Rapamycin increases rDNA stability by enhancing association of Sir2 with rDNA in Saccharomyces cerevisiae
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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.
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Genetic regulation of mTOR signal transduction can slow the aging of many organisms.
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- Authors
- Ha, C. W., & Huh, W.-K.
- Affiliations
- Seoul National University (KR)
- Corresponding author
- Huh, Won-Ki
- ORCID
- Huh, Won-Ki
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-10-14
- Volume
- 39
- Issue
- 4
- Pages
- 1336-1350
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC3045593
- OpenAlex
- W2130780975
- Cited by
- 77
- References
- 71
- Citations by year
- 2026: 3 · 2024: 4 · 2023: 6 · 2022: 5 · 2021: 2 · 2020: 5 · 2019: 2 · 2018: 6 · 2017: 4 · 2016: 10 · 2015: 5 · 2014: 7 · 2013: 4 · 2012: 11
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- rapamycin, TORC1 inhibition, Sir2, ribosomal DNA, aging, nitrogen starvation, transcriptional silencing, homologous recombination, histone deacetylation, Net1, Saccharomyces cerevisiae
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Acetylation, Cell Nucleolus, DNA, Ribosomal, Histones, Nicotinamidase, Nitrogen, Nuclear Proteins, Saccharomyces cerevisiae, Signal Transduction, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Sirolimus, Gene Silencing, Saccharomyces cerevisiae Proteins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Sirtuin 2
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