RESUMO
Telomeres are nucleoprotein structures that cap the ends of the linear eukaryotic chromosomes, thus protecting their stability and integrity. They play important roles in DNA replication and repair and are central to our understanding of aging and cancer development. In rapidly dividing cells, telomere length is maintained by the activity of telomerase. About 400 TLM (telomere length maintenance) genes have been identified in yeast, as participants of an intricate homeostasis network that keeps telomere length constant. Two papers have recently shown that despite this extremely complex control, telomere length can be manipulated by external stimuli. These results have profound implications for our understanding of cellular homeostatic systems in general and of telomere length maintenance in particular. In addition, they point to the possibility of developing aging and cancer therapies based on telomere length manipulation.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Sirolimo/farmacologia , Estresse Fisiológico , Homeostase do Telômero/genética , Encurtamento do Telômero , Proteínas de Ligação a Telômeros/genética , Telômero/genética , Telômero/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , HumanosRESUMO
Telomeres protect the chromosome ends from degradation and play crucial roles in cellular aging and disease. Recent studies have additionally found a correlation between psychological stress, telomere length, and health outcome in humans. However, studies have not yet explored the causal relationship between stress and telomere length, or the molecular mechanisms underlying that relationship. Using yeast as a model organism, we show that stresses may have very different outcomes: alcohol and acetic acid elongate telomeres, whereas caffeine and high temperatures shorten telomeres. Additional treatments, such as oxidative stress, show no effect. By combining genome-wide expression measurements with a systematic genetic screen, we identify the Rap1/Rif1 pathway as the central mediator of the telomeric response to environmental signals. These results demonstrate that telomere length can be manipulated, and that a carefully regulated homeostasis may become markedly deregulated in opposing directions in response to different environmental cues.
Assuntos
Proteínas de Saccharomyces cerevisiae/genética , Estresse Fisiológico , Homeostase do Telômero/genética , Proteínas de Ligação a Telômeros/genética , Telômero/genética , Fatores de Transcrição/genética , Ácido Acético/farmacologia , Álcoois/farmacologia , Cromossomos Fúngicos/efeitos dos fármacos , Cromossomos Fúngicos/metabolismo , Interação Gene-Ambiente , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/fisiologia , Complexo Shelterina , Telômero/efeitos dos fármacos , Homeostase do Telômero/efeitos dos fármacos , Proteínas de Ligação a Telômeros/metabolismoRESUMO
Most of the phenotypes in nature are complex and are determined by many quantitative trait loci (QTLs). In this study we identify gene sets that contribute to one important complex trait: the ability of yeast cells to survive under alkali stress. We carried out an in-lab evolution (ILE) experiment, in which we grew yeast populations under increasing alkali stress to enrich for beneficial mutations. The populations acquired different sets of affecting alleles, showing that evolution can provide alternative solutions to the same challenge. We measured the contribution of each allele to the phenotype. The sum of the effects of the QTLs was larger than the difference between the ancestor phenotype and the evolved strains, suggesting epistatic interactions between the QTLs. In parallel, a clinical isolated strain was used to map natural QTLs affecting growth at high pH. In all, 17 candidate regions were found. Using a predictive algorithm based on the distances in protein-interaction networks, candidate genes were defined and validated by gene disruption. Many of the QTLs found by both methods are not directly implied in pH homeostasis but have more general, and often regulatory, roles.
