Abstract
Xeroderma pigmentosum (XP) is a rare inherited recessive disease characterized by severe sun sensitivity that leads to the progressive degeneration of exposed areas of skin, usually causing various forms of cutaneous malignancy. Mutations in seven of eight XP complementation groups, XP-A through -G, confer defects in the nucleotide excision repair (NER) pathway, while cells from XP-V patients have a normal NER pathway but are defective in the replication of damaged DNA. Our group previously identified DNA polymerase η (Pol η) as a product of XP-V responsible gene (POLH gene). Polη catalyzes error-free translesion synthesis (TLS) past cyclobutane pyrimidine dimer (CPD), a major DNA lesion induced by UV irradiation. DNA polymerase ι (Pol ι), encoded by POLI gene, is also a TLS polymerase that can incorporate nucleotides opposite another UV-induced DNA damage, (6-4) photoproduct, in vitro. To investigate physiological role of these polymerases, we have generated Polη and Polι deficient mice and shown that incidences of skin tumors were greatly increased in the Polη-/- Polι+/+ and Polη-/- Polι-/- mice by UV irradiation, and that epithelial and mesenchymal tumors were formed in Polη and Polι deficient mice, respectively. I will present our data on the mutation frequencies and spectra in genomic DNA isolated from UV-irradiated and unirradiated epidermis of wild-type, Polη-/- Polι+/+, Polη+/+ Polι-/-, and Polη-/- Polι-/- mice by using the rpsL transgene serving as a mutational reporter sequence.
