Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
Telomeres protect the chromosome ends from unscheduled DNA repair and degradation. Telomeres are heterochromatic domains 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, we have recently shown that telomere length is regulated by a number of epigenetic modifications, thus pointing to a higher-order control of telomere function. A key process in organ homeostasis is the mobilization of stem cells out of their niches. Defects in organ homeostasis are present both in cancer and in aging-related diseases. Here we will discuss that telomere length and the catalytic component of telomerase, Tert, are critical determinants for the mobilization of epidermal stem cells. On one hand, we will show that telomere shortening in the absence of telomerase negatively impacts on the mobilization of epidermal stem cells. On the other hand, Tert over-expression in the absence of changes in telomere length significantly increases the mobilization of epidermal stem cells, thus providing a mechanism by which Tert may promote tumorigenesis independently of telomere length. Finally, we will describe the generation and characterization of mice with constitutive expression of the telomere-binding protein TRF2 in the skin. TRF2 mice show a remarkable phenotype in the skin consisting of hyper-pigmentation, hair loss, dry skin, as well as increased skin tumors, all of which are reminiscent of the skin abnormalities characteristic of Xeroderma pigmentosum (XP) syndrome. We propose that the XP-like skin phenotypes described here for 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.
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