Patients with
xeroderma pigmentosum (XP),
a DNA repair disorder, run a large risk of developing
skin cancer in sun-exposed areas.
Cancer proneness in these patients correlates with a mammalian SOS-like response, "enhanced reactivation (ER) of viruses." Here, we report that radiation-induced activation of the
ornithine decarboxylase (ODC) gene, a putative proto-oncogene, is required for this response. Various diploid fibroblast strains derived from a non-
cancer-prone subclass of XP patients, which lack the ER response, were irradiated with 2 J/m2 and assessed for gene induction. In these fibroblasts, an absence of induction of ODC by UV-C was observed at the levels of
mRNA,
protein, and
enzyme activity. This lack of induction is quite specific because the genes for fos and
collagenase were induced as they were in normal XP cells. The apparent linkage between non-
cancer proneness and a lack of ER and ODC induction was confirmed in a fibroblast strain derived from a patient with another DNA repair disorder,
trichothiodystrophy, which does not lead to
cancer proneness: in these cells, no induction of the ER response nor of ODC occurs after UV-C irradiation. Repair deficiency, however, is not essential because the simultaneous lack of ODC and ER induction after 10 J/m2 UV-C was found in at least one repair-proficient fibroblast. Next, a specific inhibitor of ODC,
difluoromethylornithine, at a dose of 10 mM, completely blocked the ER response in cultured normal skin fibroblasts, suggesting that the ODC
enzyme is in fact essential for the ER response.
Difluoromethylornithine, although it did not affect other processes such as DNA repair, leads to a block in the cell division cycle at the G1-S transition. Interestingly, other blockers of this transition,
wortmannin (500 nM) and
mimosine (100 mM), also decreased the ER response. Finally, the ER and ODC responses also seem to be linked
after treatment with X-irradiation (3 Gy), suggesting that both are part of a general response to DNA damage, at least in human skin fibroblasts. Apart from the abnormal ER and ODC responses, fibroblasts from non-
tumor-prone XP patients react in the same way to radiation as do fibroblasts from
tumor-prone XP patients with respect to other parameters. Thus, the lack of ODC induction after radiation may help to protect XP patients against skin
carcinogenesis.