Sirtuin 1

SIRT1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4I5I, 4IF6, 4IG9, 4KXQ, 4ZZH, 4ZZI, 4ZZJ, 5BTR
Identifiers
Aliases	SIRT1, SIR2L1, SIR2, hSIR2, SIR2alpha, Sirtuin 1
External IDs	MGI: 2135607 HomoloGene: 56556 GeneCards: SIRT1
Gene location (Human) Chr. Chromosome 10 (human)[1] Band No data available Start 67,884,669 bp[1] End 67,918,390 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band No data available Start 63,319,005 bp[2] End 63,381,704 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transcription corepressor activity • protein domain specific binding • core promoter sequence-specific DNA binding • protein C-terminus binding • keratin filament binding • transcription factor binding • metal ion binding • HLH domain binding • enzyme binding • protein deacetylase activity • histone binding • protein binding • NAD-dependent histone deacetylase activity • NAD-dependent protein deacetylase activity • histone deacetylase activity • p53 binding • nuclear hormone receptor binding • mitogen-activated protein kinase binding • deacetylase activity • bHLH transcription factor binding • NAD+ binding • identical protein binding • NAD+ ADP-ribosyltransferase activity • hydrolase activity • NAD-dependent histone deacetylase activity (H3-K9 specific) • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding Cellular component • cytoplasm • nuclear envelope • rDNA heterochromatin • chromatin silencing complex • mitochondrion • nucleus • ESC/E(Z) complex • nucleolus • nuclear chromatin • chromatin • nucleoplasm • nuclear euchromatin • PML body • nuclear heterochromatin • nuclear inner membrane • cytosol Biological process • cellular triglyceride homeostasis • positive regulation of MHC class II biosynthetic process • DNA synthesis involved in DNA repair • positive regulation of protein phosphorylation • positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway • rhythmic process • single strand break repair • muscle organ development • histone H3-K9 deacetylation • negative regulation of cellular response to testosterone stimulus • regulation of peroxisome proliferator activated receptor signaling pathway • cellular response to DNA damage stimulus • regulation of bile acid biosynthetic process • DNA replication • negative regulation of TOR signaling • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • regulation of glucose metabolic process • chromatin silencing at rDNA • negative regulation of DNA damage response, signal transduction by p53 class mediator • methylation-dependent chromatin silencing • circadian rhythm • positive regulation of cellular senescence • spermatogenesis • intrinsic apoptotic signaling pathway in response to DNA damage • cellular response to ionizing radiation • negative regulation of helicase activity • cholesterol homeostasis • response to leptin • cellular response to hypoxia • triglyceride mobilization • negative regulation of prostaglandin biosynthetic process • proteasome-mediated ubiquitin-dependent protein catabolic process • apoptotic process • peptidyl-lysine deacetylation • negative regulation of fat cell differentiation • negative regulation of peptidyl-lysine acetylation • regulation of transcription, DNA-templated • positive regulation of adaptive immune response • stress-induced premature senescence • negative regulation of androgen receptor signaling pathway • negative regulation of transforming growth factor beta receptor signaling pathway • response to oxidative stress • negative regulation of sequence-specific DNA binding transcription factor activity • negative regulation of gene expression • transcription, DNA-templated • negative regulation of cAMP-dependent protein kinase activity • pyrimidine dimer repair by nucleotide-excision repair • response to insulin • histone H3-K9 modification • positive regulation of macroautophagy • positive regulation of cholesterol efflux • protein ubiquitination • negative regulation of cell growth • positive regulation of macrophage apoptotic process • rRNA processing • regulation of brown fat cell differentiation • negative regulation of phosphorylation • viral process • DNA repair • negative regulation of neuron death • positive regulation of histone H3-K9 methylation • negative regulation of histone H3-K14 acetylation • maintenance of chromatin silencing • negative regulation of protein kinase B signaling • cell differentiation • ovulation from ovarian follicle • chromatin silencing • regulation of protein serine/threonine kinase activity • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • protein ADP-ribosylation • leptin-mediated signaling pathway • negative regulation of apoptotic process • negative regulation of transcription from RNA polymerase II promoter • chromatin organization • negative regulation of I-kappaB kinase/NF-kappaB signaling • circadian regulation of gene expression • positive regulation of angiogenesis • protein deacetylation • establishment of chromatin silencing • fatty acid homeostasis • protein destabilization • regulation of mitotic cell cycle • positive regulation of cAMP-dependent protein kinase activity • white fat cell differentiation • positive regulation of insulin receptor signaling pathway • negative regulation of transcription, DNA-templated • negative regulation of NF-kappaB transcription factor activity • peptidyl-lysine acetylation • response to hydrogen peroxide • negative regulation of cellular senescence • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • negative regulation of histone H4-K16 acetylation • positive regulation of endothelial cell proliferation • regulation of smooth muscle cell apoptotic process • behavioral response to starvation • cellular glucose homeostasis • cellular response to starvation • cellular response to tumor necrosis factor • positive regulation of DNA repair • regulation of protein import into nucleus, translocation • multicellular organism development • regulation of cell proliferation • positive regulation of cell proliferation • regulation of endodeoxyribonuclease activity • regulation of cellular response to heat • positive regulation of phosphatidylinositol 3-kinase signaling • negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway • UV-damage excision repair • histone deacetylation • positive regulation of chromatin silencing • positive regulation of transcription from RNA polymerase II promoter • angiogenesis • macrophage cytokine production • regulation of lipid storage • positive regulation of adipose tissue development • macrophage differentiation • transcription from RNA polymerase II promoter • positive regulation of smooth muscle cell differentiation • negative regulation of histone H3-K9 trimethylation • cell aging • positive regulation of apoptotic process • cellular response to hydrogen peroxide • histone H3 deacetylation • negative regulation of protein acetylation • regulation of apoptotic process • cellular response to leukemia inhibitory factor Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	23411	93759
Ensembl	ENSG00000096717	ENSMUSG00000020063
UniProt	Q96EB6	Q923E4
RefSeq (mRNA)	NM_001142498 NM_001314049 NM_012238	NM_001159589 NM_001159590 NM_019812
RefSeq (protein)	NP_001135970 NP_001300978 NP_036370	NP_001153061 NP_062786
Location (UCSC)	Chr 10: 67.88 – 67.92 Mb	Chr 10: 63.32 – 63.38 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.^[5][6][7]

SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuin homolog (biological equivalent across species) in yeast (S. cerevisiae) is Sir2. SIRT1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity).^[8]

Function

Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family.^[6]

Sirtuin 1 is downregulated in cells that have high insulin resistance and inducing its expression increases insulin sensitivity, suggesting the molecule is associated with improving insulin sensitivity.^[9] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.^{[10][11][12][13][14][15]}

In mammals, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein.^[16] SIRT1 also stimulates autophagy by preventing acetylation of proteins (via deacetylation) required for autophagy as demonstrated in cultured cells and embryonic and neonatal tissues. This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction.^[17] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.^{[10][11][12][13][14][15]}

Human aging is characterized by a chronic, low-grade inflammation level^[18] and NF-κB is the main transcriptional regulator of genes related to inflammation.^[19] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310.^[20][21]

SIRT1 plays a role in activating T helper 17 cells, which contribute to autoimmune disease; efforts to activate SIRT1 therapeutically may trigger or exacerbate autoimmune disease.^[22]

Selective ligands

Activators

• Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on progeria.^[23]
• Resveratrol has been claimed to be an activator of Sirtuin 1,^[24] but this effect has been disputed based on the fact that the initially used activity assay, using a non-physiological substrate peptide, can produce artificial results.^[25][26] Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation.^[9] However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates.^[27][28] Resveratrol also enhances the binding between Sirtuin 1 and Lamin A.^[23] In addition to resveratrol, a range of other plant-derived polyphenols have also been shown to interact with SIRT1.^[29]
• SRT-1720 was also claimed to be an activator,^[24] but this now has been questioned.^[30]

Interactions

Sirtuin 1 has been shown to interact with HEY2,^[31] PGC1-alpha,^[12] and ERR-alpha.^[10] Mir-132 microRNA has been reported to interact with Sirtuin 1 mRNA, so as to reduce protein expression. This has been linked to insulin resistance in the obese.^[32]

Human Sirt1 has been reported having 136 direct interactions in Interactomic studies involved in numerous processes.^[33]

Sir2

Sir2 (whose homolog in mammals is known as SIRT1) was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied.^[34] Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespan-extending effects of calorie restriction.^[35][36]

The three letter yeast gene symbol Sir stands for Silent Information Regulator while the number 2 is representative of the fact that it was the second SIR gene discovered and characterized.^[37][38]

In the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.^[39][40]

Method of action and observed effects

Sirtuins act primarily by removing acetyl groups from lysine residues within proteins in the presence of NAD⁺; thus, they are classified as "NAD⁺-dependent deacetylases" and have EC number 3.5.1.^[41] They add the acetyl group from the protein to the ADP-ribose component of NAD⁺ to form O-acetyl-ADP-ribose. The HDAC activity of Sir2 results in tighter packaging of chromatin and a reduction in transcription at the targeted gene locus. The silencing activity of Sir2 is most prominent at telomeric sequences, the hidden MAT loci (HM loci), and the ribosomal DNA (rDNA) locus (RDN1) from which ribosomal RNA is transcribed.

Limited overexpression of the Sir2 gene results in a lifespan extension of about 30%,^[42] if the lifespan is measured as the number of cell divisions the mother cell can undergo before cell death. Concordantly, deletion of Sir2 results in a 50% reduction in lifespan.^[42] In particular, the silencing activity of Sir2, in complex with Sir3 and Sir4, at the HM loci prevents simultaneous expression of both mating factors which can cause sterility and shortened lifespan.^[43] Additionally, Sir2 activity at the rDNA locus is correlated with a decrease in the formation of rDNA circles. Chromatin silencing, as a result of Sir2 activity, reduces homologous recombination between rDNA repeats, which is the process leading to the formation of rDNA circles. As accumulation of these rDNA circles is the primary way in which yeast are believed to "age", then the action of Sir2 in preventing accumulation of these rDNA circles is a necessary factor in yeast longevity.^[43]

Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD⁺ and reduces nicotinamide, both of which have the potential to increase the activity of Sir2. Furthermore, removing the Sir2 gene eliminates the life-extending effect of caloric restriction.^[44] Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster^[45] support these findings. As of 2006, experiments in mice are underway.^[35]

However, some other findings call the above interpretation into question. If one measures the lifespan of a yeast cell as the amount of time it can live in a non-dividing stage, then silencing the Sir2 gene actually increases lifespan ^[46] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.^[47]

In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.

Resveratrol is a substance that has been shown through experiment to have a number of life-extending and health benefits in various species; it also increases the activity of Sir2, which is the postulated reason for its beneficial effects. Resveratrol is produced by plants when they are stressed, and it is possible that plants use the substance to increase their own Sir2 activity in order to survive periods of stress.^[35] Although there is mounting evidence for this hypothesis, its validity is debated.^{[30][25][48][26]}

In the fruit fly Drosophilia melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects.^[44] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.^[49]

Activation of SIRT1 in mice

Increased expression of SIRT1 protein, when induced by a synthetic small molecule activator of SIRT1 (SRT2104), extended both the mean and maximal lifespan of mice.^[50] In these mice health was also improved as well as bone and muscle mass. Another SIRT1 activator (SRT1720) also extended lifespan and improved the health of mice.^[51]

Homologous recombination

SIRT1 protein actively promotes homologous recombination (HR) in human cells, and likely promotes recombinational repair of DNA breaks.^[52] SIRT1 mediated HR requires the WRN protein.^[52] WRN protein functions in double-strand break repair by HR.^[53] WRN protein is a RecQ helicase, and in its mutated form gives rise to Werner syndrome, a genetic condition in humans characterized by numerous features of premature aging. These findings link SIRT1 function to HR, a DNA repair process that is likely necessary for maintaining the integrity of the genome during aging.^[52]

References

Further reading

External links

• Corante weblog by Derek Lowe about sir2 and SIRT1 research.
• SIRT1 human gene location in the UCSC Genome Browser.
• SIRT1 human gene details in the UCSC Genome Browser.