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1.
Nature ; 552(7684): 263-267, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-29186112

RESUMO

Three distinct RNA polymerases transcribe different classes of genes in the eukaryotic nucleus. RNA polymerase (Pol) III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including tRNAs and 5S rRNA. The historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. Target of rapamycin kinase complex 1 (TORC1) regulates Pol III activity, and is also an important determinant of longevity. This raises the possibility that Pol III is involved in ageing. Here we show that Pol III limits lifespan downstream of TORC1. We find that a reduction in Pol III extends chronological lifespan in yeast and organismal lifespan in worms and flies. Inhibiting the activity of Pol III in the gut of adult worms or flies is sufficient to extend lifespan; in flies, longevity can be achieved by Pol III inhibition specifically in intestinal stem cells. The longevity phenotype is associated with amelioration of age-related gut pathology and functional decline, dampened protein synthesis and increased tolerance of proteostatic stress. Pol III acts on lifespan downstream of TORC1, and limiting Pol III activity in the adult gut achieves the full longevity benefit of systemic TORC1 inhibition. Hence, Pol III is a pivotal mediator of this key nutrient-signalling network for longevity; the growth-promoting anabolic activity of Pol III mediates the acceleration of ageing by TORC1. The evolutionary conservation of Pol III affirms its potential as a therapeutic target.


Assuntos
Longevidade/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , RNA Polimerase III/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/enzimologia , Caenorhabditis elegans/fisiologia , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/enzimologia , Drosophila melanogaster/fisiologia , Evolução Molecular , Feminino , Alimentos , Intestinos/citologia , Intestinos/enzimologia , Longevidade/efeitos dos fármacos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Biossíntese de Proteínas , RNA Polimerase III/antagonistas & inibidores , RNA Polimerase III/deficiência , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/fisiologia , Células-Tronco/citologia , Células-Tronco/enzimologia
2.
Life Sci ; 62(4): 275-82, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9450498

RESUMO

RNA polymerases transcribe nuclear genes for ribosomal RNA thus representing ribosomal biogenesis. RNA polymerase I transcribes class I genes, coding for large ribosomal RNA and is located in the nucleolus. RNA polymerase III transcribes class III genes, those that encode a number of small ribosomal RNA molecules. Both RNA polymerases form ribosomal biogenesis in a concerted action and have a common subunit, RPA40, essential for function and integrity. The aim of our study was to study the influence of hypoxia/asphyxia on transcription of this subunit as deterioration of ribosomal biogenesis may not be compatible with life. To test this hypothesis we used a nonsophisticated model of neonatal asphyxia. Rat pups were exposed to various asphyctic periods up to twenty minutes and heart tissue was taken for the evaluation of mRNA RPA40 levels, pH measurements and histological evaluation of the nucleolus by silver staining. mRNA RPA40 levels gradually decreased with the length of the asphyctic period paralleling the decrease of pH. Silver staining was remarkably decreased at the asphyctic period of 20 minutes. Our findings of decreased transcription of this essential RNA polymerase subunit indicate impairment of the ribosomal RNA synthetizing machinery and the histological findings suggest its structural relevance. This is the first in vivo observation of deteriorated RNA polymerase in asphyxia/hypoxia.


Assuntos
Asfixia Neonatal/enzimologia , Miocárdio/enzimologia , RNA Polimerase III/deficiência , RNA Polimerase I/deficiência , RNA Mensageiro/metabolismo , Actinas/metabolismo , Animais , Asfixia Neonatal/genética , Feminino , Humanos , Concentração de Íons de Hidrogênio , Recém-Nascido , Miocárdio/patologia , Gravidez , RNA Polimerase I/genética , RNA Polimerase III/genética , Ratos , Ratos Sprague-Dawley , Transcrição Gênica
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