The SIRT1 gene spans about 34 kb including nine exons. The SIRT1 promoter contains a CCAAT box and a number of NF-kappaB and GATA transcription factor binding sites in addition to a small 350-bp CpG island in the 5 flanking genomic region. The gene encodes a 747 amino acids protein with a predictive molecular weight of 81.7 kDa and an isoelectric point of 4.55 (Alcaín and Villalba, 2009).

SIRT1 transcription is under the control of at least two negative feedback loops that keep its induction tightly regulated under conditions of oxidative stress. SIRT1 promoter can be regulated by E2F1 and HIC1 during cellular stress. E2F1 directly binds to the SIRT1 promoter at a consensus site located at bp position -65 and appears to regulate the basal expression level of SIRT1. Such high levels of SIRT1 lead to a negative feedback loop where E2F1 activity is inhibited by SIRT1-mediated deacetylation. By contrast, the tumor suppressor HIC1 and SIRT1 form a transcriptional repression complex that directly binds SIRT1 promoter and represses SIRT1 transcription thereby inhibiting SIRT1-mediated p53 deacetylation and inactivation. Two HIC1 binding sites have been assigned to base pair positions -1116 and -1039 within the SIRT1 promoter (Chen et al., 2005). In addition, two functional p53 binding sites (-178 bp and -168 bp), which normally repress SIRT1 expression, have been identified. Furthermore, SIRT1 transcription is upregulated by MYC that binds at SIRT1 promoter position -80 and by STAT5 that binds at positions -2235 and -1838 in response to BCR-ABL oncogenic stress (Yuan et al., 2012).
SIRT1 expression is also regulated at the posttranscriptional level by HuR. It has been demonstrated that HuR, a ubiquitously expressed RNA binding protein, associates with the 3 UTR of the SIRT1 mRNA under physiological conditions and helps to stabilize the transcript. This interaction results in increased SIRT1 mRNA stability and thus in elevated protein levels. Conversely, the HuR-SIRT1 mRNA complex is being disrupted upon oxidative stress, which finally leads to decreased mRNA stability and therefore decreased SIRT protein levels. In addition, several microRNA (miR) species negatively regulate SIRT1 mRNA by targeting its 3 UTR, including miR-34a and miR-200a (reviewed in Roth and Chen, 2014).

None identified.

Human SIRT1 encodes 747 amino acids protein with a nuclear localization signal (NLS) at the N-terminus (aa 41-46) and a sirtuin homology domain at the center (aa 261-447); this domain is a conserved catalytic domain for deacetylation. The catalytic activity of SIRT1 is dependent on the cofactor nicotinamide adenine dinucleotide (NAD⁺).

Expression appears to be ubiquitous in adult tissues (although at different levels). Two proteins have been identified to regulate the SIRT1 activity both positively and negatively through complex formation in the context of the cellular stress response. The first identified direct regulator of SIRT1 was the active regulator of SIRT1 (AROS). The AROS protein is known to significantly enhance the activity of SIRT1 on acetylated p53 both in vitro and in cell lines thereby promoting the inhibitory effect of SIRT1 on p53-mediated transcriptional activity of pro-apoptotic genes (e.g. Bax and p21Waf-1) under conditions of DNA-damage. A negative regulator of SIRT1, DBC-1 (deleted in breast cancer-1), has recently been identified. DBC1 binds directly to the catalytic domain of SIRT1, preventing substrate binding to SIRT1 and inhibiting SIRT1 activity. Reduction of DBC1 inhibits p53-mediated apoptosis after induction of double-stranded DNA breaks owing to SIRT1-mediated p53 deacetylation. Both factors represent the first endogenous, direct regulators of SIRT1 function. SIRT1 activity is also regulated by cis-elements of its own peptides. The SIRT1 C-terminal region (aa 631-635) is a disordered domain, and it interacts with SIRT1 catalytic core domain by competing with DBC1 and activates SIRT1 activity (Kang et al., 2011). A small rigid region at the N-terminus (aa 190-244) of SIRT1 appears to mediates allosteric activators for the SIRT1 catalytic core function (Hubbard et al., 2013). In addition, SIRT1 activity is subjected to regulation by other posttranslational modifications such as sumoylation, phosphorylation and methylation in response to stress signaling and cell cycle changes (reviewed in Wang and Chen, 2013). As an NAD-dependent enzyme, SIRT1 activity is regulated by cellular NAD metabolism in which NAD salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) is often co-activated with SIRT1 to maintain the deacetylase activity (Wang et al., 2011; Menssen et al., 2012).

SIRT1 is predominately in the nucleus (although SIRT1 does have some important cytoplasmic functions as well). In addition to possessing two NLSs, SIRT1 contains two nuclear export signals. Thus, the exposure of nuclear localization signals versus nuclear export signals may dictate the cytosolic versus nuclear localization of SIRT1.

SIRT1 has been reported to play a key role in a variety of physiological processes such as metabolism, neurogenesis and cell survival due to its ability to deacetylate both histone and numerous nonhistone substrates.
(1) Lysines 9 and 14 in the amino-terminal tail of histone H3 and lysine 16 of histone H4 are deacetylated by yeast Sir2 and mammalian SIRT1 (Sir2alpha).
(2) Metabolic homeostasis is controlled by SIRT1-mediated deacetylation and thus activation of the peroxisome proliferation activating receptor (PPAR)-gamma co-activator-1a (PGC-1a), which stimulates mitochondrial activity and subsequently increases glucose metabolism, which in turn improves insulin sensitivity. SIRT1 represses PPAR-gamma, a key regulator of adipogenesis, by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). The upregulation of SIRT1 triggers lipolysis and loss of fat.
(3) The activation of SIRT1 appears to be neuroprotective in animal models for Alzheimers disease and amyotrophic lateral sclerosis as well as optic neuritis mainly due to decreased deacetylation of the tumor suppressor p53 and PGC-1a.
(4) SIRT1 represses p53-dependent apoptosis in response to DNA damage and oxidative stress and promotes cell survival under cellular stress induced by etoposide treatment or irradiation.
(5) SIRT1 activates FOXO1 and FOXO4, which promote cell-cycle arrest by inducing p27kip1; SIRT1 also induces cellular resistance to oxidative stress by increasing the levels of manganese superoxide dismutase and GADD45 (growth arrest and DNA damage-inducible protein 45).
(6) SIRT1 inhibits the transcriptional activity of NF-kappaB by deacetylating NF-kappaBs subunit, RelA/p65, at lysine 310. Thus, although SIRT1 is capable of protecting cells from p53-induced apoptosis, it may augment apoptosis by repressing NF-kappaB. SIRT1 is reported to bind CTIP2 (BCL11B B-cell CLL/lymphoma 11B) and accelerate the transcriptional repression by this molecule. CTIP2 represses the transcription of its target genes and is implicated in hematopoietic cell development.
(7) SIRT1 deacetylates and activates functions of several DNA repair factors, including KU70, NBS1, APE1, XPA/C and WRN for multiple DNA damage repair pathways to cope with genotoxic stress. Stimulated repair may help cells avoid catastrophic genomic events and survive the damage.
(8) SIRT1 is involved in epigenetic regulation of genes and chromatin. SIRT1 deacetylates several histone tail lysines: histone H4 lysine 16 (H4K16), histone H3 K9 and K14, and histone H1 K26. These modifications of histone tails are closely related to gene silencing and heterochromatin formation that may underlie certain biological processes. SIRT1 can deacetylate DNA methyltransferase 1 (DNMT1) and can either enhance or hinder its methyltransferase activity, thus indirectly affecting global or local DNA methylation patterns. SIRT1 is a component of the polycomb repressor complex (PRC) that is involved in silencing genes during normal development. SIRT1 directly complexes with EZH2, a H3K27 methyltransferase within PRC II complex, and is an integral part of the PRCs silencing functions. A SIRT1-containing PRC complex, termed PRC4, is specifically found in transformed cells and embryonic stem cells. In addition, SIRT1 interacts and deacetylates the SUV39H1 methyltransferase, promoting histone H3 methylation and fostering heterochromatin formation, and repressing rRNA transcription to protect cells from energy deprivation-dependent apoptosis (reviewed in Roth and Chen, 2014).

SIRT1 is the mammalian homologue closest to yeast NAD+-dependent deacetylase Sir2 (silent information regulation 2). It was originally identified as a lifespan extending gene when over-expressed in budding yeast, Caenorhabditis elegans, and Drosophila melanogaster. The SIR2 gene is broadly conserved in organisms ranging from bacteria to humans. The accession numbers for the amino acid sequences used are as follows: yeast Sir2 (CAA25667), mouse Sir2alpha (AAF24983), human Sirt1 (AAD40849). All of the sirtuin proteins contain the ~275 residue sirtuin homology domain. In many instances a highly conserved protein domain represents a conserved functional binding site for a metabolite or biomolecule and such conserved binding site domains are often found within enzymatic catalytic domains.

A germ line mutation L107P of SIRT1 was found in a family with type I diabetes. Expression of this mutant SIRT1 in insulin-producing cells stimulated production of nitric oxide, cytokines and chemokines, and decreased anti-inflammatory activity of pancreatic beta cells (Biason-Lauber et al., 2013).

A small number of SIRT1 somatic mutations were registered in human cancer databases but the mutation rate is typically very low (