Telomeres are chromosome end-capping structures, which protect the chromosome ends from unscheduled DNA repair and degradation. Telomeres are composed of repetitive DNA (TTAGGG repeats) bound to an array of specialized proteins. The length of telomere repeats and the integrity of telomere-binding proteins are both important for telomere protection. In addition, telomeres are regulated by a number of epigenetic modifications, thus pointing to a higher-order control of telomere length and function.
First, we will describe the generation and characterization of mice with altered expression of the telomere-binding protein TRF2: K5-TRF2 mice. These mice represent the first viable mouse model with altered TRF2 expression described to date. K5-TRF2 mice show a remarkable phenotype in the skin consisting of hyper-pigmentation, hair loss, dry skin, as well as increased tumors, all of which are reminiscent of the skin abnormalities characteristic of Xeroderma pigmentosum (XP) syndrome. At a cellular and molecular level, the skin of these mice presents a dramatic telomere shortening, loss of the telomeric G-strand overhang, as well as increased gamma-H2AX damage foci. K5-TRF2 skin is also more sensitive to UV irradiation, as indicated by increased UV-induced DNA adducts and carcinogenesis. We propose that the XP-like skin phenotypes described here for K5-TRF2 mice are the result of a combination of defective DNA repair together with short telomeres, thus pinpointing to the roles of TRF2 in the context of the organism. In addition, this new mouse model demonstrates the impact of altered TRF2 expression both on cancer and aging.
Second, we will describe an unprecedented role for telomerase and telomere length in epidermal stem cell mobilization, which anticipates their known role in cancer and aging.