Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1*

doi:10.1074/JBC.M205670200

Paper

Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1*

Published Nov 22, 2002 · Kevin J. Bitterman, Rozalyn M. Anderson, H. Cohen

The Journal of Biological Chemistry

Q1 SJR score

1,008

Citations

58

Influential Citations

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Abstract

The Saccharomyces cerevisiae Sir2 protein is an NAD+-dependent histone deacetylase that plays a critical role in transcriptional silencing, genome stability, and longevity. A human homologue of Sir2, SIRT1, regulates the activity of the p53 tumor suppressor and inhibits apoptosis. The Sir2 deacetylation reaction generates two products:O-acetyl-ADP-ribose and nicotinamide, a precursor of nicotinic acid and a form of niacin/vitamin B3. We show here that nicotinamide strongly inhibits yeast silencing, increases rDNA recombination, and shortens replicative life span to that of asir2 mutant. Nicotinamide abolishes silencing and leads to an eventual delocalization of Sir2 even in G1-arrested cells, demonstrating that silent heterochromatin requires continual Sir2 activity. We show that physiological concentrations of nicotinamide noncompetitively inhibit both Sir2 and SIRT1 in vitro. The degree of inhibition by nicotinamide (IC50< 50 μm) is equal to or better than the most effective known synthetic inhibitors of this class of proteins. We propose a model whereby nicotinamide inhibits deacetylation by binding to a conserved pocket adjacent to NAD+, thereby blocking NAD+ hydrolysis. We discuss the possibility that nicotinamide is a physiologically relevant regulator of Sir2 enzymes.

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Study Snapshot

Nicotinamide inhibits yeast silencing and accelerates aging, suggesting it may be a physiologically relevant regulator of Sir2 enzymes.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1*

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References

Steps in Assembly of Silent Chromatin in Yeast: Sir3-Independent Binding of a Sir2/Sir4 Complex to Silencers and Role for Sir2-Dependent Deacetylation

The assembly of silent chromatin in yeast involves Sir2-independent binding to DNA sites, Sir2-dependent histone deacetylation, and histone H3 and H4 tails, supporting a stepwise model for silent chromatin assembly in Saccharomyces cerevisiae.

Manipulation of a Nuclear NAD+ Salvage Pathway Delays Aging without Altering Steady-state NAD+ Levels*

Increasing dosage of NPT1 in yeast extends its life span by up to 60% without altering steady-state NAD+ levels, suggesting increased availability of NAD+ to Sir2 is responsible for the Sir2-dependent extension of life span.

Human SIR2 deacetylates p53 and antagonizes PML/p53‐induced cellular senescence

SIRT1 deacetylase acts as a novel negative regulator of p53 function, rescuing premature cellular senescence in primary mouse embryo fibroblasts.

Conserved Enzymatic Production and Biological Effect of O-Acetyl-ADP-ribose by Silent Information Regulator 2-like NAD+-dependent Deacetylases*

O-acetyl-ADP-ribose, produced by Sir2-like enzymes, delays oocyte maturation and embryo cell division in blastomeres, with its production being conserved across yeast, Drosophila, and human.

Mutations in Saccharomyces cerevisiae gene SIR2 can have differential effects on in vivo silencing phenotypes and in vitro histone deacetylation activity.

Mutations in yeast SIR2 can have diverse effects on gene silencing and histone deacetylation, with some not directly correlating in vitro and in vivo effects.

Citations

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Metabolic profiles of four Bifidobacterium strains reveal distinct health effects and potential applications in probiotic development.

Salmonella-induced SIRT1 and SIRT3 are crucial for maintaining the metabolic switch in bacteria and host for successful pathogenesis

SIRT1 and SIRT3 play a crucial role in mediating the immune-metabolic switch in Salmonella-infected macrophages, regulating bacterial growth and dissemination.

The Multifaceted Role of Endothelial Sirt1 in Vascular Aging: An Update

Sirt1 plays a key role in preventing vascular aging and its decline can lead to endothelial dysfunction, promoting cardiovascular diseases.

Longitudinal Study of Seafood and Fish Oil Supplement Intake and Risk of Persistent Tinnitus.

Regular consumption of tuna, light-meat fish, or shellfish is associated with a lower risk of developing persistent tinnitus in females, while fish oil supplement use is associated with a higher risk.

Activation and inhibition of sirtuins: From bench to bedside

Sirtuin modulation may have therapeutic effects in age-related diseases like diabetes, cardiovascular, neurodegenerative disorders, and cancer by affecting cellular homeostasis and gene expression.