TRANSLATIONAL IMPACT
Clinical issue
The diseases referred to here as ‘telopathies’ are caused by germline mutations in telomerase components or telomere binding proteins. Patients with telopathies suffer from accelerated telomere shortening and premature death owing to exhaustion of the regenerative capacity of stem cells (i.e. impairment of bone marrow stem cells causing severe bone marrow aplasia). Thus, these telopathies are generally considered to be ‘stem cell diseases’. In the skin, telopathies are characterized by hyperpigmentation and an increased susceptibility to skin cancer. These skin phenotypes resemble those of xeroderma pigmentosum (XP) patients, a UV sensitivity syndrome caused by defects in the nucleotide excision repair (NER) machinery. Interestingly, mice with increased levels of the TRF2 telomere-binding protein in the skin (K5TRF2 mice) recapitulate the skin phenotypes of telopathies, as well as those of XP patients. K5TRF2 mice have critically short telomeres, which are rescued in the absence of the XPF/ERCC1 NER nuclease, thus linking telomeres to NER. Here, the authors use K5TRF2 mice as a model to investigate the pathways connecting stem cell dysfunction and telomere uncapping.
Results
The authors show that K5TRF2 mice have severely impaired epidermal stem cell (ESC) functionality in vivo and ex vivo, which cannot be rescued by overexpression of telomerase. In the absence of XPF, however, both telomere length and stem cell functionality are significantly rescued. Interestingly, abrogation of p53 also rescues stem cell functionality without telomere elongation. In addition, the p53 deficiency rescues skin hyperpigmentation and simultaneously accelerates the progression of skin carcinogenesis.
Implications and future directions
The findings described here highlight an important role for uncapped telomeres in the pathobiology of the cancer and aging phenotypes associated with telopathies. Furthermore, this study suggests that p53 limits the contribution of ESCs with dysfunctional telomeres to tissue regeneration, in order to limit pathology. These observations advance our understanding of telopathies, as well as other diseases characterized by the presence of critically short telomeres and premature stem cell dysfunction.
