stromelysin-1 and stromelysin-2 by UV is almost absent in cells lacking c-fos which correlates with a reduced UV induction of AP-1 DNA-binding and transactivation activity. The repair of UV-induced DNA lesions was not affected, as shown by unscheduled DNA synthesis and host cell reactivation assays. These data demonstrate that c-Fos is involved in a novel protective function other than DNA repair against the harmful consequences of UVC.
Insights
Cells lacking the c-Fos protein show increased sensitivity to UV radiation, indicating c-Fos plays a protective role beyond DNA repair against UVC damage.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- The transcription factor AP-1 (Fos/Jun) is crucial for cellular responses to various stimuli, including UV radiation.
- The specific role of c-Fos in the cellular response to short-wavelength ultraviolet (UVC) radiation requires further elucidation.
Purpose of the Study:
- To investigate the essential function of the UV-inducible transcription factor AP-1, specifically c-Fos, in the cellular response to UVC radiation.
- To determine if c-Fos plays a role in DNA repair or other protective mechanisms against UVC-induced damage.
Main Methods:
- Utilized mouse 3T3 fibroblasts genetically modified to lack the c-fos gene.
- Assessed clonogenic survival, proliferation, and cell cycle arrest following UVC irradiation.
- Measured transcriptional induction of c-Fos target genes (collagenase I, stromelysin-1, stromelysin-2).
- Evaluated AP-1 DNA-binding and transactivation activity.
- Assessed DNA repair capacity using unscheduled DNA synthesis and host cell reactivation assays.
Main Results:
- Cells lacking c-fos exhibited significantly reduced clonogenic survival and proliferation after UVC exposure.
- This UV hypersensitivity was characterized by increased cell death, including apoptosis, and prolonged cell cycle arrest recovery.
- Transcriptional induction of c-Fos target genes and AP-1 activity were markedly diminished in c-fos-deficient cells.
- No impairment in the repair of UV-induced DNA lesions was observed in these cells.
Conclusions:
- c-Fos is essential for cellular protection against the cytotoxic effects of UVC radiation.
- The protective function of c-Fos is independent of its role in DNA repair.
- These findings reveal a novel role for c-Fos in mitigating UVC-induced cellular damage.