Rapamycin increases rDNA stability by enhancing association of Sir2 with rDNA in Saccharomyces cerevisiae.
The target of rapamycin (TOR) kinase is an evolutionarily conserved key regulator of eukaryotic cell growth and proliferation. Recently, it has been reported that inhibition of TOR signaling pathway can delay aging and extend lifespan in several eukaryotic organisms, but how lifespan extension is mediated by inhibition of TOR signaling is poorly understood. Here we report that rapamycin treatment and nitrogen starvation, both of which cause inactivation of TOR complex 1 (TORC1), lead to enhanced association of Sir2 with ribosomal DNA (rDNA) in Saccharomyces cerevisiae. TORC1 inhibition increases transcriptional silencing of RNA polymerase II-transcribed gene integrated at the rDNA locus and reduces homologous recombination between rDNA repeats that causes formation of toxic extrachromosomal rDNA circles. In addition, TORC1 inhibition induces deacetylation of histones at rDNA. We also found that Pnc1 and Net1 are required for enhancement of association of Sir2 with rDNA under TORC1 inhibition. Taken together, our findings suggest that inhibition of TORC1 signaling stabilizes the rDNA locus by enhancing association of Sir2 with rDNA, thereby leading to extension of replicative lifespan in S. cerevisiae.
Ha
Cheol Woong
CW
School of Biological Sciences, Research Center for Functional Cellulomics, Institute of Microbiology, Seoul National University, Seoul 151-747, Republic of Korea.
Huh
Won-Ki
WK
D000107:Acetylation; D018797:Cell Cycle Proteins / Q000502:physiology; D002466:Cell Nucleolus / Q000187:drug effects / Q000648:ultrastructure; D004275:DNA, Ribosomal / Q000378:metabolism*; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism; D009535:Nicotinamidase / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism; D009687:Nuclear Proteins / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D056565:Sirtuin 2 / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004275:DNA, Ribosomal; D006657:Histones; D009535:Nicotinamidase; D009584:Nitrogen; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; D020123:Sirolimus; D056565:Sirtuin 2; C119300:Net1 protein, S cerevisiae; C083324:TOR1 protein, S cerevisiae; C087778:SIR2 protein, S cerevisiae; C474330:PNC1 protein, S cerevisiae