Trends in Pharmacological Sciences
The emerging therapeutic potential of sirtuin-interacting drugs: from cell death to lifespan extension
Section snippets
Historical perspective: Sir proteins and silencing of yeast chromatin
Sir1–4 (silent information regulator 1–4) proteins were first shown to be involved in silencing at cell-mating type loci and telomeres in yeast. Subsequent studies showed that Sir2 also participates in the silencing and suppression of recombination at yeast ribosomal DNA (rDNA). Later, additional Sir2 homologues (Hst1–4) that were also involved in silencing were identified 6, 7, 8, 9, 10.
Yeast sirtuins are deacetylases that are involved in a peculiar silencing process. Following the recruitment
New clues: evolutionary conserved, NAD-dependent chromatin remodelling enzymes
Numerous Sir2 homologues have been identified in different organisms 8, 9 (Table 1). Phylogenetic analysis of conserved core sequences in archeans, bacteria, yeasts, plants, protozoans and metazoans reveals that sirtuins can be grouped into five different classes (designated I–IV and U) and are present in all eukaryotes, suggesting ancestral biological functions 16, 17. SIRT1 is the human orthologue of yeast Sir2 and is the best-characterized member among mammalian sirtuins. SIRT1 is a nuclear
Sirtuins and the genetic control of aging: fungi, worms, fruit flies and more?
In 1995, Guarente and colleagues reported that the lifespan of yeast is extended by >30% in the strain mutant Sir4–42, which lacks the C-terminal domain of Sir4 [40]. Importantly, concomitant mutation of sir2 or sir3 suppressed lifespan extension in Sir4–42 mutants [40]. Additional work from the same group demonstrated that deletion of sir3 or sir4 in yeast causes loss of silencing and 20% reduction in lifespan [41]. Similarly, sir2 deletion increases rDNA recombination and shortens lifespan by
An intriguing NAD connection
Several findings show that NAD metabolism (Figure 2) regulates sirtuin functioning [46]. For example, mutation of npt1, the gene encoding yeast nicotinate phosphoribosyl transferase, which participates in NAD re-synthesis, reduces the concentration of intracellular NAD by a factor of 2.5, impairs silencing at telomeres and rDNA and abolishes Sir2-dependent yeast lifespan extension 27, 44, 48. Opposite effects on silencing and longevity are induced by npt1 overexpression [49]. Similarly,
Non-histone targets
Mounting evidence demonstrates that sirtuins also target a substantial number of non-histone proteins. For example, SIRT1 deacetylates the TATA box-binding protein TAF(I)68, thereby repressing activation of RNA polymerase I [57]. SIRT1 also targets CTIP2 (COUP-TF interacting protein 2) and enhances CTIP2-dependent silencing [58]. Similarly, sirtuin-dependent deacetylation promotes activity of the BCL6 (B-cell lymphoma 6) transcriptional repressor [59]. It is well known that acetylation of p53
Acetyl-ADP-ribose: an orphan metabolite in the midst of metabolic networks
When injected into immature starfish oocytes at concentrations in the range of 0.32–5.00 mM, acetyl-ADP-ribose induces delay and then block of oocyte maturation, whereas at 16 mM acetyl-ADP-ribose quickly triggers oocyte death [32]. The finding that microinjection of human SIRT2 or yeast Hst2 also blocks starfish oocyte maturation and early embryo development [32] suggests that acetyl-ADP-ribose might mediate some of the effects of sirtuins. Evidence that acetyl-ADP-ribose has a short half-life
Therapeutic potential of chemical modulators of sirtuin activity
To date, a significant array of chemical inhibitors and activators of sirtuins have been identified and made available for basic research (Figure 4). Evidence that NAD-dependent deacetylation has a short half-life 11, 12, 13, 14 suggests that these chemicals substantially affect sirtuin signalling (Figure 5). Accordingly, the SIRT1 activator resveratrol decreases acetylation-dependent p53 activation and protects human cells from p53-dependent apoptosis [71]. Similarly, resveratrol suppresses
Acknowledgements
This review is dedicated to the silent teacher. We thank friends for helpful comments.
References (79)
- et al.
Deacetylase enzymes: biological functions and the use of small-molecule inhibitors
Chem. Biol.
(2002) - et al.
The molecular biology of the SIR proteins
Gene
(2001) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1
J. Biol. Chem.
(2002)Mammalian SIRT1 represses forkhead transcription factors
Cell
(2004)Microarray deacetylation maps determine genome-wide functions for yeast histone deacetylases
Cell
(2002)Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity
Biochem. Biophys. Res. Commun.
(1999)Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins
Biochem. Biophys. Res. Commun.
(2000)Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state
Mol. Cell
(2003)The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase
Mol. Cell
(2003)Role of NAD(+) in the deacetylase activity of the SIR2-like proteins
Biochem. Biophys. Res. Commun.
(2000)
Structural identification of 2′- and 3′-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+-dependent histone/protein deacetylases
J. Biol. Chem.
Conserved enzymatic production and biological effect of O-acetyl-ADP-ribose by silent information regulator 2-like NAD+-dependent deacetylases
J. Biol. Chem.
Structural basis for the NAD-dependent deacetylase mechanism of Sir2
J. Biol. Chem.
Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases
J. Biol. Chem.
Structural basis for the mechanism and regulation of Sir2 enzymes
Mol. Cell
Co-enzyme specificity of Sir2 protein deacetylases: implications for physiological regulation
J. Biol. Chem.
Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae
Cell
Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease
Curr. Opin. Cell Biol.
Linking chromatin function with metabolic networks: Sir2 family of NAD(+)-dependent deacetylases
Trends Biochem. Sci.
Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels
J. Biol. Chem.
PARP-1: killer or conspirator? The suicide hypothesis revisited
Trends Pharmacol. Sci.
The new life of a centenarian: signalling functions of NAD(P)
Trends Biochem. Sci.
Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression
J. Biol. Chem.
Negative control of p53 by Sir2alpha promotes cell survival under stress
Cell
hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase
Cell
The interaction between FOXO and SIRT1: tipping the balance towards survival
Trends Cell Biol.
Analysis of O-acetyl-ADP-ribose as a target for Nudix ADP-ribose hydrolases
J. Biol. Chem.
Calorie restriction in rhesus monkeys
Exp. Gerontol.
Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis
Mol. Cell
Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening
J. Biol. Chem.
Identification of selective inhibitors of NAD+-dependent deacetylases using phenotypic screens in yeast
J. Biol. Chem.
Translating the histone code
Science
Epigenetics in human disease and prospects for epigenetic therapy
Nature
Acetylation: a regulatory modification to rival phosphorylation?
EMBO J.
Histone-deacetylase inhibitors: novel drugs for the treatment of cancer
Nat. Rev. Drug Discov.
Sir2 links chromatin silencing, metabolism, and aging
Genes Dev.
The Sir2 family of protein deacetylases
Annu. Rev. Biochem.
Diversity in the Sir2 family of protein deacetylases
J. Leukoc. Biol.
Small molecules that regulate lifespan: evidence for xenohormesis
Mol. Microbiol.
Cited by (169)
Protective effect and mechanism of nicotinamide adenine dinucleotide against optic neuritis in mice with experimental autoimmune encephalomyelitis
2021, International ImmunopharmacologyCitation Excerpt :Therefore, the anti-ON effect of NAD+ on EAE might be attributed to its regulatory function on the immune response. SIRT1 is a well-known NAD+ dependent deacetylase that promotes cell stress responses and cell survival [33,34]. Studies show that activation of SIRT1 can prevent the viral-induced optic neuritis in optic nerve trauma and RGC loss in EAE [35,36].
Small molecules in regeneration
2021, Regenerative NephrologySirtuins as regulators and the regulated molecules of exosomes
2021, Sirtuin Biology in Medicine: Targeting New Avenues of Care in Development, Aging, and DiseaseSirtuins and metabolic regulation: Food and supplementation
2021, Sirtuin Biology in Cancer and Metabolic Disease: Cellular Pathways for Clinical DiscoveryIsoparvifuran isolated from Dalbergia odorifera attenuates H<inf>2</inf>O<inf>2</inf>-induced senescence of BJ cells through SIRT1 activation and AKT/mTOR pathway inhibition
2020, Biochemical and Biophysical Research Communications