title: The thyroid hormone receptor β induces DNA damage and premature senescence.
abstract: There is increasing evidence that the thyroid hormone (TH) receptors (THRs) can play a role in aging, cancer and degenerative diseases. In this paper, we demonstrate that binding of TH T3 (triiodothyronine) to THRB induces senescence and deoxyribonucleic acid (DNA) damage in cultured cells and in tissues of young hyperthyroid mice. T3 induces a rapid activation of ATM (ataxia telangiectasia mutated)/PRKAA (adenosine monophosphate-activated protein kinase) signal transduction and recruitment of the NRF1 (nuclear respiratory factor 1) and THRB to the promoters of genes with a key role on mitochondrial respiration. Increased respiration leads to production of mitochondrial reactive oxygen species, which in turn causes oxidative stress and DNA double-strand breaks and triggers a DNA damage response that ultimately leads to premature senescence of susceptible cells. Our findings provide a mechanism for integrating metabolic effects of THs with the tumor suppressor activity of THRB, the effect of thyroidal status on longevity, and the occurrence of tissue damage in hyperthyroidism.
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Zambrano
authors.forename: Verónica
authors.initials: V
authors.lastname: García-Carpizo
authors.forename: María Esther
authors.initials: ME
authors.lastname: Gallardo
authors.forename: Raquel
authors.initials: R
authors.lastname: Villamuera
authors.forename: Maria Ana
authors.initials: MA
authors.lastname: Gómez-Ferrería
authors.forename: Angel
authors.initials: A
authors.lastname: Pascual
authors.forename: Nicolas
authors.initials: N
authors.lastname: Buisine
authors.forename: Laurent M
authors.initials: LM
authors.lastname: Sachs
authors.forename: Rafael
authors.initials: R
authors.lastname: Garesse
authors.forename: Ana
authors.initials: A
authors.lastname: Aranda
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism*; D014284:Triiodothyronine / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D037042:Thyroid Hormone Receptors beta; D016159:Tumor Suppressor Protein p53; D014284:Triiodothyronine; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D055372:AMP-Activated Protein Kinases