Telomeres and metabolism: part 1. Functional interplay between telomere maintenance and mtor pathways. Part 2. Rap1 role in chemically-induced hepatocellular carcinoma

• Autores: Iole Ferrara Romeo
• Directores de la Tesis: María Antonia Blasco Marhuenda (dir. tes.), Paula Martínez Rodríguez (codir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2019
• Idioma: español
• Tribunal Calificador de la Tesis: Rosario Perona Abellón (presid.), Pablo José Fernández Marcos (secret.), Purificación Muñoz Moruno (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Telomeres are specialized nucleoprotein structures at the end of linear chromosomes that protect them from degradation and repair activities. Dysfunctional telomeres activate a DNA damage response, which eventually results in cell growth arrest, senescence and/or apoptosis, leading to a reduction of the regenerative potential of the tissues. Telomeres shorten with each cell division throughout the organismal life and telomere shortening is defined as a primary cause of aging-associated diseases. The development of metabolic disorders, in turn, is also a phenotype of advancing age. Although some works have reported about the link between telomeres and metabolism, it still remains a fairly unexplored field to date.

    Telomeres are elongated by the telomerase, a specialized enzyme whose expression is very restricted in adulthood. Telomerase deficiency in mice and humans leads to short telomeres, premature appearance of age-related diseases, and a shorter lifespan. Inhibition of the nutrient sensing pathway regulated by the mechanistic target of rapamycin (mTOR) increases lifespan in numerous species from yeast to mice and is considered a major target to delay aging and age-related pathologies. In light of the beneficial effects of the mTOR pathway inhibition in extending longevity, we have addressed whether rapamycin treatment could ameliorate the premature aging phenotypes and the decreased longevity of telomerase-deficient mice with short telomeres. This is of potential relevance as mTOR inhibitors could represent new potential treatments for human patients suffering from “telomere syndromes”. To address the role of mTOR in the survival of telomerase-deficient mice with short telomeres (second generation, G2, Terc-/- mice), we treated them with rapamycin, an inhibitor of mTOR. We found that chronic rapamycin treatment decreased the survival of G2 Terc-/- mice, in marked contrast to significant lifespan extension in the case of similarly treated wild-type controls. Telomerase-deficient mice with short telomeres have a hyper-activated mTOR pathway. By using mouse genetics, we further confirm that abrogation of the mTOR downstream target S6 kinase 1 in S6K1-/-/Terc-/- double mutant mice also decreases mouse longevity compared to single Terc-/- controls, in contrast to lifespan extension in the case of single S6K1-/- female mice. Together, these findings demonstrate that the mTOR pathway is an essential survival pathway in the context of telomerase deficiency and the presence of short telomeres, and its inhibition in this setting is deleterious.

    The protein component of the telomere is a six-protein complex named shelterin. RAP1 is a component of shelterin known to have both telomeric and non-telomeric functions and is involved in the regulation of metabolic programs. RAP1-deficient mice develop obesity and hepatic steatosis, being these phenotypes more severe in females than in males. As hepatic steatosis and obesity have been related to increased liver cancer in mice and humans, we set out to address whether RAP1 deficiency results in increased liver cancer upon chemical liver carcinogenesis. We found that Rap1-/- females were more susceptible to DEN-induced liver damage and hepatocellular carcinoma (HCC). DEN-treated Rap1-/- female livers showed an earlier onset of both premalignant and malignant lesions that metastasize more rapidly to the lungs. These findings highlight an important role for RAP1 in protection from liver damage and liver cancer.