XPF nuclease-dependent telomere loss and increased DNA damage in mice overexpressing TRF2 result in premature aging and cancer
Authors
Muñoz P, Blanco R, Flores JM, Blasco MA
Institution
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid
Country
Spain
Year
2005
Journal
Nature Genetics
Abstract
TRF2 is a telomere-binding protein that has a role in telomere protection. We generated mice that overexpress TRF2 in the skin. These mice had a severe phenotype in the skin in response to light, consisting of premature skin deterioration, hyperpigmentation and increased skin cancer, which resembles the human syndrome xeroderma pigmentosum. Keratinocytes from these mice were hypersensitive to ultraviolet irradiation and DNA crosslinking agents. The skin cells of these mice had marked telomere shortening, loss of the telomeric G-strand overhang and increased chromosomal instability. Telomere loss in these mice was mediated by XPF, a structure-specific nuclease involved in ultraviolet-induced damage repair and mutated in individuals with xeroderma pigmentosum. These findings suggest that TRF2 provides a crucial link between telomere function and ultraviolet-induced damage repair, whose alteration underlies genomic instability, cancer and aging. Finally, we show that a number of human skin tumors have increased expression of TRF2, further highlighting a role for TRF2 in skin cancer.
Product use
Isolation and cultivation for analysis of G-strad overhang, Q-FISH analysis on metaphases, combined immuno-Q-FISH and confocal immunofluorescence, MMC treatment, UV irradiation and γ irradiation