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The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms
Open accessAbstract
The SIR genes are determinants of life span in yeast mother cells. Here we show that life span regulation by the Sir proteins is independent of their role in nonhomologous end joining. The short life span of a sir3 or sir4 mutant is due to the simultaneous expression of a and alpha mating-type information, which indirectly causes an increase in rDNA recombination and likely increases the production of extrachromosomal rDNA circles. The short life span of a sir2 mutant also reveals a direct failure to repress recombination generated by the Fob1p-mediated replication block in the rDNA. Sir2p is a limiting component in promoting yeast longevity, and increasing the gene dosage extends the life span in wild-type cells. A possible role of the conserved SIR2 in mammalian aging is discussed.
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“Loss of Sir2 increases rDNA recombination and shortens life span; whereas an extra genomic copy of Sir2, which increases rDNA stability, extends life span (Kaeberlein et al., 1999”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Kaeberlein et al., 1999
In the citing paper
“Loss of Sir2 increases rDNA recombination and shortens life span; whereas an extra genomic copy of Sir2, which increases rDNA stability, extends life span (Kaeberlein et al., 1999”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Kaeberlein et al., 1999
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“Furthermore, increasing the level of Sir2 in yeast increases lifespan (Kaeberlein et al., 1999).”
From The Aging Epigenome (2016) · cites this paper as Kaeberlein et al., 1999
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“In Saccharomyces cervisae , the Sir2 gene was found to prolong the replicative lifespan of yeast mother cells before undergoing senescence”
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InfluentialSIRT1 Inhibition Alleviates Gene Silencing in Fragile X Mental Retardation Syndrome
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“The histone deacetylase SIR2 was found to extend yeast life span when overexpressed, as was found in worms and flies (150, 151).”
BackgroundÅström, S. U., Cline, T. W., & Rine, J. (2003) · Genetics · doi:10.1093/genetics/163.3.931 · Cited by 83
Vergnes, B., Séréno, D., Madjidian-Sereno, N., Lemesre, J.-L., & Ouaissi, A. (2002) · Gene · doi:10.1016/s0378-1119(02)00842-9 · Cited by 83
On Acetyl-CoA as a Gauge of Cellular Metabolic StatePreprint
Cai, L., & Tu, B. P. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2011.76.010769 · Cited by 89
Cellular Senescence and Vascular Disease: Novel Routes to Better Understanding and Therapy
Yin, H., & Pickering, J. G. (2016) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2016.02.051 · Cited by 82
Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators
Klein, M. A., & Denu, J. M. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.rev120.011438 · Cited by 87
Rogina, B., & Tissenbaum, H. A. (2024) · Frontiers in Genetics · doi:10.3389/fgene.2024.1393181 · Cited by 93
Guan, X., Lin, P. C., Knoll, E., & Chakrabarti, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0107729 · Cited by 87
“Sirtuins, the highly conserved orthologs of the yeast Sir2 enzyme found in a wide range of organisms ranging from bacteria to man, have been implicated in aging and the regulation of metabolism and genome stability [2,3].”
BackgroundSIRT1 Contains N- and C-terminal Regions That Potentiate Deacetylase Activity
Pan, M., Yuan, H., Brent, M. M., Ding, E. C., & Marmorstein, R. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.285031 · Cited by 83
“The founding member of this protein family, Saccharomyces cerevisiae Sir2p, one of five yeast sirtuin proteins including HST1–4, is a limiting factor in yeast aging, because deletion of the SIR2 gene results in reduced replicative lifespan (5), and additional copies of SIR2 result in increased yeast replicative lifesp…”
BackgroundZhou, X., Xu, J., Ni, Y.-H., Chen, X., Zhang, H., Zhang, X., Liu, W.-J., Luo, L., & Fu, Y. (2014) · Journal of Ovarian Research · doi:10.1186/s13048-014-0097-z · Cited by 82
“Accumulated evidence has revealed that SIRT1 is crucial for caloric restriction-induced longevity [41-43], and SIRT1 genetic variation is related to obesity”
BackgroundParadigms and pitfalls of yeast longevity research
Sinclair, D. A. (2002) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(02)00023-4 · Cited by 82
Kiran, S., Oddi, V., & Ramakrishna, G. (2014) · Experimental Cell Research · doi:10.1016/j.yexcr.2014.11.001 · Cited by 85
Mitochondrial Sirtuins in Cancer: Emerging Roles and Therapeutic Potential
George, J., & Ahmad, N. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-2733 · Cited by 81
Nahhas, F. A., Dryden, S. C., Abrams, J., & Tainsky, M. A. (2007) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-007-9478-6 · Cited by 81
“Yeast strains that over-express Sir2 have an extended life span whereas null mutants show a decreased life span through a mechanism involving the suppression of recombination between rDNA repeats [7, 8].”
BackgroundRoles of NAD / NADH and NADP+ / NADPH in Cell Death
Xia, W., Wang, Z., Wang, Q., Han, J., Zhao, C., Hong, Y., Zeng, L., Tang, L., & Ying, W. (2009) · Current Pharmaceutical Design · doi:10.2174/138161209787185832 · Cited by 82
Desouki, M. M., Doubinskaia, I., Gius, D. R., & Abdulkadir, S. A. (2014) · Human Pathology · doi:10.1016/j.humpath.2014.01.004 · Cited by 80
“Sirtuins are Nicotinamide adenine dinucleotide (NAD+) dependent class III histone deacetylases are present from bacteria to humans (4).”
BackgroundFission Yeast and Other Yeasts as Emergent Models to Unravel Cellular Aging in Eukaryotes
Roux, A. E., Chartrand, P., Ferbeyre, G., & Rokeach, L. A. (2009) · The Journals of Gerontology Series A · doi:10.1093/gerona/glp152 · Cited by 84
Nicotinamide adenine dinucleotide: beyond a redox coenzyme
Lin, H. (2007) · Organic & Biomolecular Chemistry · doi:10.1039/b706887e · Cited by 82
Neurodegenerative diseases: Lessons from genome‐wide screens in small model organisms
van Ham, T. J., Breitling, R., Swertz, M. A., & Nollen, E. A. A. (2009) · EMBO Molecular Medicine · doi:10.1002/emmm.200900051 · Cited by 82
Spontaneous rDNA copy number variation modulates Sir2 levels and epigenetic gene silencingPreprint
Michel, A. H., Kornmann, B., Dubrana, K., & Shore, D. (2005) · Genes & Development · doi:10.1101/gad.340205 · Cited by 84
“2000), and longer life span (Fig. 5; Kaeberlein et al. 1999).”
BackgroundMethodResultInfluentialThe emerging role of epigenetics in cellular and organismal aging
Bandyopadhyay, D., & Medrano, E. E. (2003) · Experimental Gerontology · doi:10.1016/j.exger.2003.09.009 · Cited by 104
Resveratrol Boosts Cognitive Function by Targeting SIRT1
Cao, W., Dou, Y., & Li, A. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2586-8 · Cited by 80
Duszka, K., Gregor, A., Guillou, H., König, J. S., & Wahli, W. (2020) · Cells · doi:10.3390/cells9071708 · Cited by 86
DAF-16/Forkhead Box O Transcription Factor: Many Paths to a Single Fork(head) in the Road
Yen, K., Narasimhan, S. D., & Tissenbaum, H. A. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3490 · Cited by 82
Acetate metabolism and aging: An emerging connection
Shimazu, T., Hirschey, M. D., Huang, J.-Y., Ho, L., & Verdin, E. M. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.05.001 · Cited by 80
“For instance, expressing one extra copy of Sir2 increases yeast replicative life span, whereas deleting Sir2 shortens replicative life span (Kaeberlein et al., 1999).”
The functional significance of nuclear receptor acetylation
Popov, V. M., Wang, C., Shirley, L. A., Rosenberg, A., Lisanti, M. P., Nevalainen, M. T., Fu, M., & Pestell, R. G. (2007) · Steroids · doi:10.1016/j.steroids.2006.12.001 · Cited by 80
“In Saccharomyces cerevisiae, SIR2 extends the replicative lifespan [8].”
BackgroundCaballero, A., Ugidos, A., Liu, B., Öling, D., Kvint, K., Hao, X., Mignat, C. A., Nachin, L., Molin, M., & Nyström, T. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.03.021 · Cited by 78
“SOV1 Deficiency Increases Sir2p-Dependent Silencing at rDNA- and HM Mating-Type Loci Increasing nuclear silencing or reducing translation are two means of extending yeast life span (Kaeberlein et al., 1999; Steffen et al., 2008), the latter of which is linked to an increased expression of the nutrient-responsive trans…”
BackgroundMethod
Metadata
- Authors
- Kaeberlein, M., McVey, M., & Guarente, L.
- Affiliations
- Massachusetts Institute of Technology (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1999-10-01
- Volume
- 13
- Issue
- 19
- Pages
- 2570-2580
- ISSN
- 0890-9369 (ISSN-L)
- PMC
- PMC317077
- OpenAlex
- W2157649587
- Cited by
- 2,253
- References
- 52
- Citations by year
- 2026: 27 · 2025: 64 · 2024: 50 · 2023: 80 · 2022: 76 · 2021: 91 · 2020: 93 · 2019: 101 · 2018: 126 · 2017: 73 · 2016: 123 · 2015: 104 · 2014: 111 · 2013: 127 · 2012: 123
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM07287, T32GM007287)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- Sir2p, Sir3p, longevity, lifespan regulation, Saccharomyces cerevisiae, non-homologous end joining, replication block, gene dosage, aging
- MeSH terms
- Mating Factor, DNA-Binding Proteins, DNA, Fungal, DNA, Ribosomal, Fungal Proteins, Histone Deacetylases, Peptides, Phenotype, Saccharomyces cerevisiae, Trans-Activators, Mutagenesis, Saccharomyces cerevisiae Proteins, Sirtuins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Sirtuin 2
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