DNA stability and structure need to be preserved during life to ensure proper cellular and organismal functions. End-of-chromosome complexes, telomeres, also use maintenance mechanisms to prevent DNA damage and shortening during progressive cell divisions. This is known to be crucial for healthy aging.
Researchers from the German Mouse Clinic at Helmholtz Munich have generated a mouse model with Ten1 deficiency, which shows premature aging and shorter telomeres. The pathological phenotypes observed resemble Dyskeratosis Congenita (DC), a rare genetic human disease that belongs to the group of Telomere Biology Disorders (TBDs). The study was supported by colleagues from the DZNE (Bonn, Germany), CNIO (Madrid, Spain) and NCI (Bethesda, USA).
TEN1 is part of the telomeric CST complex (CTC1, STN1 and TEN1) and plays a pivotal role in telomere maintenance and DNA replication. After generating Ten1 homozygous knockout mice, the team of researchers could show that telomeres were shortened, the number of telomeric foci was decreased and the life span of the animals was reduced compared to wildtype controls. It was also evident that proliferating cells were reduced, apoptosis was increased, and stem cells were depleted in the model, accompanied by an activation of the p53/p21 signaling pathway.
This study shows for the first time the impact of functional TEN1 on telomere stability and integrity. As Ten1 deficiency leads to accelerated aging, the new insights can pave the way to understanding molecular aspects of aging mechanisms by perturbance of telomeric protection pathways. In addition, the unique model can facilitate the development of therapeutic interventions for TBDs as well as related pathologies.
Sanz-Moreno, Becker, Xie et al., 2025: Loss of Ten1 in mice induces telomere shortening and models human dyskeratosis congenita. Science Advances. DOI: 10.1126/sciadv.adp8093