A LACK OF RADIATION-INDUCED ORNITHINE DECARBOXYLASE ACTIVITY PREVENTSENHANCED REACTIVATION OF HERPES-SIMPLEX VIRUS AND IS LINKED TO NONCANCER PRONENESS IN XERODERMA-PIGMENTOSUM PATIENTS

Patients with xeroderma pigmentosum (XP), a DNA repair disorder. run a large risk of developing skin cancer in sun-exposed areas, Cancer pro neness in these patients correlates with a mammalian SOS-like response , ''enhanced reactivation (ER) of viruses.'' Here, we report that radi ation-induced activation of the ornithine decarboxylase (ODC) gene, a putative proto-oncogene, is required for this response, Various diploi d fibroblast strains derived from a non-cancer-prone subclass of XP pa tients, which lack the ER response, were irradiated with 2 J/m(2) and assessed for gene induction. In these fibroblasts, an absence of induc tion of ODC by UV-C was observed at the levels of mRNA, protein, and e nzyme activity, This lack of induction is quite specific because the g enes for fos and collagenase were induced as they were in normal XP ce lls. The apparent linkage between non-cancer proneness and a lack of E R 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 th e ER response nor of ODC occurs after UV-C irradiation. Repair deficie ncy however, is not essential because the simultaneous lack of ODC and ER induction after 10 J/m(2) UV-C was found in at least one repair-pr oficient fibroblast, Nest, a specific inhibitor of ODC, difluoromethyl ornithine, at a dose of 10 mM, completely blocked the ER response in c ultured 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 G(1)-S transition. Interestingly, o ther blockers of this transition, wortmannin (500 nM) and mimosine (10 0 mM), also decreased the ER response, Finally, the ER and ODC respons es also seem to be linked after treatment with X-irradiation (3 Gy), s uggesting that both are part of a general response to DNA damage, at l east in human skin fibroblasts. Apart from the abnormal ER and ODC res ponses, 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 rad iation may help to protect XP patients against skin carcinogenesis.