TY  - JOUR
AU  - Sanz-Moreno, Adrián
AU  - Becker, Lore
AU  - Xie, Kan
AU  - da Silva-Buttkus, Patricia
AU  - Dragano, Nathalia R V
AU  - Aguilar-Pimentel, Antonio
AU  - Amarie, Oana V
AU  - Calzada-Wack, Julia
AU  - Kraiger, Markus
AU  - Leuchtenberger, Stefanie
AU  - Seisenberger, Claudia
AU  - Marschall, Susan
AU  - Rathkolb, Birgit
AU  - Scifo, Enzo
AU  - Liu, Ting
AU  - Thanabalasingam, Anoja
AU  - Sanchez-Vazquez, Raul
AU  - Martinez, Paula
AU  - Blasco, Maria A
AU  - Savage, Sharon A
AU  - Fuchs, Helmut
AU  - Ehninger, Dan
AU  - Gailus-Durner, Valérie
AU  - de Angelis, Martin Hrabê
TI  - Loss of Ten1 in mice induces telomere shortening and models human dyskeratosis congenita.
JO  - Science advances
VL  - 11
IS  - 15
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DZNE-2025-00516
SP  - eadp8093
PY  - 2025
AB  - Telomere length regulation is essential for genome stability as short telomeres can trigger cellular senescence and apoptosis constituting an integral aspect of biological aging. Telomere biology disorders (TBDs) such as dyskeratosis congenita (DC) are rare, inherited diseases with known mutations in at least 16 different genes encoding components of the telomere maintenance complexes. The precise role of TEN1, part of the CST complex (CTC1, STN1, and TEN1), and the consequences of its loss of function in vivo are not yet known. We investigated the first viable murine model of Ten1 deficiency created by CRISPR-Cas9-mediated exon 3 deletion. Ten1 homozygous knockout mice present with telomere attrition, short life span, skin hyperpigmentation, aplastic anemia, and cerebellar hypoplasia. Molecular analyses revealed a reduction of proliferating cells, increased apoptosis, and stem cell depletion with activation of the p53/p21 signaling pathway. Our data demonstrate that Ten1 deficiency causes telomere shortening and associates with accelerated aging.
KW  - Animals
KW  - Dyskeratosis Congenita: genetics
KW  - Dyskeratosis Congenita: pathology
KW  - Dyskeratosis Congenita: metabolism
KW  - Mice
KW  - Telomere Shortening: genetics
KW  - Disease Models, Animal
KW  - Mice, Knockout
KW  - Humans
KW  - Apoptosis: genetics
KW  - Tumor Suppressor Protein p53: metabolism
KW  - Telomere: genetics
KW  - Telomere: metabolism
KW  - Telomere-Binding Proteins: genetics
KW  - Telomere-Binding Proteins: deficiency
KW  - Signal Transduction
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
KW  - Telomere-Binding Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40215293
C2  - pmc:PMC11988282
DO  - DOI:10.1126/sciadv.adp8093
UR  - https://pub.dzne.de/record/277989
ER  -