Increased Susceptibility to UV-Induced Skin Carcinogenesis in Polymerase η–deficient Mice

Abstract

Xeroderma pigmentosum variant (XPV) patients with mutations in the DNA polymerase H (pol h) gene are hypersensitive to sunlight and have greatly increased susceptibility to sunlight-induced skin cancer. Consistent with the ability of Pol H to efficiently bypass UV light-induced cyclobutane pyrimidine dimers, XPV cells lacking Pol H have diminished capacity to replicate UV-damaged DNA and are sensitive to UV light-induced killing and mutagenesis. To better understand these and other Pol H functions, we generated Pol H-deficient mice. Mice homozygous for a null mutation in pol h are viable, fertile, and do not show any obvious spontaneous defects during the first year of life. However, fibroblasts derived from these mutant mice are sensitive to killing by exposure to UV light, and all Pol H-deficient mice develop skin tumors after UV irradiation, in contrast to the wild-type littermate controls that did not develop such tumors. These results and biochemical studies of translesion synthesis by mouse Pol H indicate that Pol H-dependent bypass of cyclobutane pyrimidine dimers suppresses UV light-induced skin cancer in mice. Moreover, 37.5% of pol h heterozygous mice also developed skin cancer during 5 months after a 5-month exposure to UV light, suggesting that humans who are heterozygous for mutations in pol h may also have an increased risk of skin cancer. (Cancer Res 2006; 66(1): 87-94)

UV-B Radiation Induces Epithelial Tumors in Mice Lacking DNA Polymerase η and Mesenchymal Tumors in Mice Deficient for DNA Polymerase ι

“…The increasing incidence of tumors in mice lacking only one Polh allele indicates that heterozygous XP-V patients may be more susceptible to cancer than are normal individuals that are chronically exposed to sunlight. Similar results for UV-induced skin carcinogenesis in an independently generated mouse deficient for a single allele of Pol were recently reported by Lin et al (36).…”

Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities

“…However, in a 2-y study, no increase in the incidence of tumors of any type was found with pol η KO (pol η −/− ) mice (15). Instead, we found pol η −/− mice develop metabolic abnormalities that induce obesity.…”

Human DNA Polymerase η and Its Regulatory Mechanisms

“…However,ˆbroblasts from these mice showed enhanced sensitivity to UV, and all of the Polh-deˆcient mice developed skin tumors after UV-irradiation. These results conˆrm that Polh prevents UVinduced cell death and skin cancer by catalyzing the accurate bypass of CPDs in mice as well as in humans (73,74).…”