Q923E4 (SIRT1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
NAD-dependent deacetylase sirtuin-1
EC=3.5.1.-

Alternative name(s):
SIR2-like protein 1
SIR2alpha
Short name=Sir2
Short name=mSIR2a

Cleaved into the following chain:

1. SirtT1 75 kDa fragment
   Short name=75SirT1

Gene names

Name:	Sirt1
Synonyms:	Sir2l1

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	737 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metobolism, apoptosis and autophagy. Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD+/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD+/NADP+ ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor acivity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, FOXO1, KAT5/TIP60, RB1 and HIC1. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A-mediated transcription. Required for the repression of ESRRG by CREBZF. Modulates AP-1 transcription factor activity. Deacetylates NR1H3 AND NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates ACSS2 leading to its activation, and HMGCS1. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in nuclear location and activation of FOXO1 leading to increased gluconeogenesis in liver. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insuline-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-537' and 'Lys-540' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1-dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transacivation and contributes to its stability. Deacteylates MECOM/EVI1. Isoform 2 is shown to deacetylate 'Lys-382' of p53/TP53, however with lower activity than isoform 1. In combination, the two isoforms exert an additive effect. Isoform 2 regulates p53/TP53 expression and cellular stress response and is in turn repressed by p53/TP53 presenting a SIRT1 isoform-dependent auto-regulatory loop. Ref.3 Ref.4 Ref.5 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Ref.20 Ref.21 Ref.22 Ref.23 Ref.24 Ref.26 Ref.27 Ref.28 Ref.30 Ref.32 Ref.33 Ref.36 Ref.37 Ref.42 Ref.43 SirtT1 75 kDa fragment: catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly By similarity. Ref.3 Ref.4 Ref.5 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17 Ref.18 Ref.20 Ref.21 Ref.22 Ref.23 Ref.24 Ref.26 Ref.27 Ref.28 Ref.30 Ref.32 Ref.33 Ref.36 Ref.37 Ref.42 Ref.43
Catalytic activity	NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein.
Cofactor	Binds 1 zinc ion per subunit By similarity.
Enzyme regulation	Activated by resveratrol (3,5,4'-trihydroxy-trans-stilbene), butein (3,4,2',4'-tetrahydroxychalcone), piceatannol (3,5,3',4'-tetrahydroxy-trans-stilbene), Isoliquiritigenin (4,2',4'-trihydroxychalcone), fisetin (3,7,3',4'-tetrahydroxyflavone) and quercetin (3,5,7,3',4'-pentahydroxyflavone). MAPK8/JNK1 and RPS19BP1/AROS act as positive regulators of deacetylation activity By similarity. Inhibited by nicotinamide. Negatively regulated by KIAA1967 By similarity. Ref.3
Subunit structure	Found in a complex with PCAF and MYOD1 By similarity. Component of the eNoSC complex, composed of SIRT1, SUV39H1 and RRP8. Interacts with HES1, HEY2 and PML. Interacts with RPS19BP1/AROS. Interacts with KIAA1967/DBC1 (via N-terminus); the interaction disrupts the interaction between SIRT1 and p53/TP53. Interacts with SETD7; the interaction induces the dissociation of SIRT1 from p53/TP53 and increases p53/TP53 activity. Interacts with MYCN, NR1I2, CREBZF, TSC2, TLE1, FOS, JUN, NR0B2, PPARG, NCOR, IRS1, IRS2 and NMNAT1. Interacts with HNF1A; the interaction occurs under nutrient restriction. Interacts with SUZ12; the interaction mediates the association with the PRC4 histone methylation complex which is specific as an association with PCR2 and PCR3 complex variants is not found By similarity. Ref.3 Ref.7 Ref.9 Ref.14 Ref.20 Ref.26 Ref.33 Ref.34 Ref.40 Ref.42
Subcellular location	Nucleus › PML body. Cytoplasm By similarity. Note: Recruited to the nuclear bodies via its interaction with PML. Colocalized with APEX1 in the nucleus. May be found in nucleolus, nuclear euchromatin, heterochromatin and inner membrane. Shuttles between nucleus and cytoplasm By similarity. Ref.25 Ref.26 Ref.27 SirtT1 75 kDa fragment: Cytoplasm By similarity. Mitochondrion By similarity Ref.25 Ref.26 Ref.27.
Tissue specificity	Widely expressed. Weakly expressed in liver and skeletal muscle. Ref.6
Induction	By calorie restriction which induces endothelial nitric oxide synthase (eNOS) expression. Induced in liver by pyruvate during fasting. Ref.3 Ref.10 Ref.11 Ref.15 Ref.17 Ref.18 Ref.19 Ref.21 Ref.23 Ref.30 Ref.33 Ref.36
Post-translational modification	Phosphorylated. Phosphorylated by STK4/MST1, resulting in inhibition of SIRT1-mediated p53/TP53 deacetylation. Phosphorylation by MAPK8/JNK1 at Ser-46 and Thr-522 leads to increased nuclear localization and enzymatic activity. Phosphorylation at Thr-522 by DYRK1A and DYRK3 acivates deacetylase activity and promotes cell survival. Phosphorylation by mammalian target of rapamycin complex 1 (mTORC1) at Ser-46 inhibits deacetylation activity. Phosphorylated by CaMK2, leading to increased p53/TP53 and NF-kappa-B p65/RELA deacetylation activity By similarity. Ref.35 Ref.38 Proteolytically cleaved by cathepsin B upon TNF-alpha treatment to yield catalytic inactive but stable SirtT1 75 kDa fragment (75SirT1) By similarity. S-nitrosylated by GAPDH, leading to inhibit the NAD-dependent protein deacetylase activity.
Disruption phenotype	High degeree of embryonic and postnatal lethality. Decreased levels of histone H3 containing a trimethyl group at its lysine 9 position (H3K9me3) in regions of heterochromatin. Attenuates spermatogenesis but not oogenesis with reduced numbers of mature sperm and spermatogenic precursors. Mice develop an autoimmune-like condition with late onset diabetes insipidus. Prostatic intraepithelial neoplasia associated with reduced autophagy. Ref.6 Ref.27 Ref.29 Ref.31 Ref.43
Sequence similarities	Belongs to the sirtuin family. Contains 1 deacetylase sirtuin-type domain.

Ontologies

Keywords
Biological process	Apoptosis Differentiation Myogenesis Transcription Transcription regulation rRNA processing
Cellular component	Cytoplasm Mitochondrion Nucleus
Coding sequence diversity	Alternative splicing
Ligand	Metal-binding NAD Zinc
Molecular function	Developmental protein Hydrolase
PTM	Acetylation Phosphoprotein S-nitrosylation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Uncategorized	regulation of transcription from RNA polymerase II promoter by nuclear hormone receptor Inferred from mutant phenotype. Source: BHF-UCL
Biological process	DNA damage response, signal transduction by p53 class mediator resulting in induction of apoptosis Inferred from sequence or structural similarity. Source: UniProtKB DNA synthesis involved in DNA repair Inferred from mutant phenotype. Source: UniProtKB angiogenesis Inferred from sequence or structural similarity. Source: UniProtKB apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cellular glucose homeostasis Inferred from mutant phenotype Ref.18. Source: UniProtKB cellular response to hypoxia Inferred from sequence or structural similarity. Source: UniProtKB cellular response to ionizing radiation Inferred from mutant phenotype. Source: UniProtKB cellular response to starvation Inferred from mutant phenotype Ref.9. Source: BHF-UCL cellular response to tumor necrosis factor Inferred from sequence or structural similarity. Source: UniProtKB fatty acid homeostasis Inferred from mutant phenotype Ref.23. Source: UniProtKB muscle organ development Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of NF-kappaB transcription factor activity Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of fat cell differentiation Inferred from mutant phenotype Ref.9. Source: BHF-UCL negative regulation of peptidyl-lysine acetylation Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of phosphorylation Inferred from mutant phenotype. Source: UniProtKB negative regulation of protein kinase B signaling cascade Inferred from mutant phenotype. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: UniProtKB ovulation from ovarian follicle Inferred from mutant phenotype Ref.6. Source: MGI positive regulation of DNA repair Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of anti-apoptosis Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of cell proliferation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of macroautophagy Inferred from direct assay Ref.32Ref.43. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay Ref.13. Source: UniProtKB proteasomal ubiquitin-dependent protein catabolic process Inferred from sequence or structural similarity. Source: UniProtKB protein ubiquitination Inferred from sequence or structural similarity. Source: UniProtKB pyrimidine dimer repair by nucleotide-excision repair Inferred from mutant phenotype. Source: UniProtKB rRNA processing Inferred from electronic annotation. Source: UniProtKB-KW regulation of endodeoxyribonuclease activity Inferred from sequence or structural similarity. Source: UniProtKB regulation of glucose metabolic process Inferred from mutant phenotype Ref.23. Source: UniProtKB regulation of mitotic cell cycle Inferred from sequence or structural similarity. Source: UniProtKB single strand break repair Inferred from sequence or structural similarity. Source: UniProtKB spermatogenesis Inferred from mutant phenotype Ref.6. Source: MGI transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW triglyceride mobilization Inferred from mutant phenotype Ref.9. Source: BHF-UCL white fat cell differentiation Inferred from mutant phenotype Ref.9. Source: BHF-UCL
Cellular component	PML body Inferred from electronic annotation. Source: UniProtKB-SubCell cytoplasm Inferred from direct assay Ref.25. Source: UniProtKB nuclear euchromatin Inferred from sequence or structural similarity. Source: UniProtKB nuclear heterochromatin Inferred from direct assay Ref.27. Source: UniProtKB nuclear inner membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	NAD+ binding Inferred from electronic annotation. Source: InterPro NAD-dependent histone deacetylase activity (H3-K9 specific) Inferred from direct assay Ref.39. Source: UniProtKB bHLH transcription factor binding Inferred from sequence or structural similarity. Source: UniProtKB enzyme binding Inferred from physical interaction Ref.39. Source: UniProtKB p53 binding Inferred from physical interaction Ref.3. Source: BHF-UCL protein domain specific binding Inferred from physical interaction Ref.9. Source: BHF-UCL transcription corepressor activity Inferred from mutant phenotype Ref.9. Source: BHF-UCL zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Clock	O08785	11	EBI-1802585,EBI-79859
Dyrk1a	Q61214	4	EBI-1802585,EBI-80344
Dyrk3	Q922Y0	7	EBI-1802585,EBI-5242007
E2F1	Q01094	3	EBI-1802585,EBI-448924	From a different organism.
Ppargc1a	O70343	3	EBI-1802585,EBI-1371053
RB1	P06400	4	EBI-1802585,EBI-491274	From a different organism.
RBL1	P28749	2	EBI-1802585,EBI-971402	From a different organism.
RBL2	Q08999	2	EBI-1802585,EBI-971439	From a different organism.
TP53	P04637	4	EBI-1802585,EBI-366083	From a different organism.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q923E4-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q923E4-2)

Also known as: delta-exon8;

The sequence of this isoform differs from the canonical sequence as follows:
     446-629: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed By similarity
	Chain	2 – 737	736	NAD-dependent deacetylase sirtuin-1		PRO_0000110257
	Chain	2 – 525	524	SirtT1 75 kDa fragment By similarity		PRO_0000415290
Regions
	Domain	236 – 490	255	Deacetylase sirtuin-type
	Nucleotide binding	253 – 272	20	NAD By similarity
	Nucleotide binding	337 – 341	5	NAD By similarity
	Region	2 – 268	267	Interaction with HIST1H1E
	Motif	32 – 39	8	Nuclear localization signal
	Motif	138 – 145	8	Nuclear export signal
	Motif	223 – 230	8	Nuclear localization signal
	Motif	425 – 431	7	Nuclear export signal
	Compositional bias	2 – 131	130	Ala-rich
	Compositional bias	155 – 158	4	Poly-Asp
Sites
	Active site	355	1	Proton acceptor
	Metal binding	363	1	Zinc By similarity
	Metal binding	366	1	Zinc By similarity
	Metal binding	387	1	Zinc By similarity
	Metal binding	390	1	Zinc By similarity
Amino acid modifications
	Modified residue	2	1	N-acetylalanine By similarity
	Modified residue	14	1	Phosphoserine By similarity
	Modified residue	16	1	Phosphoserine By similarity
	Modified residue	25	1	Phosphoserine By similarity
	Modified residue	46	1	Phosphoserine; by MAPK8 By similarity
	Modified residue	387	1	S-nitrosocysteine Ref.39
	Modified residue	390	1	S-nitrosocysteine Ref.39
	Modified residue	522	1	Phosphothreonine; by DYRK1A, DYRK3 and MAPK8 Ref.38
	Modified residue	527	1	Phosphoserine By similarity
	Modified residue	649	1	Phosphoserine; by CaMK2 Ref.35
	Modified residue	651	1	Phosphoserine; by CaMK2 By similarity
Natural variations
	Alternative sequence	446 – 629	184	Missing in isoform 2.		VSP_042190
Experimental info
	Mutagenesis	37 – 38	2	RR → AA: Abolishes nuclear localization; when associated with A-227; A-228; A-229 and A-230.
	Mutagenesis	138 – 145	8	LLLTDGLL → AAATGAA: Abolishes nuclear export; when associated with A-425; A-427; A-428; A-429; A-430 and A-431.
	Mutagenesis	154	1	S → A: Abolishes in vitro phosphorylation by CaMK2; when associated with A-649; A-651 and A-683. Ref.35
	Mutagenesis	227 – 230	4	KKRK → AAAA: Abolishes nuclear localization; when associated with A-37 and A-38. Ref.25
	Mutagenesis	355	1	H → Y: Loss of function. Loss of E2F1 inhibition. Ref.3 Ref.7 Ref.20
	Mutagenesis	363	1	C → S: Does not affect S-nitrosylation. Ref.39
	Mutagenesis	366	1	C → S: Does not affect S-nitrosylation. Ref.39
	Mutagenesis	387	1	C → S: Impairs S-nitrosylation. Abolishes S-nitrosylation; when associated with S-390. Ref.39
	Mutagenesis	390	1	C → S: Impairs S-nitrosylation. Abolishes S-nitrosylation; when associated with S-387. Ref.39
	Mutagenesis	425 – 431	7	VDLLIVI → ADAAAAA: Abolishes nuclear export; when associated with A-138; A-139; A-140; A-144 and A-145. Ref.25
	Mutagenesis	522	1	T → D: Increased deactetylase activity toward p53/TP53 and increases restistance to genotoxic stress (mimicks residue phosphorylation).
	Mutagenesis	522	1	T → V: Reduces phosphorylation. Impairs deactetylase activity toward p53/TP53 and decreases restistance to genotoxic stress.
	Mutagenesis	649	1	S → A: Abolishes in vitro phosphorylation by CaMK2; when associated with A-154; A-651 and A-683. Ref.35
	Mutagenesis	651	1	S → A: Abolishes in vitro phosphorylation by CaMK2; when associated with A-154; A-649 and A-683. Ref.35
	Mutagenesis	683	1	S → A: Abolishes in vitro phosphorylation by CaMK2; when associated with A-154; A-649 and A-651. Ref.35

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 31, 2003. Version 2. Checksum: 7F15625E29433119	FASTA	737	80,372
	10 20 30 40 50 60 MADEVALALQ AAGSPSAAAA MEAASQPADE PLRKRPRRDG PGLGRSPGEP SAAVAPAAAG 70 80 90 100 110 120 CEAASAAAPA ALWREAAGAA ASAEREAPAT AVAGDGDNGS GLRREPRAAD DFDDDEGEEE 130 140 150 160 170 180 DEAAAAAAAA AIGYRDNLLL TDGLLTNGFH SCESDDDDRT SHASSSDWTP RPRIGPYTFV 190 200 210 220 230 240 QQHLMIGTDP RTILKDLLPE TIPPPELDDM TLWQIVINIL SEPPKRKKRK DINTIEDAVK 250 260 270 280 290 300 LLQECKKIIV LTGAGVSVSC GIPDFRSRDG IYARLAVDFP DLPDPQAMFD IEYFRKDPRP 310 320 330 340 350 360 FFKFAKEIYP GQFQPSLCHK FIALSDKEGK LLRNYTQNID TLEQVAGIQR ILQCHGSFAT 370 380 390 400 410 420 ASCLICKYKV DCEAVRGDIF NQVVPRCPRC PADEPLAIMK PEIVFFGENL PEQFHRAMKY 430 440 450 460 470 480 DKDEVDLLIV IGSSLKVRPV ALIPSSIPHE VPQILINREP LPHLHFDVEL LGDCDVIINE 490 500 510 520 530 540 LCHRLGGEYA KLCCNPVKLS EITEKPPRPQ KELVHLSELP PTPLHISEDS SSPERTVPQD 550 560 570 580 590 600 SSVIATLVDQ ATNNNVNDLE VSESSCVEEK PQEVQTSRNV ENINVENPDF KAVGSSTADK 610 620 630 640 650 660 NERTSVAETV RKCWPNRLAK EQISKRLEGN QYLFVPPNRY IFHGAEVYSD SEDDVLSSSS 670 680 690 700 710 720 CGSNSDSGTC QSPSLEEPLE DESEIEEFYN GLEDDTERPE CAGGSGFGAD GGDQEVVNEA 730 IATRQELTDV NYPSDKS
	Isoform 2 (delta-exon8) [UniParc]. Checksum: 3426394C5CF062E9	FASTA	553	59,875
	10 20 30 40 50 60 MADEVALALQ AAGSPSAAAA MEAASQPADE PLRKRPRRDG PGLGRSPGEP SAAVAPAAAG 70 80 90 100 110 120 CEAASAAAPA ALWREAAGAA ASAEREAPAT AVAGDGDNGS GLRREPRAAD DFDDDEGEEE 130 140 150 160 170 180 DEAAAAAAAA AIGYRDNLLL TDGLLTNGFH SCESDDDDRT SHASSSDWTP RPRIGPYTFV 190 200 210 220 230 240 QQHLMIGTDP RTILKDLLPE TIPPPELDDM TLWQIVINIL SEPPKRKKRK DINTIEDAVK 250 260 270 280 290 300 LLQECKKIIV LTGAGVSVSC GIPDFRSRDG IYARLAVDFP DLPDPQAMFD IEYFRKDPRP 310 320 330 340 350 360 FFKFAKEIYP GQFQPSLCHK FIALSDKEGK LLRNYTQNID TLEQVAGIQR ILQCHGSFAT 370 380 390 400 410 420 ASCLICKYKV DCEAVRGDIF NQVVPRCPRC PADEPLAIMK PEIVFFGENL PEQFHRAMKY 430 440 450 460 470 480 DKDEVDLLIV IGSSLKVRPV ALIPSNQYLF VPPNRYIFHG AEVYSDSEDD VLSSSSCGSN 490 500 510 520 530 540 SDSGTCQSPS LEEPLEDESE IEEFYNGLED DTERPECAGG SGFGADGGDQ EVVNEAIATR 550 QELTDVNYPS DKS

References

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[1]	"Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase." Imai S., Armstrong C.M., Kaeberlein M., Guarente L. Nature 403:795-800(2000) [PubMed: 10693811] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Swiss Webster / NIH.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 545-737. Tissue: Mammary tumor.
[3]	"Negative control of p53 by Sir2alpha promotes cell survival under stress." Luo J., Nikolaev A.Y., Imai S., Chen D., Su F., Shiloh A., Guarente L., Gu W. Cell 107:137-148(2001) [PubMed: 11672522] [Abstract] Cited for: FUNCTION, INTERACTION WITH TP53, ENZYME REGULATION, MUTAGENESIS OF HIS-355.
[4]	"Acetylation of TAF(I)68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription." Muth V., Nadaud S., Grummt I., Voit R. EMBO J. 20:1353-1362(2001) [PubMed: 11250901] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF TAF1B.
[5]	"The absence of SIR2alpha protein has no effect on global gene silencing in mouse embryonic stem cells." McBurney M.W., Yang X., Jardine K., Bieman M., Th'ng J., Lemieux M. Mol. Cancer Res. 1:402-409(2003) [PubMed: 12651913] [Abstract] Cited for: FUNCTION.
[6]	"The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis." McBurney M.W., Yang X., Jardine K., Hixon M., Boekelheide K., Webb J.R., Lansdorp P.M., Lemieux M. Mol. Cell. Biol. 23:38-54(2003) [PubMed: 12482959] [Abstract] Cited for: TISSUE SPECIFICITY, DISRUPTION PHENOTYPE.
[7]	"Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state." Fulco M., Schiltz R.L., Iezzi S., King M.T., Zhao P., Kashiwaya Y., Hoffman E., Veech R.L., Sartorelli V. Mol. Cell 12:51-62(2003) [PubMed: 12887892] [Abstract] Cited for: FUNCTION, INTERACTION WITH MYOD1 AND PCAF, MUTAGENESIS OF HIS-355.
[8]	"Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice." Cheng H.-L., Mostoslavsky R., Saito S., Manis J.P., Gu Y., Patel P., Bronson R., Appella E., Alt F.W., Chua K.F. Proc. Natl. Acad. Sci. U.S.A. 100:10794-10799(2003) [PubMed: 12960381] [Abstract] Cited for: FUNCTION.
[9]	"Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma." Picard F., Kurtev M., Chung N., Topark-Ngarm A., Senawong T., Machado De Oliveira R., Leid M., McBurney M.W., Guarente L. Nature 429:771-776(2004) [PubMed: 15175761] [Abstract] Cited for: FUNCTION IN ADIPODIGENESIS, FUNCTION IN FAT MOBILIZATION, INTERACTION WITH PPARG AND NCOR1.
[10]	"Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases." Hallows W.C., Lee S., Denu J.M. Proc. Natl. Acad. Sci. U.S.A. 103:10230-10235(2006) [PubMed: 16790548] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF ACSS2, FUNCTION IN REGULATION OF ACCS2.
[11]	"SIRT1 deacetylates and positively regulates the nuclear receptor LXR." Li X., Zhang S., Blander G., Tse J.G., Krieger M., Guarente L. Mol. Cell 28:91-106(2007) [PubMed: 17936707] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF NR1H3 AND NR1H2, FUNCTION IN REGULATION OF NR1H3.
[12]	"SIRT1 regulates apoptosis and Nanog expression in mouse embryonic stem cells by controlling p53 subcellular localization." Han M.K., Song E.K., Guo Y., Ou X., Mantel C., Broxmeyer H.E. Cell Stem Cell 2:241-251(2008) [PubMed: 18371449] [Abstract] Cited for: FUNCTION IN APOPTOSIS.
[13]	"Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity." Daitoku H., Hatta M., Matsuzaki H., Aratani S., Ohshima T., Miyagishi M., Nakajima T., Fukamizu A. Proc. Natl. Acad. Sci. U.S.A. 101:10042-10047(2004) [PubMed: 15220471] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF FOXO1.
[14]	"Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses." Chen W.Y., Wang D.H., Yen R.C., Luo J., Gu W., Baylin S.B. Cell 123:437-448(2005) [PubMed: 16269335] [Abstract] Cited for: INTERACTION WITH HIC1.
[15]	"Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice." Moynihan K.A., Grimm A.A., Plueger M.M., Bernal-Mizrachi E., Ford E., Cras-Meneur C., Permutt M.A., Imai S. Cell Metab. 2:105-117(2005) [PubMed: 16098828] [Abstract] Cited for: FUNCTION IN REGULATION OF INSULIN SECRETION.
[16]	"SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1." Bouras T., Fu M., Sauve A.A., Wang F., Quong A.A., Perkins N.D., Hay R.T., Gu W., Pestell R.G. J. Biol. Chem. 280:10264-10276(2005) [PubMed: 15632193] [Abstract] Cited for: FUNCTION.
[17]	"Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes." Frescas D., Valenti L., Accili D. J. Biol. Chem. 280:20589-20595(2005) [PubMed: 15788402] [Abstract] Cited for: FUNCTION IN REGULATION OF FOXO1.
[18]	"Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1." Rodgers J.T., Lerin C., Haas W., Gygi S.P., Spiegelman B.M., Puigserver P. Nature 434:113-118(2005) [PubMed: 15744310] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF PPARGC1A, FUNCTION IN REGULATION OF GLUCOSE HOMEOSTASIS, INDUCTION.
[19]	"Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS." Nisoli E., Tonello C., Cardile A., Cozzi V., Bracale R., Tedesco L., Falcone S., Valerio A., Cantoni O., Clementi E., Moncada S., Carruba M.O. Science 310:314-317(2005) [PubMed: 16224023] [Abstract] Cited for: INDUCTION.
[20]	"Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage." Wang C., Chen L., Hou X., Li Z., Kabra N., Ma Y., Nemoto S., Finkel T., Gu W., Cress W.D., Chen J. Nat. Cell Biol. 8:1025-1031(2006) [PubMed: 16892051] [Abstract] Cited for: FUNCTION, INTERACTION WITH E2F1, MUTAGENESIS OF HIS-355.
[21]	"Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells." Bordone L., Motta M.C., Picard F., Robinson A., Jhala U.S., Apfeld J., McDonagh T., Lemieux M., McBurney M., Szilvasi A., Easlon E.J., Lin S.J., Guarente L. PLoS Biol. 4:E31-E31(2006) [PubMed: 16366736] [Abstract] Cited for: FUNCTION IN REGULATION OF INSULIN SECRETION.
[22]	"Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1." Wong S., Weber J.D. Biochem. J. 407:451-460(2007) [PubMed: 17620057] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF RB1.
[23]	"Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha." Gerhart-Hines Z., Rodgers J.T., Bare O., Lerin C., Kim S.H., Mostoslavsky R., Alt F.W., Wu Z., Puigserver P. EMBO J. 26:1913-1923(2007) [PubMed: 17347648] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF PPARGC1A, FUNCTION IN REGULATION OF MUSCLE METABOLISM.
[24]	"SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylation." Kume S., Haneda M., Kanasaki K., Sugimoto T., Araki S., Isshiki K., Isono M., Uzu T., Guarente L., Kashiwagi A., Koya D. J. Biol. Chem. 282:151-158(2007) [PubMed: 17098745] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF SMAD7.
[25]	"Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1." Tanno M., Sakamoto J., Miura T., Shimamoto K., Horio Y. J. Biol. Chem. 282:6823-6832(2007) [PubMed: 17197703] [Abstract] Cited for: SUBCELLULAR LOCATION, MUTAGENESIS OF 38-ARG-ARG-39; 138-LEU--LEU-145; 227-LYS--LYS-230 AND 425-VAL--ILE-431.
[26]	"The direct involvement of SirT1 in insulin-induced insulin receptor substrate-2 tyrosine phosphorylation." Zhang J. J. Biol. Chem. 282:34356-34364(2007) [PubMed: 17901049] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH IRS1 AND IRS2.
[27]	"SIRT1 regulates the histone methyl-transferase SUV39H1 during heterochromatin formation." Vaquero A., Scher M., Erdjument-Bromage H., Tempst P., Serrano L., Reinberg D. Nature 450:440-444(2007) [PubMed: 18004385] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE.
[28]	"Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt." Fulco M., Cen Y., Zhao P., Hoffman E.P., McBurney M.W., Sauve A.A., Sartorelli V. Dev. Cell 14:661-673(2008) [PubMed: 18477450] [Abstract] Cited for: FUNCTION.
[29]	"sirt1-null mice develop an autoimmune-like condition." Sequeira J., Boily G., Bazinet S., Saliba S., He X., Jardine K., Kennedy C., Staines W., Rousseaux C., Mueller R., McBurney M.W. Exp. Cell Res. 314:3069-3074(2008) [PubMed: 18687325] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[30]	"SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation." Lan F., Cacicedo J.M., Ruderman N., Ido Y. J. Biol. Chem. 283:27628-27635(2008) [PubMed: 18687677] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF STK11, FUNCTION IN POSSIBLE REGULATION OF STK11.
[31]	"Sirt1 deficiency attenuates spermatogenesis and germ cell function." Coussens M., Maresh J.G., Yanagimachi R., Maeda G., Allsopp R. PLoS ONE 3:E1571-E1571(2008) [PubMed: 18270565] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[32]	"A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy." Lee I.H., Cao L., Mostoslavsky R., Lombard D.B., Liu J., Bruns N.E., Tsokos M., Alt F.W., Finkel T. Proc. Natl. Acad. Sci. U.S.A. 105:3374-3379(2008) [PubMed: 18296641] [Abstract] Cited for: FUNCTION IN AUTOPHAGY.
[33]	"Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation." Purushotham A., Schug T.T., Xu Q., Surapureddi S., Guo X., Li X. Cell Metab. 9:327-338(2009) [PubMed: 19356714] [Abstract] Cited for: FUNCTION IN REGULATION OF PPARA, INTERACTION WITH PPARA.
[34]	"Enzymes in the NAD+ salvage pathway regulate SIRT1 activity at target gene promoters." Zhang T., Berrocal J.G., Frizzell K.M., Gamble M.J., DuMond M.E., Krishnakumar R., Yang T., Sauve A.A., Kraus W.L. J. Biol. Chem. 284:20408-20417(2009) [PubMed: 19478080] [Abstract] Cited for: INTERACTION WITH NMNAT1.
[35]	"CK2 is the regulator of SIRT1 substrate-binding affinity, deacetylase activity and cellular response to DNA-damage." Kang H., Jung J.W., Kim M.K., Chung J.H. PLoS ONE 4:E6611-E6611(2009) [PubMed: 19680552] [Abstract] Cited for: PHOSPHORYLATION AT SER-649, MUTAGENESIS OF SER-154; SER-649; SER-651 AND SER-683.
[36]	"SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism." Ponugoti B., Kim D.H., Xiao Z., Smith Z., Miao J., Zang M., Wu S.Y., Chiang C.M., Veenstra T.D., Kemper J.K. J. Biol. Chem. 285:33959-33970(2010) [PubMed: 20817729] [Abstract] Cited for: FUNCTION IN DEACETYLATION OF SREBF1, FUNCTION IN REGULATION OF SREBF1.
[37]	"SIRT1 contributes to telomere maintenance and augments global homologous recombination." Palacios J.A., Herranz D., De Bonis M.L., Velasco S., Serrano M., Blasco M.A. J. Cell Biol. 191:1299-1313(2010) [PubMed: 21187328] [Abstract] Cited for: FUNCTION IN TELOMERE MAINTENANCE.
[38]	"DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1." Guo X., Williams J.G., Schug T.T., Li X. J. Biol. Chem. 285:13223-13232(2010) [PubMed: 20167603] [Abstract] Cited for: PHOSPHORYLATION AT THR-522, MUTAGENEIS OF THR-522.
[39]	"GAPDH mediates nitrosylation of nuclear proteins." Kornberg M.D., Sen N., Hara M.R., Juluri K.R., Nguyen J.V., Snowman A.M., Law L., Hester L.D., Snyder S.H. Nat. Cell Biol. 12:1094-1100(2010) [PubMed: 20972425] [Abstract] Cited for: S-NITROSYLATION AT CYS-387 AND CYS-390, MUTAGENESIS OF CYS-363; CYS-366; CYS-387 AND CYS-390.
[40]	"KRIT1 regulates the homeostasis of intracellular reactive oxygen species." Goitre L., Balzac F., Degani S., Degan P., Marchi S., Pinton P., Retta S.F. PLoS ONE 5:E11786-E11786(2010) [PubMed: 20668652] [Abstract] Cited for: INTERACTION WITH FOXO1.
[41]	"SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53." Lynch C.J., Shah Z.H., Allison S.J., Ahmed S.U., Ford J., Warnock L.J., Li H., Serrano M., Milner J. PLoS ONE 5:E13502-E13502(2010) [PubMed: 20975832] [Abstract] Cited for: ALTERNATIVE SPLICING (ISOFORM 2).
[42]	"A nutrient-sensitive interaction between Sirt1 and HNF-1alpha regulates Crp expression." Grimm A.A., Brace C.S., Wang T., Stormo G.D., Imai S. Aging Cell 10:305-317(2011) [PubMed: 21176092] [Abstract] Cited for: FUNCTION, INTERACTION WITH HNF1A.
[43]	"Disruption of a Sirt1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formation." Powell M.J., Casimiro M.C., Cordon-Cardo C., He X., Yeow W.S., Wang C., McCue P.A., McBurney M.W., Pestell R.G. Cancer Res. 71:964-975(2011) [PubMed: 21189328] [Abstract] Cited for: FUNCTION IN AUTOPHAGY, DISRUPTION PHENOTYPE.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF214646 mRNA. Translation: AAF24983.1. BC006584 mRNA. Translation: AAH06584.1.
IPI	IPI00134988.
RefSeq	NP_062786.1. NM_019812.2.
UniGene	Mm.351459.
3D structure databases
ProteinModelPortal	Q923E4.
SMR	Q923E4. Positions 229-488.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-47052N.
IntAct	Q923E4. 22 interactions.
STRING	Q923E4.
PTM databases
PhosphoSite	Q923E4.
Proteomic databases
PRIDE	Q923E4.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000020257; ENSMUSP00000020257; ENSMUSG00000020063. ENSMUST00000120239; ENSMUSP00000112595; ENSMUSG00000020063.
GeneID	93759.
KEGG	mmu:93759.
NMPDR	fig|10090.3.peg.13798.
Organism-specific databases
CTD	23411.
MGI	MGI:2135607. Sirt1.
Phylogenomic databases
GeneTree	ENSGT00550000074996.
HOGENOM	HBG403109.
HOVERGEN	HBG054192.
InParanoid	Q923E4.
OMA	GEPLRKR.
OrthoDB	EOG4RNB8G.
PhylomeDB	Q923E4.
Gene expression databases
ArrayExpress	Q923E4.
Bgee	Q923E4.
Genevestigator	Q923E4.
GermOnline	ENSMUSG00000020063. Mus musculus.
Family and domain databases
InterPro	IPR003000. NAD-dep_deAcase_sirtuin. [Graphical view]
KO	K11411.
PANTHER	PTHR11085. SIR2. 1 hit.
Pfam	PF02146. SIR2. 1 hit. [Graphical view]
PROSITE	PS50305. SIRTUIN. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	351639.
SOURCE	Search...

Entry information

Entry name

SIRT1_MOUSE

Accession

Primary (citable) accession number: Q923E4
Secondary accession number(s): Q9QXG8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 31, 2003
Last sequence update:	October 31, 2003
Last modified:	January 25, 2012
This is version 100 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program