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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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Earls, L. R., Westmoreland, J. J., & Zakharenko, S. S. (2014) · Ageing Research Reviews · doi:10.1016/j.arr.2014.03.004 · Cited by 60
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“In the field of CR and aging research many investigators were searching for life prolonging genes and were fortunate to first identify in yeast a silence information regulator 2 (Sir2) gene [65].”
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“The mechanisms underlying the difference in RLS between haploid and diploid cells in this background is not known; however, this effect appears to be dependent on genetic background, since diploids are slightly shorter lived than haploids in the W303 strain.(8) A variety of different methods have been used to measure…”
MethodSelf-citationhpr1Δ Affects Ribosomal DNA Recombination and Cell Life Span in Saccharomyces cerevisiae
Merker, R. J., & Klein, H. L. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.2.421-429.2002 · Cited by 62
“We examined ERCs in young cells because, thus far, any factor suggested to have a positive or negative effect on rDNA circle formation in aged cells also shows the same effect in young unsorted cells (9, 21, 24).”
BackgroundMicrobial ageing and longevity
Moger-Reischer, R. Z., & Lennon, J. T. (2019) · Nature Reviews Microbiology · doi:10.1038/s41579-019-0253-y · Cited by 59
Xue, Y., Fu, W., Yu, P., Li, Y., Yu, X., Xu, H., & Sui, D. (2023) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.2c06926 · Cited by 62
Interference Between DNA Replication and Transcription as a Cause of Genomic Instability
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SirT1 catalytic activity is required for male fertility and metabolic homeostasis in mice
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“sial and perhaps strain specific (5, 6), sir2 is also an”
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“Finally, the Sir2-like proteins, which affect gene expression, are being studied in organisms such as yeas”
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Rho, J. M., & Sankar, R. (2008) · Epilepsia · doi:10.1111/j.1528-1167.2008.01857.x · Cited by 61
“It has been reported that increased Sir2 activity lengthens life span, and that calorie restriction increases Sir2 levels and does not promote longevity in Sir2 knockouts (Kaeberlein et al., 1999; Lin et al., 2000; Tissenbaum & Guarente, 2001; Lin et al., 2004; Rogina & Helfand, 2004).”
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Lillycrop, K. A., Hoile, S. P., Grenfell, L. R., & Burdge, G. C. (2014) · Proceedings of The Nutrition Society · doi:10.1017/s0029665114000081 · Cited by 64
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Self-citationThe role of the ribosome in the regulation of longevity and lifespan extension
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“Deletion of the yeast homologue of SIRT1 (sir2) results in hyper-recombination of rDNA and a reduction of the organismal lifespan by half.(39) The amplification of rDNA genes counteracts their recombination-mediated loss through activation of a bidirectional noncoding promoter found within rDNA spacer sequences (E-Pro…”
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“Sirtuins are NAD+ dependent protein deacetylases that slow aging in lower organisms (Kaeberlein et al., 1999).”
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“…span extension and interacts with Sir2, a protein involved in silencing of Pol II transcription at the rDNA locus (Bryk et al , 1997; Smith and Boeke, 1997), rDNA recombination (Gottlieb and Esposito, 1989; Kobayashi et al , 2004) and ageing (Sinclair and Guarente, 1997; Kaeberlein et al , 1999).”
Fusion, fission, and transport control asymmetric inheritance of mitochondria and protein aggregates
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“A Δsir2 mutant, lacking a NAD+-dependent histone deacetylase of the sirtuin family, was included in this analysis as a control, because this strain is known to have a shortened replicative lifespan (Kaeberlein et al., 1999).”
Sirtuins and Immuno-Metabolism of Sepsis
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“In yeast, this lifespan extension is achieved by promoting genomic stability [4], regulating gene expression [5, 6] and suppressing the formation of extra-ribosomal circles [1, 7].”
BackgroundAfter the grape rush: Sirtuins as epigenetic drug targets in neurodegenerative disorders
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BackgroundInfluentialRegulation of vitamin metabolism by p53 and p63 in development and cancer
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BackgroundSir2 deletion prevents lifespan extension in 32 long‐lived mutants
Delaney, J. R., Sutphin, G. L., Dulken, B. W., Sim, S., Kim, J. R., Robison, B., Schleit, J., Murakami, C. J., Carr, D. T., An, E. H., et al. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2011.00742.x · Cited by 63
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“…(Sinclair and Guarente, 1997), and factors that influence ERC formation significantly alter RLS. Sir2 inhibits ERC production and RLS is accordingly decreased in sir2 cells (Kaeberlein et al., 1999), whereas fob1 cells have increased RLSs because Fob1 promotes ERC formation (Defossez et al., 1999).”
Delaney, J. R., Murakami, C., Chou, A., Carr, D. T., Schleit, J., Sutphin, G. L., An, E. H., Castanza, A. S., Fletcher, M., Goswami, S., et al. (2012) · Experimental Gerontology · doi:10.1016/j.exger.2012.12.001 · Cited by 60
“This instability can be suppressed by overexpression of the histone deacetylase Sir2 or deletion of the replication fork block protein Fob1, which both extend RLS (Defossez et al., 1999; Kaeberlein et al., 1999).”
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Yeast as a model to study mitochondrial mechanisms in ageing
de Barros, M. H., da Cunha, F. M., de Oliveira, G. A., Tahara, E. B., & Kowaltowski, A. J. (2010) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2010.04.008 · Cited by 58
The Roles of Mitochondrial Dysfunction and Reactive Oxygen Species in Aging and Senescence
Zia, A., Farkhondeh, T., Pourbagher‐Shahri, A. M., & Samarghandian, S. (2021) · Current Molecular Medicine · doi:10.2174/1566524021666210218112616 · Cited by 70
Damage segregation at fissioning may increase growth rates: A superprocess model
Evans, S. N., & Steinsaltz, D. (2007) · Theoretical Population Biology · doi:10.1016/j.tpb.2007.02.004 · Cited by 57
“[KMG99].”
SIRT1 is required for the effects of rapamycin on high glucose-inducing mesangial cells senescence
Zhang, S., Cai, G., Fu, B., Feng, Z., Ding, R., Bai, X., Liu, W., Zhuo, L., Sun, L., Liu, F., et al. (2012) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2012.04.005 · Cited by 57
“The Sir2 was shown to extend the life span of budding yeast by repressing genome instability (Sinclair and Guarente, 1997; Kaeberlein et al., 1999).”
BackgroundHistone deacetylases and their role in motor neuron degeneration
Lazo-Gómez, R., Ramírez-Jarquín, U. N., Tovar‐y‐Romo, L. B., & Tapia, R. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00243 · Cited by 58
“When overexpressed, the product of this gene extended the lifespan of budding yeast by repressing genomic instability (Kaeberlein et al., 1999).”
BackgroundSynthesizing and Salvaging NAD+: Lessons Learned from Chlamydomonas reinhardtii
Lin, H., Kwan, A. L., & Dutcher, S. K. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1001105 · Cited by 57
“upregulation of Sir2 in yeast [41,74], flies [75], and mammals”
BackgroundGanley, A. R. D., & Kobayashi, T. (2011) · Molecular Biology and Evolution · doi:10.1093/molbev/msr117 · Cited by 57
Epigenomics and the Regulation of Aging
Boyd-Kirkup, J. D., Green, C. D., Wu, G., Wang, D., & Han, J. J. (2013) · Epigenomics · doi:10.2217/epi.13.5 · Cited by 57
SIRT6 Overexpression Improves Various Aspects of Mouse Healthspan
Roichman, A., Kanfi, Y., Glazz, R., Naiman, S., Amit, U., Landa, N., Tinman, S., Stein, I., Pikarsky, E., Leor, J., et al. (2016) · The Journals of Gerontology Series A · doi:10.1093/gerona/glw152 · Cited by 56
“In yeast, an extra copy of the sirtuin homolog SIR2 gene extends its replicative lifespan, while SIR2 deletion shortens it (3).”
BackgroundDeprez, M.-A., Eskes, E., Winderickx, J., & Wilms, T. (2018) · FEMS Yeast Research · doi:10.1093/femsyr/foy048 · Cited by 62
HDACs and the senescent phenotype of WI-38 cells
Place, R. F., Noonan, E. J., & Giardina, C. A. (2005) · BMC Cell Biology · doi:10.1186/1471-2121-6-37 · Cited by 57
“In addition, the NAD+-dependent Sir2 histone deacetylase has been identified to contribute to the replicative life-span in yeast, thus suggesting that the mammalian Sir2-related class III HDACs may contribute to senescence in normal human cell types, as well [51,52].”
Ray, A., Hector, R. E., Roy, N., Song, J.-H., Berkner, K. L., & Runge, K. W. (2003) · Nature Genetics · doi:10.1038/ng1132 · Cited by 57
“These data were in marked contrast with the order-of-magnitude differences seen in long-lived yeast strains in which rDNA recombination is suppresse”
Aging and genetic instability in yeast
McMurray, M. A., & Gottschling, D. E. (2004) · Current Opinion in Microbiology · doi:10.1016/j.mib.2004.10.008 · Cited by 57
Linking SIRT2 to Parkinson’s Disease
Garske, A. L., Smith, B. C., & Denu, J. M. (2007) · ACS Chemical Biology · doi:10.1021/cb700160d · Cited by 59
Senescence and epigenetic dysregulation in cancer
Neumeister, P., Albanese, C., Balent, B., Greally, J., & Pestell, R. G. (2002) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(02)00079-1 · Cited by 56
Balancing DNA repair to prevent ageing and cancer
Stead, E. R., & Bjedov, I. (2021) · Experimental Cell Research · doi:10.1016/j.yexcr.2021.112679 · Cited by 62
Chromatin modifications: The driving force of senescence and aging?
DiMauro, T., & David, G. (2009) · Aging · doi:10.18632/aging.100023 · Cited by 58
“In yeast, worms and flies, extra copies of sirtuins extend replicative lifespan, and the deacetylase enzymatic activity of sirtuins is required for this function [37-40].”
BackgroundSIRT1, neuronal cell survival and the insulin/IGF-1 aging paradox
Tang, B. L. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.02.001 · Cited by 58
Büttner, S., Delay, C., Franssens, V., Bammens, T., Ruli, D., Zaunschirm, S., de Oliveira, R. M., Outeiro, T. F., Madeo, F., Buée, L., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013700 · Cited by 59
“On the one hand, enhanced Sir2 activity extends replicative longevity or the number of buddings of a mother cell [51], while on the other hand, the protein seems to act as inhibitor of chronological ageing and the ability of yeast cells to maintain their viability in stationary phase [52].”
BackgroundCharacterization of Nuclear Sirtuins: Molecular Mechanisms and Physiological Relevance
Toiber, D., Sebastián, C., & Mostoslavsky, R. (2011) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-21631-2_9 · Cited by 57
Mitochondrial sirtuins and metabolic homeostasis
Pirinen, E., Sasso, G. L., & Auwerx, J. H. (2012) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2012.05.001 · Cited by 57
Telomere length inheritance and aging
Kappei, D., & Londoño‐Vallejo, A. (2007) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2007.10.009 · Cited by 57
SIRT5 deacetylates and activates urate oxidase in liver mitochondria of mice
Nakamura, Y., Ogura, M., Ogura, K., Tanaka, D., & Inagaki, N. (2012) · FEBS Letters · doi:10.1016/j.febslet.2012.10.009 · Cited by 55
“It is also reported that disruption of SIR2, which is a NAD-dependent histone deacetylase in nucleus, abolishes lifespan extension by calorie restriction in yeast [5].”
BackgroundSirt6 regulates lifespan in Drosophila melanogaster
Taylor, J. R., Wood, J. G., Mizerak, E., Hinthorn, S. J., Liu, J., Finn, M., Gordon, S., Zingas, L., Chang, C.-Y., Klein, M. A., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2111176119 · Cited by 56
“Mammalian genomes contain seven sirtuins, and sirtuin overexpression (OE) has been shown to extend lifespan in yeast (3), worms (4), flies (5, 6), and mice (7).”
Galow, A.-M., & Peleg, S. (2022) · Cells · doi:10.3390/cells11030468 · Cited by 60
The role of SIRT3 in homeostasis and cellular health
Trinh, D., Halabi, L. A., Brar, H., Kametani, M., & Nash, J. E. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1434459 · Cited by 57
“…(SIRTs) are a family of NAD + -dependent deacetylases and ribosyltransferases (Michan and Sinclair, 2007; Huang et al., 2010; Li and Kazgan, 2011) linked with cytoprotective function and extended lifespan (Kaeberlein et al., 1999; Howitz et al., 2003; Law et al., 2009; Benigni et al., 2019).”
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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