Regulação da amplificação do DNA ribossomal pela via TOR

quarta-feira, julho 22, 2015

Regulation of ribosomal DNA amplification by the TOR pathway

Carmen V. Jack a,1, Cristina Cruz a,1, Ryan M. Hull a, Markus A. Keller b, Markus Ralser b,c, and Jonathan Houseley a,2

a Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom;

b Cambridge Systems Biology Centre and Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, United Kingdom;

c Division of Physiology and Metabolism, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom

Edited by Jasper Rine, University of California, Berkeley, CA, and approved June 26, 2015 (received for review March 27, 2015)


We tend to think of our genome as an unchanging store of information; however, recent evidence suggests that genomes vary between different cells in the same organism. How these differences arise and what effects they have remain unknown, but clearly our genome can change. In a single-celled organism, genome changes occur at random, and advantageous changes slowly propagate by natural selection. However, it is known that the DNA encoding ribosomes can change simultaneously in a whole population. Here we show that signaling pathways that sense environmental nutrients control genome change at the ribosomal DNA. This demonstrates that not all genome changes occur at random and that cells possess specific mechanisms to optimize their genome in response to the environment.


Repeated regions are widespread in eukaryotic genomes, and key functional elements such as the ribosomal DNA tend to be formed of high copy repeated sequences organized in tandem arrays. In general, high copy repeats are remarkably stable, but a number of organisms display rapid ribosomal DNA amplification at specific times or under specific conditions. Here we demonstrate that target of rapamycin (TOR) signaling stimulates ribosomal DNA amplification in budding yeast, linking external nutrient availability to ribosomal DNA copy number. We show that ribosomal DNA amplification is regulated by three histone deacetylases: Sir2, Hst3, and Hst4. These enzymes control homologous recombination-dependent and nonhomologous recombination-dependent amplification pathways that act in concert to mediate rapid, directional ribosomal DNA copy number change. Amplification is completely repressed by rapamycin, an inhibitor of the nutrient-responsive TOR pathway; this effect is separable from growth rate and is mediated directly through Sir2, Hst3, and Hst4. Caloric restriction is known to up-regulate expression of nicotinamidase Pnc1, an enzyme that enhances Sir2, Hst3, and Hst4 activity. In contrast, normal glucose concentrations stretch the ribosome synthesis capacity of cells with low ribosomal DNA copy number, and we find that these cells show a previously unrecognized transcriptional response to caloric excess by reducing PNC1 expression. PNC1 down-regulation forms a key element in the control of ribosomal DNA amplification as overexpression of PNC1 substantially reduces ribosomal DNA amplification rate. Our results reveal how a signaling pathway can orchestrate specific genome changes and demonstrate that the copy number of repetitive DNA can be altered to suit environmental conditions.

ribosomal DNA homologous recombination Sir2 copy number variation TOR