Abstract
Xeroderma pigmentosum (XP), a UV-sensitivity syndrome characterized by skin hyperpigmentation, premature aging, and increased skin cancer, is caused by defects in the nucleotide excision repair (NER) pathway. XP shares phenotypical characteristics with telomere-associated diseases like Dyskeratosis congenita and mouse models with dysfunctional telomeres, including mice deficient for telomerase (Terc(-/-) mice). Thus, we investigated a hypothesized role for telomerase and telomere dysfunction in the pathobiology of XP by comparing Xpc(-/-)-mutant mice and Xpc(-/-)G1-G3Terc(-/-) double-mutant mice and exposed them to UV radiation. Chronically UV-exposed Xpc(-/-) skin displayed shorter telomeres on an average compared with wild-type skin. Strikingly, this effect was reversed by an additional deficiency in the telomerase. Moreover, aberrantly long telomeres were observed in the double-mutant mice. Telomere lengthening in the absence of telomerase suggested activation of the alternative lengthening of telomeres (ALT) in the UV-exposed skin of the double mutants. Mechanistic investigations revealed an elevated susceptibility for UV-induced p53 patches, known to represent precursor lesions of carcinomas, in Xpc(-/-)G1-G3Terc(-/-) mice where a high number of UV-induced skin tumors occurred that were characterized by aggressive growth. Taken together, our results establish a role for xeroderma pigmentosum, complementation group C (XPC) in telomere stability, particularly upon UV exposure. In absence of telomerase, critically short telomeres in XP mutants seem to aggravate this pathology, associated with an increased tumor incidence, by activating the ALT pathway of telomere lengthening.
Highlights
Xeroderma pigmentosum (XP) is an autosomal recessive human skin disorder with a marked increase in skin cancer prevalence after exposure to sunlight, thereby underlining the biologic relevance of the DNA repair mechanism called nucleotide excision repair (NER; reviewed in ref. 1)
Xpc prevents telomere fragility Telomere dysfunction and DNA damage induced by UV
Q-FISH on mouse epidermis did not reveal major changes in telomere length in aged matched mice from G1-G3TercÀ/À in Xpcþ/þ and XpcÀ/À background (Supplementary Fig. S2A–S2C), a trend to shorter telomeres is observed in the latter, both in vivo and in vitro. These results suggest that XPC is dispensable for telomere length maintenance
Summary
Xeroderma pigmentosum (XP) is an autosomal recessive human skin disorder with a marked increase in skin cancer prevalence after exposure to sunlight, thereby underlining the biologic relevance of the DNA repair mechanism called nucleotide excision repair (NER; reviewed in ref. 1). Xeroderma pigmentosum (XP) is an autosomal recessive human skin disorder with a marked increase in skin cancer prevalence after exposure to sunlight, thereby underlining the biologic relevance of the DNA repair mechanism called nucleotide excision repair XP-associated skin pathologies are remarkably similar to those of patients suffering from telomere disorders, such as Dyskeratosis congenita. These patients show a shortened lifespan, cutaneous pigmentation, premature hair graying, dystrophy of the nails, leukoplakia of the oral mucosa, anemia, and predisposition to cancer resulting from a mutation in telomerase [3,4,5]
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