Human xeroderma pigmentosum variant cells are deficient in pol eta (XP-V/POLH gene), affecting translesion synthesis following solar ultraviolet (UV) light-induced DNA damage. Consequently, these patients have a high frequency of skin tumors in regions exposed to sunlight. We investigated how XP-V cells respond to UVA light, corresponding to the most intense solar UV to reach patients. These cells are more sensitive to UVA light when compared to control cells, but interestingly, an oxidative stress effect is induced in these cells, inhibiting the repair capacity of these cells. The XP-V cells present both replication and cell cycle block completely protected in cells pre-treated with N-acetyl cysteine antioxidant agent. Mutagenesis in these cells through whole-exome sequencing also revealed that UVA-irradiation increase in C>T transitions, mainly at potential pyrimidine dimer sites, but also a substantial contribution of C>A transversions, potentially due to oxidized bases, even in XP-V cells V non-irradiated. Interestingly, the mutation profile of skin tumors from XP-V patients also discloses strong participation of C>A mutations in a particular sequence context. Moreover, some tumors revealed a mutation signature related to tobacco chewing. The results indicate that oxidation may be responsible for at least part of the phenotype in XP-V patients. Thus, including antioxidant protection in the everyday life of XP-V patients may contribute to the improvement of their life quality. Interestingly, XP-V skin tumors also presented a high frequency of retrotransposition insertion, compared to skin tumors from normal population. We are now investigating the mechanisms responsible for these transposition events, as the increase in single stranded DNA observed in XP-V cells replicating their damaged DNA may provide a substrate for retrotransposition.
Financial Support: FAPESP, CNPq, CAPES.