Genetic dissection of the mechanisms underlying telomere-associated diseases: impact of thr TRF2 telomeric protein on mouse epidermal stem cells
Authors
Stout GJ and Blasco MA
Institution
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Center, 3 Melchor Fernandez Almagro, E-28029, Madrid
Country
Spain
Year
2009
Journal
Disease Models & Mechanisms
Abstract
TRF2 is a telomere-binding protein involved in the protection of chromosome ends. Interestingly, TRF2 is overexpressed in a number of human cancers. Mice with increased TRF2 expression (K5TRF2 mice) display a severe skin phenotype including an increase in skin cancer and premature skin degeneration, which includes increased skin hyperpigmentation and skin dryness; these pathologies are concomitant with dramatic telomere shortening and increased chromosomal instability. Here, we show that K5TRF2 mice have a severe epidermal stem cell (ESC) dysfunction, which is reversed by abrogation of p53 in the absence of rescue of telomere length. Importantly, p53 deletion also rescues severe skin hyperpigmentation in these mice through regulation of alpha-melanocyte-stimulating hormone (α-MSH). In addition, skin carcinogenesis is accelerated in K5TRF2/p53−/−mice owing to attenuated p21 induction, which enables cell proliferation to resume. Altogether, these results reveal the existence of a DNA damage-dependent checkpoint that acts on ESCs with critically short telomeres and restricts skin proliferation, thereby increasing protection against skin cancer; however, the checkpoint also leads to premature skin aging phenotypes. Finally, the results described here are relevant to our understanding of the pathobiology of those human diseases that are characterized by the presence of critically short telomeres (hereafter referred to as ‘telopathies’), such as dyskeratosis congenita which causes severe skin phenotypes including skin hyperpigmentation and skin cancer.
Product use
Isolation and cultivation for colony formation assay
Tissue type
Epidermal
Tissue info
K5Tert/K5TRF2 double mutant mice and Xpf (Ercc4)/K5TRF2 mice