Sirtuin 1

Sirtuin 1
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 4I5I​, 4IF6​, 4IG9​, 4KXQ​
Identifiers
Symbols	SIRT1 ; SIR2; SIR2L1; hSIR2
External IDs	OMIM: 604479 MGI: 2135607 HomoloGene: 56556 ChEMBL: 4506 GeneCards: SIRT1 Gene
Gene ontology Molecular function • core promoter sequence-specific DNA binding • p53 binding • transcription corepressor activity • NAD+ ADP-ribosyltransferase activity • histone deacetylase activity • protein binding • protein C-terminus binding • transcription factor binding • NAD-dependent histone deacetylase activity • deacetylase activity • enzyme binding • protein deacetylase activity • NAD-dependent protein deacetylase activity • nuclear hormone receptor binding • histone binding • identical protein binding • HLH domain binding • bHLH transcription factor binding • metal ion binding • NAD-dependent histone deacetylase activity (H3-K9 specific) • mitogen-activated protein kinase binding • NAD+ binding • keratin filament binding Cellular component • nuclear chromatin • nucleus • nuclear envelope • nuclear inner membrane • nucleoplasm • chromatin silencing complex • nuclear euchromatin • nuclear heterochromatin • nucleolus • cytoplasm • mitochondrion • PML body • rDNA heterochromatin • ESC/E(Z) complex Biological process • single strand break repair • negative regulation of transcription from RNA polymerase II promoter • chromatin silencing at rDNA • pyrimidine dimer repair by nucleotide-excision repair • DNA synthesis involved in DNA repair • angiogenesis • ovulation from ovarian follicle • cellular glucose homeostasis • positive regulation of protein phosphorylation • positive regulation of adaptive immune response • DNA replication • DNA repair • chromatin organization • chromatin silencing • establishment of chromatin silencing • maintenance of chromatin silencing • methylation-dependent chromatin silencing • transcription, DNA-templated • rRNA processing • protein ADP-ribosylation • protein deacetylation • triglyceride mobilization • cellular response to DNA damage stimulus • response to oxidative stress • spermatogenesis • regulation of mitotic cell cycle • muscle organ development • cell aging • positive regulation of cell proliferation • cellular response to starvation • gene expression • negative regulation of gene expression • positive regulation of cholesterol efflux • regulation of glucose metabolic process • viral process • positive regulation of macroautophagy • protein ubiquitination • histone deacetylation • peptidyl-lysine acetylation • negative regulation of cell growth • negative regulation of transforming growth factor beta receptor signaling pathway • negative regulation of prostaglandin biosynthetic process • protein destabilization • positive regulation of chromatin silencing • negative regulation of TOR signaling • regulation of endodeoxyribonuclease activity • negative regulation of NF-kappaB transcription factor activity • response to insulin • circadian regulation of gene expression • regulation of protein import into nucleus, translocation • regulation of smooth muscle cell apoptotic process • cellular response to heat • peptidyl-lysine deacetylation • cellular triglyceride homeostasis • regulation of peroxisome proliferator activated receptor signaling pathway • regulation of gene expression, epigenetic • regulation of cell proliferation • negative regulation of phosphorylation • response to hydrogen peroxide • behavioral response to starvation • cholesterol homeostasis • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • positive regulation of apoptotic process • negative regulation of apoptotic process • negative regulation of I-kappaB kinase/NF-kappaB signaling • proteasome-mediated ubiquitin-dependent protein catabolic process • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process • negative regulation of sequence-specific DNA binding transcription factor activity • negative regulation of DNA damage response, signal transduction by p53 class mediator • positive regulation of MHC class II biosynthetic process • negative regulation of fat cell differentiation • positive regulation of DNA repair • negative regulation of gene expression, epigenetic • negative regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • positive regulation of insulin receptor signaling pathway • white fat cell differentiation • negative regulation of helicase activity • positive regulation of histone H3-K9 methylation • negative regulation of protein kinase B signaling • fatty acid homeostasis • negative regulation of androgen receptor signaling pathway • histone H3-K9 modification • cellular response to hydrogen peroxide • regulation of bile acid biosynthetic process • UV-damage excision repair • histone H3 deacetylation • cellular response to tumor necrosis factor • negative regulation of histone H3-K14 acetylation • cellular response to hypoxia • cellular response to ionizing radiation • stress-induced premature senescence • regulation of cellular response to heat • negative regulation of neuron death • negative regulation of protein acetylation • negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway • positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway • histone H3-K9 deacetylation • positive regulation of macrophage apoptotic process • negative regulation of cAMP-dependent protein kinase activity • positive regulation of cAMP-dependent protein kinase activity • negative regulation of histone H4-K16 acetylation • negative regulation of cellular response to testosterone stimulus • negative regulation of peptidyl-lysine acetylation • negative regulation of cellular senescence • positive regulation of cellular senescence Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	23411	93759
Ensembl	ENSG00000096717	ENSMUSG00000020063
UniProt	Q96EB6	Q923E4
RefSeq (mRNA)	NM_001142498	NM_001159589
RefSeq (protein)	NP_001135970	NP_001153061
Location (UCSC)	Chr 10: 67.88 – 67.92 Mb	Chr 10: 63.32 – 63.38 Mb
PubMed search

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.^[1][2][3]

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).^[4]

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.^[2]

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.^[5] 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.^{[6][7][8][9][10][11]}

Selective ligands

Activators

• Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on Progeria.^[12]
• Resveratrol has been claimed to be an activator of Sirtuin 1,^[13] 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.^[14][15] Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation.^[5] However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates.^[16][17] Resveratrol also enhances the binding between Sirtuin 1 and Lamin A.^[12]
• SRT-1720 was also claimed to be an activator,^[13] but this now has been questioned.^[18]

Interactions

Sirtuin 1 has been shown to interact with HEY2,^[19] PGC1-alpha,^[8] and ERR-alpha.^[6] 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.^[20]

Human Sirt1 has been reported having 136 direct interactions in Interactomic studies involved in numerous processes.^[21]

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.