High susceptibility to ultraviolet-induced carcinogenesis in mice lacking XPC

Abstract

Compromise of genetic information by mutation may result in the dysregulation of cellular growth control and subsequent tumour formation. Xeroderma pigmentosum (XP) is a rare autosomal disease characterized by hypersensitivity of the skin to sunlight and > 1,000-fold increased risk of skin cancers in sun-exposed parts of the body. Cell fusion studies have revealed eight complementation groups in XP (A-G, and an XP-variant form); group C is one of the most common forms of the disease. We have isolated a mouse homologue of the human gene for XP group C and generated XPC-deficient mice by using embryonic stem cell technology. Mice homozygous for the XPC mutant allele (xpcm1/xpcm1) are viable and do not exhibit an increased susceptibility to spontaneous tumour generation at one year of age. However, xpcm1/xpcm1 mice were found to be highly susceptible to ultraviolet-induced carcinogenesis compared with mice heterozygous for the mutant allele (xpcm1/+) and wild-type controls. Homozygous xpcm1 mutant mice also display a spectrum of ultraviolet-exposure-related pathological skin and eye changes consistent with the human disease xeroderma pigmentosum group C.

Regulation of epidermal apoptosis and DNA repair by E2F1 in response to ultraviolet B radiation

“…XP is characterized by extreme sensitivity to UV light, resulting in advanced degenerative changes on sun-exposed areas of the skin and eyes and a high predisposition to cancer. Deletion of NER genes in experimental animals that are then subjected to UV carcinogenesis protocols has corroborated these findings, demonstrating that NER is a primary defense against UV-induced cancer (de Vries et al, 1995;Nakane et al, 1995;Sands et al, 1995;Berg et al, 2000).…”

Modulation of DNA damage/DNA repair capacity by XPC polymorphisms

“…Deficiency in XPC has been implicated in tumorigenesis. For example, XPC-defective mice were highly prone to skin cancer following exposure to UV radiation [3] and also susceptible to common cancers such as lung, esophageal, and bladder cancers when exposed to chemical carcinogens [4].…”

Tumor-prone phenotype of the DDB2-deficient mice

“…Mice harboring mutation in the XPA or XPC gene did not develop spontaneous tumors, however, they developed tumors at a high frequency upon UVB irradiation for a period of 20-30 weeks (Nakane et al, 1995;Sands et al, 1995). A recent study on DDB2À/À mice reported high incidences of UV-induced skin carcinogenesis (Itoh et al, 2004).…”