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 ; This work was supported by grants from Ministerio de Economía y Competitividad (BFU2011-28958 to A. Aranda and SAF2009-11150 to A. Pascual), from the Instituto de Salud Carlos III (RD012/0036/0030 to A. Aranda; and PI 07/0167 and PI 10/0703 to R. Garesse), from the Comunidad de Madrid (S2011/BMD-2328 TIRONET to A. Aranda), and European Union grant project CRESCENDO (FP6-018652 to A. Aranda and L.M. Sachs).
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