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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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Cites
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“Likewise, mutations that enhance ERC formation shorten the longevity of mother cells (Kaeberlein et al., 1999).”
BackgroundStructural Insights into Intermediate Steps in the Sir2 Deacetylation Reaction
Hawse, W. F., Hoff, K. G., Fatkins, D. G., Daines, A. M., Zubkova, O. V., Schramm, V. L., Zheng, W., & Wolberger, C. (2008) · Structure · doi:10.1016/j.str.2008.05.015 · Cited by 116
“Numerous biological processes including aging (Kaeberlein et al., 1999), HIV transcription (Pagans et al., 2005), gene silencing (Johnson et *Correspondence: cwolberg@jhmi.edu.”
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Bitto, A., Wang, A. M., Bennett, C. F., & Kaeberlein, M. R. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025114 · Cited by 122
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Yu, M., Zhang, H., Wang, B. Z., Zhang, Y., Zheng, X., Shao, B., Zhuge, Q., & Jin, K. (2021) · Cells · doi:10.3390/cells10030660 · Cited by 117
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Sirtuin‐independent effects of nicotinamide on lifespan extension from calorie restriction in yeast
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“Thus, we conclude that HST2 plays no role in determining longevity in yeast under standard growth conditions in either BY4742 or W303AR5, and that Hst2 does not repress rDNA recombination or ERC formation in W303AR5.”
BackgroundMethodInfluentialSelf-citationdSir2 in the Adult Fat Body, but Not in Muscles, Regulates Life Span in a Diet-Dependent Manner
Banerjee, K. K., Ayyub, C., Syed, Z. A., Mandot, V., Prasad, N. G., & Kolthur‐Seetharam, U. (2012) · Cell Reports · doi:10.1016/j.celrep.2012.11.013 · Cited by 117
“Sir2 was identified as a key determinant of longevity in Saccharomyces cerevisiae (Delaney et al., 2011; Kaeberlein et al., 1999).”
BackgroundRedox-regulating sirtuins in aging, caloric restriction, and exercise
Radak, Z. O., Koltai, E., Taylor, A. W., Higuchi, M., Kumagai, S., Ohno, H., Goto, S., & Boldogh, I. R. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.01.004 · Cited by 115
“In the budding yeast Saccharomyces cerevisiae, the Sir proteins are involved in a wide array of cellular processes, including the nonhomologous end-joining repair of DNA [17], the stabilization of the replication forks in the ribosomal (r) DNA to prevent DNA breaks, recombination, and the generation of extrachromosoma…”
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Pallauf, K., Giller, K., Huebbe, P., & Rimbach, G. H. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/707421 · Cited by 116
“An inhibitory mutation of the Sirt1 ortholog SIR2 in yeast shortened lifespan, whereas overexpression of SIR2 extended lifespan [62].”
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Self-citationSirtuin 7 in cell proliferation, stress and disease: Rise of the Seventh Sirtuin!
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Finding a Target for Resveratrol
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“Deleting FOB1 suppresses the short RLS of a sir2Δ mutant (Kaeberlein et al., 1999), although viewed differently, deleting SIR2 still suppresses the extended RLS of a fob1Δ mutant, strongly suggesting that Sir2 has additional functions in promoting longevity that are independent of the rDNA.”
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“Aging has been shown to cause DNA damage, degeneration of the nuclear architecture, loss of histones, loss of histone modification ( Kaeberlein et al., 1999 ; Scaffidi and Misteli, 2006 ; Burgess et al., 2012 ).”
BackgroundImpaired quality control of mitochondria: Aging from a new perspective
Weber, T. A., & Reichert, A. S. (2010) · Experimental Gerontology · doi:10.1016/j.exger.2010.03.018 · Cited by 112
“Also the extent or way of CR appears to be crucial as e.g. when using a moderate protocol of CR the yeast sirtuin Sir2 was reported to be required for the CR-dependent increase of the number of cell divisions a mother cell can undergo (termed replicative lifespan) in yeast (Kaeberlein et al., 1999).”
BackgroundCellular Senescence in Yeast Is Regulated by rDNA Noncoding Transcription
Saka, K., Ide, S., Ganley, A. R. D., & Kobayashi, T. (2013) · Current Biology · doi:10.1016/j.cub.2013.07.048 · Cited by 109
The autophagy–NAD axis in longevity and disease
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“Indeed, several roles have been attributed to them, including cell cycle progression and chromosome stability (32), DNA damage repair (33), and life span extension in yeast (34) and Caenorhabditis elegans (35).”
BackgroundMetabolic effects of resveratrol: Addressing the controversies
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“Increasing the expression of Sirt1 has extended lifespan in yeast [14], worms [15], and flies [10].”
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Sirtuin 6: linking longevity with genome and epigenome stability
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“CR was also reported to reduce rDNA recombination in W303AR5, as measured by loss of an ADE2 marker from the rDNA (Lamming et al., 2005).”
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Canto, C., & Auwerx, J. H. (2011) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2012.76.010439 · Cited by 111
“lifespan (Kaeberlein et al., 1999).”
Integrating the DNA damage and protein stress responses during cancer development and treatment
Gorgoulis, V. G., Pefani, D., Pateras, I. S., & Trougakos, I. P. (2018) · The Journal of Pathology · doi:10.1002/path.5097 · Cited by 108
“The stability of the repetitive and recombinogenic-prone rDNA sequences requires chromatin silencing complexes [162,164,165].”
BackgroundInduction of Hypothalamic Sirt1 Leads to Cessation of Feeding via Agouti-Related Peptide
Sasaki, T., Kim, H.-J., Kobayashi, M., Kitamura, Y.-I., Yokota‐Hashimoto, H., Shiuchi, T., Minokoshi, Y., & Kitamura, T. (2010) · Endocrinology · doi:10.1210/en.2009-1319 · Cited by 109
“tion of life span in species as diverse as yeast (4), worms (5),”
BackgroundKwan, E. X., Foss, E. J., Tsuchiyama, S. K., Alvino, G. M., Kruglyak, L., Kaeberlein, M. R., Raghuraman, M. K., Brewer, B. J., Kennedy, B. K., & Bedalov, A. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003329 · Cited by 108
“This modulation of lifespan by rDNA locus inheritance was found to be independent of Sir2 and Fob1, two previously established regulators of yeast longevity that interact with the rDNA locus [5,11], suggesting that the rDNA locus itself has intrinsic properties important for lifespan modulation.”
Self-citationSirtuin-1 regulation of mammalian metabolism
Gillum, M. P., Erion, D. M., & Shulman, G. I. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.09.005 · Cited by 110
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“Sir2 overexpression increases lifespan (Tissenbaum and Guarente 2001) with mutations causing a severe reduction in lifespan (Kaeberlein et al. 1999).”
BackgroundBiological characteristics and pathogenicity of Acanthamoeba
Wang, Y., Jiang, L., Zhao, Y., Ju, X., Wang, L., Jin, L., Fine, R. D., & Li, M. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1147077 · Cited by 108
“, 2000), and sirtuin overexpression is known to extend the lifespan by silencing HML and HMR loci and inhibiting the formation of extrachromosomal rDNA circles (Sinclair and Guarente, 1997; Kaeberlein et al., 1999).”
BackgroundIdentification of serum sirtuins as novel noninvasive protein markers for frailty
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“Based on the Surface Plasmon Resonance (SPR) data, the area under the ROC curves was calculated to measure the utility of each protein as potential marker for frailty.”
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Epigenetics in Saccharomyces cerevisiaePreprint
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“In Saccharomyces cerevisiae , C. elegans , and Drosophila melanogaster , increased copy number or expression of the SIR2 gene extends lifespan 30–50% (Kaeberlein et al ., 1999; Tissenbaum & Guarente, 2001; Rogina & Helfand, 2004).”
BackgroundGenomic Instability and Epigenetic Changes during Aging
López-Gil, L., Pascual‐Ahuir, A., & Proft, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814279 · Cited by 130
Sirt3, Mitochondrial ROS, Ageing, and Carcinogenesis
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Gárdián, G., Yang, L., Cléren, C., Calingasan, N. Y., Klivènyi, P., & Beal, M. F. (2004) · NeuroMolecular Medicine · doi:10.1385/nmm:5:3:235 · Cited by 107
Narala, S. R., Allsopp, R. C., Wells, T. B., Zhang, G., Prasad, P., Coussens, M. J., Rossi, D. J., Weissman, I. L., & Vaziri, H. (2008) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-09-0965 · Cited by 106
“Increased dosage of SIR2 extends replicative lifespan in certain strains of S. cerevisiae (Kaeberlein et al., 1999) and increases longevity of Caenorhabditis elegans (Tissenbaum and Guarente, 2001).”
BackgroundYoshida, K., Bacal, J., Desmarais, D., Padioleau, I., Tsaponina, O., Chabes, A., Pantesco, V., Dubois, E., Parrinello, H., Skrzypczak, M., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.04.032 · Cited by 106
“ERC disappeared in sir2D fob1D cells (Figures 2C, 2D, and S3A), which is consistent with earlier studies (Kaeberlein et al., 1999; Pasero et al., 2002).”
Regulation of RNA Polymerase I Transcription in Development, Disease, and Aging
Sharifi, S., & Bierhoff, H. (2018) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-062917-012612 · Cited by 108
Yechoor, V. K., Patti, M., Ueki, K., Laustsen, P. G., Saccone, R., Rauniyar, R. K., & Kahn, C. R. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407574101 · Cited by 106
Sirt1 protects the heart from aging and stress
Hsu, C., Odewale, I., Alcendor, R. R., & Sadoshima, J. (2008) · Biological Chemistry · doi:10.1515/bc.2008.032 · Cited by 108
“It has attracted much attention in recent years because it is linked to life span extension under CR in Saccharomyces cerevisiae (Kaeberlein et al., 1999).”
Molecular links between aging and adipose tissue
Picard, F., & Guarente, L. (2005) · International Journal of Obesity · doi:10.1038/sj.ijo.0802912 · Cited by 105
Self-citationNicotinamide extends replicative lifespan of human cells
Kang, H. T., Lee, H. I., & Hwang, E. S. (2006) · Aging Cell · doi:10.1111/j.1474-9726.2006.00234.x · Cited by 105
“…to inhibit the activities of yeast Sir2, a NAD + -dependent histone deacetylase (Luo et al. , 2001; Bitterman et al. , 2002) involved in gene silencing and genome stabilization (Guarente, 1999; Tanny et al. , 1999) as well as the doubling capacity (Kaeberlein et al. , 1999; Kim et al. , 2004).”
BackgroundLongevity: Lesson from Model Organisms
Taormina, G., Ferrante, F., Vieni, S., Grassi, N., Russo, A. G., & Mirisola, M. G. (2019) · Genes · doi:10.3390/genes10070518 · Cited by 112
“In yeast, sirtuins promote longevity [159]; in particular, it has been reported that Sir2 mediates life-span extension due by calorie restriction [160].”
BackgroundTranscriptional silencing in Saccharomyces cerevisiae and Schizosaccharomyces pombe
Huang, Y. C. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.7.1465 · Cited by 104
SIRT1 and SIRT3 Deacetylate Homologous Substrates: AceCS1,2 and HMGCS1,2
Hirschey, M. D., Shimazu, T., Capra, J. A., Pollard, K. S., & Verdin, E. M. (2011) · Aging · doi:10.18632/aging.100339 · Cited by 105
Stern, N., Hochman, A., Zemach, N., Weizman, N., Hammel, I., Shiloh, Y., Rotman, G., & Barzilai, A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m106798200 · Cited by 104
Increased expression of Drosophila Sir 2 extends life span in a dose-dependent manner
Whitaker, R., Faulkner, S., Miyokawa, R., Burhenn, L., Henriksen, M., Wood, J. G., & Helfand, S. L. (2013) · Aging · doi:10.18632/aging.100599 · Cited by 106
Cheng, Y., Takeuchi, H., Sonobe, Y., Jin, S., Wang, Y., Horiuchi, H., Parajuli, B., Kawanokuchi, J., Mizuno, T., & Suzumura, A. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.02.001 · Cited by 102
“Sirtuin 1 (SIRT1) is a NAD-dependent histone deacetylase involved in induction of lifespan extension by calorie restriction (CR) in many organisms, including yeast, worms, flies, and mice (Kaeberlein et al., 1999; Tissenbaum and Guarente, 2001; Rogina and Helfand, 2004; Morselli et al., 2010).”
Khan, M., Ullah, R., Rehman, S. U., Shah, S. A., Saeed, K. M., Muhammad, T., Park, H. Y., Jo, M. H., Choe, K., Rutten, B. P. F., et al. (2019) · Cells · doi:10.3390/cells8080928 · Cited by 102
Autophagy: Multiple Mechanisms to Protect Skin from Ultraviolet Radiation-Driven Photoaging
Wang, M., Pourzand, C., Lei, X., & Zhong, J. L. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/8135985 · Cited by 103
“The NAD(+)-dependent sirtuin enzymes are well-known modulators of aging, enhancing the lifespan of organisms [80] due to their extensive biological roles in metabolic control, cell death and survival, gene repression, repair of damaged DNA, morphogenesis, natural aging, and inflammation [81].”
BackgroundCan yeast systems biology contribute to the understanding of human disease?
Petranović, D., & Nielsen, J. (2008) · Trends in biotechnology · doi:10.1016/j.tibtech.2008.07.008 · Cited by 107
Regulation of lifespan by histone deacetylase
Chang, K. T., & Min, K. (2002) · Ageing Research Reviews · doi:10.1016/s1568-1637(02)00003-x · Cited by 99
Single Cell Analysis of Yeast Replicative Aging Using a New Generation of Microfluidic Device
Zhang, Y., Luo, C., Zou, K., Xie, Z., Brandman, O., Ouyang, Q., & Li, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048275 · Cited by 102
“We chose two genes that are well known to regulate lifespan: Sir2 and Fob1, the deletion of which shortens or extends lifespan respectively [15],[16].”
BackgroundSmith, B. C., & Denu, J. M. (2005) · Biochemistry · doi:10.1021/bi052014t · Cited by 102
“The growing interest in the silent information regulator 2 (Sir2 or sirtuin) family of proteins lies in their involvement in a rapidly expanding list of cellular processes including gene silencing (1,2), cell cycle regulation (3), fatty acid metabolism (4), apoptosis (5-7), and lifespan extension (8-10).”
BackgroundThe Sir proteins of Saccharomyces cerevisiae: mediators of transcriptional silencing and much more
Gartenberg, M. R. (2000) · Current Opinion in Microbiology · doi:10.1016/s1369-5274(00)00064-3 · Cited by 101
Greer, E. L., & Brunet, A. (2008) · Journal of Cell Science · doi:10.1242/jcs.021519 · Cited by 102
“The Sirtuin family of NAD-dependent protein deacetylases was identified early on as a key regulator of replicative lifespan in yeast (Kaeberlein et al., 1999; Kennedy et al., 1995).”
BackgroundHistone Deacetylase AtSRT1 Links Metabolic Flux and Stress Response in Arabidopsis
Liu, X., Wei, W., Zhu, W., Su, L., Xiong, Z., Zhou, M., Zheng, Y., & Zhou, D. (2017) · Molecular Plant · doi:10.1016/j.molp.2017.10.010 · Cited by 102
Principles of the Molecular and Cellular Mechanisms of Aging
da Silva, P. F. L., & Schumacher, B. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2020.11.018 · Cited by 106
Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process
Chung, D. K. C., Chan, J. N. Y., Strecker, J., Zhang, W., Ebrahimi‐Ardebili, S., Lu, T., Abraham, K. J., Durocher, D., & Mekhail, K. (2015) · Nature Communications · doi:10.1038/ncomms8742 · Cited by 106
Lindstrom, D. L., Leverich, C. K., Henderson, K. A., & Gottschling, D. E. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002015 · Cited by 111
“ERCs, LOH, and life span Previously, life span extension by fob1D was interpreted as a result of reduced ERC accumulation to a degree at which RLS becomes limited by an alternative mechanism [32,42].”
BackgroundInfluentialYeast Nhp6A/B and Mammalian Hmgb1 Facilitate the Maintenance of Genome Stability
Giavara, S., Kosmidou, E., Hande, M. P., Bianchi, M. E., Morgan, A., di Fagagna, F. D., & Jackson, S. P. (2005) · Current Biology · doi:10.1016/j.cub.2004.12.065 · Cited by 100
HDAC inhibitors: A new promising drug class in anti-aging research
Pasyukova, E. G., & Vaiserman, A. M. (2017) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.08.008 · Cited by 99
Olmos, Y., Brosens, J. J., & Lam, E. W. ‐. (2010) · Drug Resistance Updates · doi:10.1016/j.drup.2010.12.001 · Cited by 100
The physiological roles of Sirt1 in skeletal muscle
Pardo, P. S., & Boriek, A. M. (2011) · Aging · doi:10.18632/aging.100312 · Cited by 105
“SIRT1 (silent information regulator 1) is the mammalian homologue of the yeast Sir2, which is implicated in lifespan extension in model organisms, such as yeast, worms and flies [1-3].”
BackgroundHong, S., Zhao, B., Lombard, D. B., Fingar, D. C., & Inoki, K. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.520734 · Cited by 101
“Increased Sir2 gene dosage has been proposed to be sufficient to extend lifespan (54, 55), which is genetically opposed to the effect of TORC1 signaling in the regulation of lifespan (56, 57).”
BackgroundChen, Z. B., Shentu, T., Wen, L., Johnson, D. A., & Shyy, J. Y.-J. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4803 · Cited by 99
“Silent mating-type information regulation 2 homolog (sirtuin 1 or SIRT1) is an NAD + -dependent class III histone deacetylase that is upregulated under caloric restriction (CR), extending the lifespan of many organisms (60,128,147).”
BackgroundAutophagy Mechanism, Regulation, Functions, and Disorders
Badadani, M. (2012) · ISRN Cell Biology · doi:10.5402/2012/927064 · Cited by 106
Yu, J., Wu, Y., & Yang, P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13587 · Cited by 98
“Sirtuin was first discovered in yeast as Sir2, which is essential for the maintenance of heterochromatin and prolongs lifespan (Kaeberlein et al. 1999).”
BackgroundThe yeast replicative aging model
He, C. Z., Zhou, C., & Kennedy, B. K. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.02.023 · Cited by 95
A forkhead in the road to longevity: the molecular basis of lifespan becomes clearer
Morris, B. J. (2005) · Journal of Hypertension · doi:10.1097/01.hjh.0000173509.45363.dd · Cited by 98
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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