Cited by 193Sirtuins and Resveratrol in MedicineGenetics, Aging, and Longevity in Model OrganismsNuclear Structure and Function

Nicotinamide Clearance by Pnc1 Directly Regulates Sir2-Mediated Silencing and Longevity

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Gallo, Christopher M., Smith, Daniel L., Smith, Jeffrey S.·2004·Molecular and Cellular Biology

Abstract

The Saccharomyces cerevisiae Sir2 protein is an NAD(+)-dependent histone deacetylase (HDAC) that functions in transcriptional silencing and longevity. The NAD(+) salvage pathway protein, Npt1, regulates Sir2-mediated processes by maintaining a sufficiently high intracellular NAD(+) concentration. However, another NAD(+) salvage pathway component, Pnc1, modulates silencing independently of the NAD(+) concentration. Nicotinamide (NAM) is a by-product of the Sir2 deacetylase reaction and is a natural Sir2 inhibitor. Pnc1 is a nicotinamidase that converts NAM to nicotinic acid. Here we show that recombinant Pnc1 stimulates Sir2 HDAC activity in vitro by preventing the accumulation of NAM produced by Sir2. In vivo, telomeric, rDNA, and HM silencing are differentially sensitive to inhibition by NAM. Furthermore, PNC1 overexpression suppresses the inhibitory effect of exogenously added NAM on silencing, life span, and Hst1-mediated transcriptional repression. Finally, we show that stress suppresses the inhibitory effect of NAM through the induction of PNC1 expression. Pnc1, therefore, positively regulates Sir2-mediated silencing and longevity by preventing the accumulation of intracellular NAM during times of stress.

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Crossref · 10.1128/mcb.24.3.1301-1312.2004

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  • A supraphysiologic dose of NAM (1-5 mM compared with 200 μM used in lifespan extension experiments) has been associated with reduced lifespan in yeast and C. elegans.

    “a supraphysiologic dose of NAM (1–5 mM as compared with 200 μM used in experiments with lifespan extension190) has also been associated with reduced lifespan in yeast and C. elegans190–192.”

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  1. [4]Ausubel, F. M., R. Brent, R. E. Kingston, D. D. Moore, J. G. Seidman, J. A. Smith, and K. Struhl (ed.). 2000. Current protocols in molecular biology, vol. 2. John Wiley & Sons, Inc., New York, N.Y.
  2. [36]Landry, J., A. Sutton, S. T. Tafrov, R. C. Heller, J. Stebbins, L. Pillus, R. Sternglanz, S. Imai, C. M. Armstrong, M. Kaeberlein, and L. Guarente. 2000. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Proc. Natl. Acad. Sci. USA 97:5807-5811.10811920 [Google Scholar]

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Authors
Gallo, C. M., Smith, D. L., & Smith, J. S.
Affiliations
University of Virginia Health System (US)
Corresponding author
Smith, Jeffrey S.
Venue
Molecular and Cellular Biology
Published
2004-02-01
Volume
24
Issue
3
Pages
1301-1312
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W2149754072
Cited by
193
References
73
Citations by year
2026: 2 · 2025: 5 · 2024: 1 · 2023: 5 · 2022: 5 · 2021: 8 · 2020: 9 · 2019: 5 · 2018: 7 · 2017: 4 · 2016: 10 · 2015: 6 · 2014: 6 · 2013: 8 · 2012: 6
FWCI
7.81
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1r03ag022685-01)
  • National Institute on Aging (AG022685)
  • National Institute of General Medical Sciences (GM-08136, S06GM008136, GM61692, R01GM061692)
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
Sir2, nicotinamide, nicotinamidase, NAD+ salvage pathway, histone deacetylase, transcriptional silencing, longevity, lifespan, telomeric silencing, rDNA silencing, FGF4, stress response, Saccharomyces cerevisiae
MeSH terms
DNA, Ribosomal, Histone Deacetylases, Nicotinamidase, Niacinamide, Saccharomyces cerevisiae, Time Factors, Telomere, Gene Silencing, Saccharomyces cerevisiae Proteins, Sirtuins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Sirtuin 2

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