Sánchez-Vázquez, RaúlBurgaz García-Oteyza, SoniaSerrano, RosaFlores Landeira, Juana MaríaMartínez, PaulaBlasco, Maria A.2025-12-182025-12-182025Sánchez-Vázquez, R., Burgaz García-Oteyza, S., Serrano, R., Flores, J. M., Martínez, P., & Blasco, M. A. (2025). Mice carrying the homologous human shelterin POT1-L259S mutation linked to pulmonary fibrosis show a telomerase deficiency-like phenotype with telomere shortening with increasing mouse generations. Genes & development, 39(23-24), 1490–1508. https://doi.org/10.1101/gad.352855.1250890-936910.1101/gad.352855.125https://hdl.handle.net/20.500.14352/129353Author contributions: M.A.B. had the original idea and secured funding. M.A.B. and P.M. supervised the research and wrote the manuscript. R.S.-V., S.B.G.-O., and P.M. performed the experiments. R.S.-V. performed most of the experiments. R.S. was responsible for animal mainte nance and assisted with animal experimentationPulmonary fibrosis is a lethal disease associated with damaging insults to the lung and with organismal aging. The presence of short and dysfunctional telomeres has been placed at the origin of this disease in a percentage of both familial and sporadic cases. Recently, a mutation in the telomere-binding protein protection of telomeres 1 in humans (hPOT1), the hPOT1-L259S mutation, was found in families with idiopathic pulmonary fibrosis. Here, we generated a Pot1a L261S knock-in mouse harboring the murine homologous hPOT1-L259S mutation. We found that the homozygous Pot1a L261S mice show shorter telomeres and degenerative pathologies in the intestine, testes, and lungs at old ages, a phenotype that is aggravated with increasing mouse generations, in striking analogy to the telomerase-deficient mouse models. Furthermore, we found that the POT1a-L261S mutant protein binds more strongly to TPP1 and to telomerase and impedes telomerase-dependent telomere lengthening in vivo. We show that telomerase activity at telomeres is reduced in the presence of POT1a-L261S, which behaves as a dominant negative mutant, thus providing a potential mechanism by which Pot1a L261S knock-in mice phenocopy the short telomere phenotype of the telomerase knockout modelengAttribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/journal article1549-5477https://doi.org/10.1101/gad.352855.12540954016open access636.09AgingPulmonary fibrosisShelterinTelomeresVeterinaria3109 Ciencias Veterinarias