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FLASH GENE
Symbol SIRT1 contributors: mct/shn - updated : 24-07-2019
HGNC name sirtuin 1
HGNC id 14929
Location 10q21.3      Physical location : 69.644.426 - 69.678.146
Synonym name
  • sirtuin (silent mating type information regulation 2, S. cerevisiae, homolog) 1
  • sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)
  • NAD-dependent deacetylase sirtuin-1
  • SIR2-like protein 1
  • SIR2alpha
  • hSIR2
  • hSIRT1
  • sir2-like 1
  • sirtuin type 1
    • Synonym symbol(s) SIR2L1, SIR2alpha, hSIR2, RP11-57G10.3
    EC.number 3.5.1.-
    DNA
    TYPE functioning gene
    STRUCTURE 33.72 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter (CAAT box)
    cytosine-phosphate-guanine/HTF
    Binding site
    text structure
  • 5' flanking genomic region, which precedes the SIRT1 open reading frame, revealed a CCAAT-box and a number of NF-kappaB and GATA transcription factor binding sites in addition to a small 350 bp CpG island
  • 3-prime UTR of SIRT1 transcripts contains AU-rich elements with HuR binding motifs
    • MAPPING cloned Y linked N status provisional
    Map cen - D10S1646 - D10S1670 - SIRT1 - D10S210 - D10S2480 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 - 3604 - 452 - 2009 19236849
    isoform b
    9 - 4110 - 747 - 2009 19236849
    isoform a
    - - - - - - 3012 22124156
  • deacetylase coding sequence is lost due to splicing between exons 2 and 9
  • binds TP53 protein
  • new, deacetylase-independent therapeutic target for SIRT1-related diseases, including cancer
    		•
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   moderately
    Digestiveintestinelarge intestinecolon moderately
     intestinesmall intestine  moderately
     liver   moderately
    Endocrinepancreas   moderately
    Lymphoid/Immunespleen   highly
     thymus   moderately
    Nervousbrain   moderately
    Reproductivefemale systemovary  highly
     female systemplacenta  highly
     male systemprostate  highly
     male systemtestis  highly
    Respiratorylung   highly
    Urinarykidney   moderately
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumskeletal moderately
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticleukocyte
    cell lineage highly expressed in neural precursor cells and contributes to neurogenesis
    cell lines SIRT1 is overexpressed in human prostate cancer cells (DU145, LNCaP, 22Rv1, and PC3)
    fluid/secretion
    at STAGE
    physiological period fetal
    Text tissues, eye
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a deacetylase sirtuin-type core domain
  • a highly conserved 275-AA catalytic core domain
  • AAs 499–747 corresponding to the C-terminus domain, are required for interaction with NR0B2 whereas the AAs 1–92 of NR0B2 protein is sufficient to interact with SIRT1
    • HOMOLOGY
    interspecies ortholog to Sir2, yeast
    ortholog to Sirt1, Mus musculus
    ortholog to Sirt1, Rattus norvegicus
    ortholog to SIRT1, Pan troglodytes
    ortholog to sirt1, Danio rerio
    Homologene
    FAMILY
  • sirtuin family
    • CATEGORY enzyme , regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm
    intracellular,nucleus,nucleoplasm,nuclear bodies,PML
    text recruited to the PML nuclear bodies
    basic FUNCTION
  • NAD(+) ADP-ribosyltransferase with a protein deacetylase activity, promoting heterochromatin formation through the coordination of several events
  • involved in cell aging and in the response to DNA damage, binds and deacetylates the p53
  • may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity
  • control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors
  • plays a key role in connecting cellular metabolism with gene silencing and aging
  • by participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers
  • nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase negative regulator of TP53, capable of modulating cellular senescence
  • key regulator of cell defenses and survival in response to stress
  • involved in chromatin remodeling and the regulation of transcription factors such as TP53
  • involved in nuclear NAD biosynthesis and in preventing axonal degeneration
  • histone deacetylase playing a critical role in transcriptional silencing, genome stability, and longevity
  • may regulate physiological processes that are impacted by calorie restriction (like up-regulating physical activity)
  • functioning in glucose homeostasis as a modulator of PPARGC1
  • modulating the effects of PPARGC1 repression of glycolytic genes in response to fasting and pyruvate
  • can promote cellular survival and increase lifespan, by deacetylating FOXO4
  • having a role as an important stress sensor molecule that links aging to neurodegeneration
  • protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling
  • promoting endothelium-dependent vasodilation by targeting endothelial nitric oxide synthase (NOS3) for deacetylation
  • playing an important role in endothelium-dependent NOS3-mediated vascular homeostasis: a role that may become more prominent during times of low calorie intake
  • promoting the survival of both aging and cancer cells
  • maintaining cell survival by regulating catalase expression and by preventing the depletion of ROS required for cell survival, in renal tubular cell
  • may be involved in the processes of glucose homeostasis and insulin secretion
  • role for SIRT1 as a critical modulator of endothelial gene expression governing postnatal vascular growth
  • might play a distinct role on differentiation under specific conditions (participated in oxidation-mediated suppression of neurogenesis)
  • potential role of brain SIRT1 in regulating energy homeostasis
  • its expression may be a good sensor of toxic neuronal processes
  • a cortactin deacetylase that deacetylates cortactin in vivo and in vitro
  • a role in protein homeostasis and the heat shock response
  • controls PPARGC1A gene expression in skeletal muscle and MYOD1 is a key mediator of this action
  • player of repressing NOTCH1-HES1 signaling pathway, and its transient translocation into the nucleus may have a role in the differentiation of neural precursor cells
  • required for high-magnitude circadian transcription of several core clock genes, including Bmal1, Rorgamma, Per2, and Cry1
  • promoting the deacetylation and degradation of PER2
  • contributing to circadian control
  • promotes replicative senescence under conditions of chronic stress
  • could retard aging and confer stress resistance to the heart, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of SIRT1
  • may exert protective effects against endothelial dysfunction by preventing stress-induced premature senescence and deranged expression of SERPINE1 and NOS3
  • has a role in protein homeostasis and the heat-shock response
  • deacetylation of NBS1 by SIRT1 plays a key role in regulation of the DNA damage response and maintenance of genomic stability
  • among the SIRT family, SIRT1 uniquely regulates angiogenesis signaling
  • plays an important role in the regulation of cell death/survival and stress response
  • protects the heart from aging and stress
  • SIRT1 could contribute and play a fonctional role to the development of human prostate cancer
  • downregulates AGTR1 expression in vascular smooth muscle cells
  • functions as an enzymatic rheostat of circadian function, transducing signals originated by cellular metabolites to the circadian clock
  • modulates neuronal differentiation
  • a possible role in cell motility through deacetylation of cortactin
  • a player of repressing Notch1-Hes1 signaling pathway, and its transient translocation into the nucleus may have a role in the differentiation of neural precursor cells
  • SIRT1 acts as an oncogene via inhibiting FOXO1 acetylation and transcription in prostate cancer
  • has a role in tumor cell migration through the deacetylation of cortactin
  • implicated in tumor invasion and metastasis and stimulates cell migration
  • exert negative control of myogenesis through deacetylation and subsequent repression of MYOD1, particularly in association with the high NAD+ levels characteristic of myoblasts
  • may have a role in retinal neurogenesis in the downstream of NR2E1
  • positive regulator of Dvl proteins (not only regulates the levels of Dvl proteins but forms a complex with them)
  • controls key stages of spermatogenesis and germ stem cell expansion and function
  • involved in stem cell function by controlling cell fate decision and/or by regulating the TP53-dependent expression of NANOG
  • regulates the expression of specific developmental genes in pluripotent embryonic stem cells, and its down-regulation is necessary for correct establishment of specific differentiation programs during stem cell differentiation
  • SIRT1 regulates NER pathway through modulation of XPA acetylation status
  • plays an important role in mediating the repressive effect of NR0B2 specifically
  • involved, at least in part, in the NR0B2-mediated repression of NR5A2 transcriptional activity
  • plays a critical role in controlling SREBP-dependent gene regulation governing lipid/cholesterol homeostasis in metazoans in response to fasting cues
  • deacetylates and inhibits SREBPF1 transactivation by decreasing its stability and its occupancy at the lipogenic genes
  • enhances XPC expression by reducing AKT-dependent nuclear localization of the transcription repressor of XPC
  • plays a critical role in tumor-suppressing global genome-nucleotide excision repair, and down-regulation of SIRT1 is associated with human skin tumorigenesis
  • control of PML and PML nuclear bodies (
  • positive regulator of telomere length and attenuates telomere shortening associated with aging, an effect dependent on telomerase activity
  • primary roles for FOXO1 and SIRT1 in regulating the cellular responses of pancreatic beta-cells to nitric oxide
  • involved in facultative heterochromatin formation through an intimate functional relationship with the H3K9me3 methyltransferase SUV39H1, a chromatin organization protein
  • acts as an intrinsic negative modulator of NOTCH1 signalling in endothelial cells
  • negatively modulates DLL4/NOTCH1 signalling in endothelial cells
  • role in maintenance of chromosome stability in mitosis, suggesting how diminished SIRT1 activity during aging and tumorigenesis may lead to aneuploidy and genomic instability
  • regulates the activities of DNMT1, a key enzyme responsible for DNA methylation
  • plays a vital role in the regulation of hepatic bile acid homeostasis through the HNF1A/NR1H4 signaling pathway
  • suppresses differentiation of hematopoietic stem/progenitor cells and contributes to the maintenance of stem cell pool
  • key molecule in glucose metabolism, and has a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase activity
  • regulates self-renewal and differentiation of Hematopoietic stem cells (HSCs)
  • RRP8 is a nucleolar protein, important for mediating the assembly of the energy-dependent nucleolar silencing complex (eNoSC), which also contains SIRT1 and SUV39H1
  • negatively regulates GH-dependent IGF1 production in the liver
  • negatively regulates GH-induced IGF1 production via deacetylation of STAT5A, STAT5B in the liver, leading to GH resistance under fasting conditions
  • SIRT1 negatively regulates the protein stability of HIPK2
  • combination of SIRT1 activators and DOT1L inhibitors shows enhanced antiproliferative activity against KMT2A-rearranged leukemia cells
  • SIRT1 and SIRT2 are NAD(+)-dependent histone deacetylases that operate as post-translational regulators for the deacetylation of acetyllysine
  • HDAC4/5 and SIRT1 have all been shown to be regulated by ubiqutination-mediated proteasome pathways
    • CELLULAR PROCESS cell life, differentiation
    cell life, cell death/apoptosis
    cell life, senescence
    nucleotide, repair
    nucleotide, transcription, regulation
    protein, post translation
    PHYSIOLOGICAL PROCESS circadian
    text chromatin silencing protein ADP-ribosylation; myogenesis
    PATHWAY
    metabolism
    signaling
  • MAPK8-SIRT1 pathway provides a new molecular mechanism for the pathogenesis of hepatic steatosis in obesity
  • NR1D1 is a new intracellular regulator of glucagon secretion via AMPK/NAMPT/SIRT1 pathway
  • role of NAMPT/NAD+/SIRT1 pathway in the regulation of GADD45A expression by controlling the acetylation levels of FOXO3
    • a component
  • complexing with FOXO3 in cells in response to oxidative stress (increasing ability to induce cell cycle arrest and inhibiting ability to induce cell death)
  • its inhibition promotes neural progenitors toward motoneuron differentiation from human embryonic stem cells
  • SIRT1 and KDM1A interact directly and play conserved and concerted roles in H4K16 deacetylation and H3K4 demethylation to repress genes regulated by the Notch signaling pathway
  • function for SIRT1 in telomere maintenance of hepatocellular carcinomas
    • INTERACTION
    DNA
  • regulates the transcriptional activity of NF-kappaB
  • binds to and represses genes controlled by the fat regulator PPAR-gamma (peroxisome proliferator-activated receptor-gamma)
    • RNA
    small molecule metal binding, cofactor,
  • Zn2+
    • protein
  • TP53, negative regulator of TP53 capable of modulating cellular senescence
  • repressor of PPARG for promoting fat mobilization in white adipocytes
  • TAF1B
  • making a complex with PCAF and MYOD1
  • HES1 and HEY2
  • PML
  • interacting with the metabolic regulator and transcriptional coactivator PPARGC1A, (direct link between the sirtuins, a family of proteins linked to lifespan determination and PGC-1alpha, a coactivator that regulates cellular metabolism)
  • FOXO transcription factor FOXO3
  • histone cluster 1, H1c, HIST1H1C
  • EP300
  • interacting with SENP1 (desumoylation by SENP1, a nuclear desumoylase, reduced its deacetylase activity)
  • interacting directly with, recruits and deacetylates SUV39H1
  • KIAA1967
  • SIRT1 controls hepatic glucose metabolism by interacting with and deacetylating PGC1A, a key transcriptional coactivator that controls glucose metabolism in the liver at the level of gene transcription
  • CLOCK-ARNTL in a circadian manner
  • histone H1
  • deacetylated FOXO1 and inhibits its transcriptional activity
  • interacts with and deacetylates PGC-1alpha
  • forkhead box O1, FOXO1
  • forms a transcriptional repression complex with HIC1
  • induce endogenous androgen receptor (AR) expression and enhance DHT-mediated AR expression
  • a positive regulator of liver X receptor (LXR) proteins
  • associates with and deacetylates the forkhead transcription factor FOXO1, an essential negative regulator of blood vessel development to restrain its anti-angiogenic activity
  • Sirt1 represses PPAR-gamma by docking with its cofactors Ncor and Smrt
  • SIRT1 associated with the MRN (MRE11-RAD50-NBS1) complex in human cells via binding to NBS1
  • clock homolog (mouse), CLOCK
  • directly inhibits the transcriptional activity of AP-1 by targeting c-JUN
  • deacetylates cortactin in vivo and in vitro
  • FOXL2
  • p300/CBP-associated factor, PCAF
  • substrate for protein kinase CSNK2A1 (SIRT1 Ser-659 and Ser-661 are major CK2 phosphorylation sites)
  • DOT1-like, histone H3 methyltransferase (S. cerevisiae) DOT1 5
  • transactivated by NR2E1 via a NR2E1-activating element
  • Tat interacting protein 60kDa, TIP60
  • deactelyates APEX1 and thus plays a vital role in maintaining genomic integrity through the regulation of the base excision repair pathway
  • cJUN N-terminal kinase JNK1
  • NR0B2
  • interacts with XPA, and the interaction is enhanced after UV irradiation
  • interacts with telomeric repeats
  • physically associates with the human bHLH repressor proteins, HES1, and HEY2
  • role for SIRT1 in the regulation of GADD45A gene expression in response to nitric oxide
  • SIRT1 was found to interact with the MYST domain of KAT8 through the deacetylase catalytic region and deacetylate autoacetylated
  • SIRT1 corepressor complex containing the histone H3K4 demethylase KDM1A and several other KDM1A-associated proteins
  • EP300 and SIRT1 were recruited to histone gene promoters in an NPAT-dependent manner
  • mechanism of SIRT1 enzymatic control through the cAMP/PKA pathway with important implications for stress responses and maintenance of energy homeostasis
  • interplay between FOXO3, SIRT1 and GADD45A is the key for the modulation of several cellular processes, including response to extracellular stress, longevity, and tumor suppression
  • NDN required for neuronal development and survival, interacts with both SIRT1 and TP53 to facilitate TP53 deacetylation
  • SIRT1 deacetylation of the enzymatic domains of KAT8 and KAT5 inhibits their acetyltransferase activity and promotes ubiquitination-dependent degradation of these proteins
  • can regulate TP53 and NFKB1 activity via deacetylation
  • novel role for GATA4 and TAL1 to affect skeletal myogenic differentiation and EPO response via cross-talk with SIRT1
  • enhancement of SIRT1 activity in response to phagocytic stimuli may reduce the accessibility of REL to the IL12A promoter and its transcriptional activation, thus regulating the IL12 p70/IL12B balance and modulating the ongoing immune response
  • SIRT1 promotes cytoplasmic localization and proteasomal degradation of RFX5 and cripples promoter recruitment of RFX5
  • SIRT1 influences RFX5-mediated repression of COL1A2 transcription by excluding RFX5 from the nucleus and promoting RFX5 degradation
  • RETN impairs SIRT1 function and induces senescence-associated phenotype in hepatocytes
  • CARM1 represses replicative senescence by methylating ELAVL1 and thereby enhancing ELAVL1 ability to regulate the turnover of CCNA1, CCNB1, FOS, SIRT1, and CDKN2A mRNAs (
  • RRP8-SIRT1 interaction was competitively inhibited by rRNA
  • negatively regulates GH-induced STAT5A, STAT5B phosphorylation and IGF1 production via deacetylation of STAT5A, STAT5B in the liver
  • KAT8 binding and acetylation of CCAR2 are inhibited after DNA damage in an ATM-dependent fashion, contributing to increased SIRT1-CCAR2 binding after DNA damage
  • SIRT1, SIRT2, positively regulate the levels of TIAM1, a Rac guanine nucleotide exchange factor (GEF)
  • FOXO3 functions downstream of SIRT1 and prevents the induction of cellular senescence by enhancing TERT gene expression
  • NAMPT protects the heart from ischemia and reperfusion injury by stimulating SIRT1
  • inactivation of CHEK2 reduces CCAR2-SIRT1 binding, thus preventing TP53 acetylation and CCAR2-induced apoptosis
  • SIRT1-RELB induction of mitochondrial biogenesis included increases in mitochondrial mass, mitochondrial-to-nuclear DNA ratios, and both nuclear and mitochondrial encoded proteins
  • SIRT1 increases RORC transcriptional activity, enhancing Th17 cell generation and function
  • ATP6V1B2 is a molecular target of SIRT1 in fat cells
  • reduced UCP1 expression under inflammation is mediated by the increased expression of CCAR2, which inhibits SIRT1 activity
  • CACUL1 tightly regulates PPARG signaling through the mutual opposition between SIRT1 and KDM1A, providing insight into its potential use for anti-obesity treatment
  • SIRT1 and NQO1 form likely a regulatory loop where SIRT1 regulates NQO1 expression and NQO1 binds and mediates the protective role of SIRT1 during mitochondrial stress
    • cell & other
    REGULATION
    activated by food deprivation to trigger fat mobilization in white adipocytes
    butein
    resveratrol
    piceatannol
    isoliquiritigenin
    fisetin
    quercetin
    AMPK
    polyphenol
    induced by reduced energy intake in in the brain
    inhibited by nicotinamide
    KIAA1967
    DBC1
    nicotinamide and sirtinol
    sirtinol (Sir two inhibitor napthol)
    Phosphorylated by MAPK8 (phosphorylates SIRT1 and induces SIRT1 activation, which is followed by ubiquitination and degradation of SIRT1)
    Other sumoylation regulates its deacetylase activity and cellular response to genotoxic stress
    regulation of the NAD(+)-dependent HDAC activity, in a circadian manner
    regulated during stem cell differentiation in the context of a yet-unknown epigenetic pathway that controls specific developmental genes in embryonic stem cells
    phosphorylated by JNK1
    its deacetylase activity is strictly modulated by resveratrol and nicotinamide
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    by various biological stresses, including caloric restriction, which has been shown to prevent numerous diseases of aging such as Alzheimer's
    constitutional       gain of function
    decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells
    constitutional     --over  
    might extend lifespan by decreasing fat storage
    constitutional     --over  
    in the vasculature during blood vessel growth, where it controls the angiogenic activity of endothelial cells
    constitutional     --low  
    precisely during human embryonic stem cell differentiation at both mRNA and protein levels
    constitutional     --low  
    promotes activation of the oncogenic AKT pathway to mediate XPC down-regulation
    tumoral     --over  
    overexpressed in hepatocellular carcinomas (HCC) cell lines and in a subset of HCC
    constitutional       loss of function
    its activity is reduced in liver and adipose tissue in response to obesity
    tumoral     --over  
    with overexpression of KIAA1967 is associated with poor prognosis of gastric carcinoma
    Susceptibility
  • to obesity in men
  • to ventricular septal defects (VSD)
  • to Parkinson disease (PD)
    • Variant & Polymorphism other
  • genetic variation in SIRT1 increases the risk for obesity, and SIRT1 genotype correlates with visceral obesity parameters in obese men
  • variants within the SIRT1 gene promoter identified in VSD patients may alter the transcriptional activities of SIRT1 gene promoter
  • genetic variants within the SIRT1 gene promoter may repress SIRT1 gene expression, contributing to PD
    • Candidate gene manipulation of Sirt1 can be a plausible therapeutic target molecule in the treatment of renal tubular damages
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerreproductiveovary
    SIRT1 inhibition by nicotinamide reduces proliferation of granulosa tumor cells (both OGCT-derived cell lines and primary explanted OGCT cells) by increasing the amount/activity of endogenous FOXL2, which provides a therapeutic lead
    neurologyneurodegenerative 
    promising avenue for therapeutic intervention in neurodegenerative disorders
    neurologyneurodegenerativealzheimer
    therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease
    cancer  
    inhibitors for SIRT1 may have anticancer potential,(impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol, with attenuated Ras-MAPK signaling in cancer cells)
    diabete  
    therapeutics targeting of SIRT1 might provide novel approaches to the treatment of endocrine-related clinical conditions such as obesity, insulin resistance syndromes, and diabetes
    osteoarticular  
    up-regulation of Sirt-1 appears to be an important consequence of resveratrol on tenocytes and may be useful in the development of future therapies for the treatment of tendinitis
    immunologyautoimmune 
    possible therapeutic use of SIRT1 inhibitors against autoimmunity
    ANIMAL & CELL MODELS
  • SIRT1 is not only induced in mouse models of neurodegeneration but also in primary cultured neurons under neurotoxic stresses
  • Sir2-alpha null mice smaller at birth and died during the early postnatal period
  • Disruption of Sirt1 expression in zebrafish and mice resulted in defective blood vessel formation and blunted ischemia-induced neovascularization
  • Sirt1-deficient mice are reported to exhibit severe neural defects, including exencephaly and disturbed neuroretinal morphogenesis
  • Sirt1 knockdown in mIMCD3 cells enhanced alpha-ENaC mRNA levels and alpha-ENaC promoter activity, and inhibited global H3K79 methylation, particularly H3K79 trimethylation, in chromatin associated with the alpha-ENaC promoter
  • mouse embryo fibroblasts lacking SIRT1 contain reduced PML protein levels (