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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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“Plusieurs auteurs ont montré que Sir2 ou ses équivalents sont requis pour l’accroissement de la longévité de la drosophile et de C. elegans par la restriction calorique, ce qui a permis d’établir un lien supplémentaire entre la longévité et le métabolisme énergétique qui a un impact direct sur le rapport NAD/NADH [29].”
BackgroundComment on " HST2 Mediates SIR2 -Independent Life-Span Extension by Calorie Restriction"
Kaeberlein, M. R., Steffen, K. K., Hu, D., Dang, N., Kerr, E. O., Tsuchiya, M., Fields, S., & Kennedy, B. K. (2006) · Science · doi:10.1126/science.1124608 · Cited by 70
Self-citationGenomic Copy-Number Loss Is Rescued by Self-Limiting Production of DNA Circles
Mansisidor, A., Molinar, T., Srivastava, P., Dartis, D. D., Delgado, A. P., Blitzblau, H. G., Klein, H. L., & Hochwagen, A. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.08.036 · Cited by 69
The SAGA Histone Deubiquitinase Module Controls Yeast Replicative Lifespan via Sir2 Interaction
McCormick, M. A., Mason, A. G., Guyenet, S. J., Dang, W., Garza, R. M., Ting, M. K., Moller, R. M., Berger, S. L., Kaeberlein, M. R., Pillus, L., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.06.037 · Cited by 71
“Therefore, we turned to regions of the genome where Sir2 function is associated with longevity: rDNA and telomeres (Dang et al., 2009; Kaeberlein et al., 1999).”
BackgroundInfluentialSelf-citationDelaney, J. R., Ahmed, U., Chou, A., Sim, S., Carr, D. T., Murakami, C. J., Schleit, J., Sutphin, G. L., An, E. H., Castanza, A. S., et al. (2012) · Aging Cell · doi:10.1111/acel.12032 · Cited by 69
“The SIR2OX strain is a tandem two-copy SIR2 strain with a URA3 marker generated by integration of a second copy of SIR2 in BY4742 as previously described (Kaeberlein et al., 1999).”
MethodSelf-citationKato, M., & Lin, S.-J. (2014) · DNA repair · doi:10.1016/j.dnarep.2014.07.009 · Cited by 71
“Overexpression (one-extra copy) of Sir2 has been shown to extend yeast replicative life span (54).”
BackgroundPérez‐Pinzón, M. A., & Koronowski, K. B. (2015) · Brain Circulation · doi:10.4103/2394-8108.162532 · Cited by 71
“[4] Initially, this was thought to occur through interaction with its associated Sir2 and Sir3 proteins, but it was not until a few years later that this phenomenon was attributed fully to Sir2.”
Wine Resveratrol: From the Ground Up
Bavaresco, L., Lucini, L., Busconi, M., Flamini, R., & Rosso, M. D. (2016) · Nutrients · doi:10.3390/nu8040222 · Cited by 75
“In addition, they have been shown to mediate the effect of calorie restriction, which results in life span extension in yeast [34], worms [35] and flies [36].”
BackgroundWyman, A. E., Noor, Z., Fishelevich, R., Lockatell, V., Shah, N. G., Todd, N. W., & Atamas, S. P. (2017) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00473.2016 · Cited by 70
“Sirtuins, best known for their role in aging, have been shown to prolong mean and maximal life span in many species across all taxonomic groups (yeast, worms, flies, mice, primates) in response to caloric restriction or activation with molecules, such as resveratrol (5, 6, 12, 22, 27, 33, 49, 63).”
BackgroundCakouros, D., & Gronthos, S. (2018) · Aging and Disease · doi:10.14336/ad.2017.1213 · Cited by 71
“Sirtuins are class III NAD+ dependent histone deacetylases [22] [35, 36].”
BackgroundAutophagy and ageing: Insights from invertebrate model organisms
Lionaki, E., Markaki, M., & Tavernarakis, N. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2012.05.001 · Cited by 61
Aging of the Retina: Molecular and Metabolic Turbulences and Potential Interventions
Campello, L., Singh, N., Advani, J., Mondal, A. K., Corso‐Díaz, X., & Swaroop, A. (2021) · Annual Review of Vision Science · doi:10.1146/annurev-vision-100419-114940 · Cited by 67
Sirtuins are crucial regulators of T cell metabolism and functions
Hamaidi, I., & Kim, S. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00739-7 · Cited by 70
Saka, K., Takahashi, A., Sasaki, M., & Kobayashi, T. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw110 · Cited by 66
“The lifespan of a sir2 mutant, in which the rDNA is quite unstable, is about half of that of wild-type yeast (12).”
BackgroundPlasmid Accumulation Reduces Life Span in Saccharomyces cerevisiae
Falcón, A. A., & Aris, J. P. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307025200 · Cited by 68
Protective Effect of Garlic on Cellular Senescence in UVB-Exposed HaCaT Human Keratinocytes
Kim, H. (2016) · Nutrients · doi:10.3390/nu8080464 · Cited by 67
“Sirtuins (silent mating type information regulation 2 homolog, SIRTs) are a family of NAD(+)-dependent enzymes and well-known modulators of lifespan in many species [10].”
BackgroundCosta‐Machado, L. F., & Fernández-Marcos, P. J. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1634953 · Cited by 66
“A major breakthrough in the history of the sirtuin family came with the discovery that SIR2, SIR3, and SIR4 could prevent genomic instability and, this way, increase lifespan [6,7].”
BackgroundThe mystery of aging and rejuvenation—a budding topic
Nyström, T., & Liu, B. (2014) · Current Opinion in Microbiology · doi:10.1016/j.mib.2014.02.003 · Cited by 71
“The rDNA repeats are transcriptionally silenced by Sir2 [6] and this protein deacetylase is counteracting yeast aging, in part, by limiting ERC accumulation [7].”
BackgroundMâncio-Silva, L., Lopez-Rubio, J.-J., Claës, A., & Scherf, A. (2013) · Nature Communications · doi:10.1038/ncomms2539 · Cited by 72
Structural Basis for Nicotinamide Inhibition and Base Exchange in Sir2 Enzymes
Sanders, B. D., Zhao, K., Slama, J. T., & Marmorstein, R. (2007) · Molecular Cell · doi:10.1016/j.molcel.2006.12.022 · Cited by 68
“Conversely, decreased Sir2 activity due to gene deletion or enzyme inhibition shortens yeast lifespan (Kaeberlein et al., 1999).”
BackgroundLo, T., Ho, J. H., Yang, M., & Lee, O. K. (2010) · Cell Transplantation · doi:10.3727/096368910x539100 · Cited by 67
Nutrient starvation promotes condensin loading to maintain rDNA stability
Tsang, C. K., Li, H., & Zheng, X. S. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601488 · Cited by 67
“Mutations in genes such as SIR2, TOP1/2 and RPA135 are known to cause formation of ERCs and/or shrinkage of rDNA array (Brewer et al, 1992; Kaeberlein et al, 1999).”
BackgroundThe Role of SIRT3 in the Brain Under Physiological and Pathological Conditions
Sidorova‐Darmos, E., Sommer, R., & Eubanks, J. H. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00196 · Cited by 66
Ravi, V., Jain, A., Khan, D., Ahamed, F., Mishra, S., Giri, M., Inbaraj, M., Krishna, S., Sarikhani, M., Maity, S., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz648 · Cited by 67
Mitochondrial health, the epigenome and healthspan
Aon, M. A., Cortassa, S., Juhaszova, M., & Sollott, S. J. (2016) · Clinical Science · doi:10.1042/cs20160002 · Cited by 66
Molecular Links between Caloric Restriction and Sir2/SIRT1 Activation
Wang, Y. (2014) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2014.38.5.321 · Cited by 68
“In yeast, integration of extra copies of Sir2 extends lifespan by up to 30% and deletion of this gene shortens life span by about 50% [21].”
BackgroundGenetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging
Sándor, S., & Kubinyi, E. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00948 · Cited by 68
“Most importantly, sirtuin genes were among the first shown to affect longevity in yeast (Kaeberlein et al., 1999), C. elegans (Tissenbaum and Guarente, 2001), Drosophila (Rogina and Helfand, 2004), and mice (Calvanese et al., 2009).”
Background
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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