Skin is a complex tissue composed of two very different compartments – the continuously renewing epidermis made up mostly by keratinocytes and the underlying matrix-rich dermis with the resting fibroblasts as its major cellular components. Both compartments are tightly interconnected and a paracrine mutual interaction is essential for epidermal growth, differentiation, and tissue homeostasis. Skin aging is commonly viewed as wrinkle formation, hair greying, and impaired wound healing. Nevertheless, the epidermis as the outermost shield needs to remain intact in order to guarantee an inside-out and outside-in barrier function throughout life time of a human being. Furthermore, the epidermis is one of the few regenerative tissues that express telomerase, the ribonucleoprotein complex that can counteract telomere erosion, one of the presently mostly favoured potential mechanisms causing cellular aging. This raises the question whether in the epidermis telomerase is able to counteract telomere erosion and thereby to prevents a telomere-dependent aging process and consequently which part of the skin is responsible for the most obvious changes associated with skin aging.
The predominant X-linked form of Dyskeratosis congenita results from mutations in DKC1, which encodes dyskerin, a protein required for ribosomal RNA modification that is also a component of the telomerase complex. We have previously found that expression of an internal fragment of dyskerin (GSE24.2) rescues telomerase activity in X-linked dyskeratosis congenita (X-DC) patient cells. Here we have found that an increased basal and induced DNA damage response occurred in X-DC cells in comparison with normal cells. DNA damage that is also localized in telomeres results in increased heterochromatin formation and senescence. Expression of a cDNA coding for GSE24.2 rescues both global and telomeric DNA damage. Furthermore, transfection of bacterial purified or a chemically synthesized GSE24.2 peptide is able to rescue basal DNA damage in X-DC cells. We have also observed an increase in oxidative stress in X-DC cells and expression of GSE24.2 was able to diminish it. Altogether our data indicated that supplying GSE24.2, either from a cDNA vector or as a peptide reduces the pathogenic effects of Dkc1 mutations and suggests a novel therapeutic approach.
Telomere shortening is considered as one of the main characteristics of cellular aging by limiting cellular division. Besides the fundamental advances through the discoveries of telomere and telomerase, which were recognized by a Nobel Prize, telomere protection remains an essential area of research. Recently, it was evidenced that studying the cross-talks between the proteins associated with telomere should provide a better understanding of the mechanistic basis for telomere-associated aging phenotypes. In this review, we discuss the current knowledge on telomere shortening, telomerase activity, and the essential role of telomere binding proteins in telomere stabilization and telomere-end protection. This review highlights the capacity of telomere binding proteins to limit cellular senescence and to maintain skin tissue homeostasis, which is of key importance to reduce accelerated tissue aging. Future studies addressing telomere protection and limitation of DNA damage response in human skin should include investigations on telomere binding proteins. As little is known about the expression of telomere binding proteins in human skin and modulation of their expression with aging, it remains an interesting ﬁeld of skin research and a key area for future skin protection and anti-aging developments.
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