Sirtuin 1

Last updated
SIRT1
SIRTUIN1.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SIRT1 , SIR2L1, SIR2, hSIR2, SIR2alpha, Sirtuin 1
External IDs OMIM: 604479; MGI: 2135607; HomoloGene: 56556; GeneCards: SIRT1; OMA:SIRT1 - orthologs
Orthologs
SpeciesHumanMouse
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: 63.15 – 63.22 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]

Contents

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 (Saccharomyces cerevisiae) is Sir2. SIRT1 is an enzyme located primarily in the cell nucleus that deacetylates transcription factors that contribute to cellular regulation (reaction to stressors, longevity). [8] [9]

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. 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. [10] 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. [11] [12]

In vitro, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein, [13] and may have a role in activating T helper 17 cells. [14]

Selective ligands

Activators

Although neither resveratrol or SRT1720 directly activate SIRT1, resveratrol, and probably SRT1720, indirectly activate SIRT1 by activation of AMP-activated protein kinase (AMPK), [25] which increases NAD+ levels (which is the cofactor required for SIRT1 activity). [26] [27] Elevating NAD+ is a more direct and reliable way to activate SIRT1. [27]

Interactions

Sirtuin 1 has been shown in vitro to interact with ERR-alpha [11] and AIRE. [28]

Human Sirt1 has been reported having 136 direct interactions in interactomic studies involved in numerous processes. [29]

Yeast homolog

Sir2 (whose homolog in mammals is known as SIRT1) was the first 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. [30] 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. [31] [32]

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. [33] [34]

In the roundworm, Caenorhabditis elegans , Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity. [35] [36]

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. [37] 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%, [38] 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. [38] 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. [39] 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. [39]

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. [40] Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster [41] support these findings. As of 2006, experiments in mice are underway. [31]

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 [42] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2. [43]

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

In the fruit fly Drosophila melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects. [40] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile. [44]

Inhibition of SIRT1

Human aging is characterized by a chronic, low-grade inflammation level, [45] and the pro-inflammatory transcription factor NF-κB is the main transcriptional regulator of genes related to inflammation. [46] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310. [47] [48] But NF-κB more strongly inhibits SIRT1. NF-κB increases the levels of the microRNA miR-34a (which inhibits nicotinamide adenine dinucleotide NAD+ synthesis) by binding to its promoter region. [49] resulting in lower levels of SIRT1.

Both the SIRT1 enzyme and the poly ADP-ribose polymerase 1 (PARP1) enzyme require NAD+ for activation. [50] PARP1 is a DNA repair enzyme, so in conditions of high DNA damage, NAD+ levels can be reduced 20–30% thereby reducing SIRT1 activity. [50]

Homologous recombination

SIRT1 protein actively promotes homologous recombination (HR) in human cells, and likely promotes recombinational repair of DNA breaks. [51] SIRT1-mediated HR requires the WRN protein. [51] WRN protein functions in double-strand break repair by HR. [52] 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. [51]

Related Research Articles

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

<span class="mw-page-title-main">Histone deacetylase</span> Class of enzymes important in regulating DNA transcription

Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.

<span class="mw-page-title-main">NF-κB</span> Family of transcription factor protein complexes

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.

<span class="mw-page-title-main">Sirtuin</span> Enzyme

Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast.

Leonard Pershing Guarente is an American biologist best known for his research on life span extension in the budding yeast Saccharomyces cerevisiae, roundworms, and mice. He is a Novartis Professor of Biology at the Massachusetts Institute of Technology.

<span class="mw-page-title-main">David A. Sinclair</span> Australian geneticist (born 1969)

David Andrew Sinclair is an Australian-American biologist and academic known for his research on aging and epigenetics. Sinclair is a professor of genetics at Harvard Medical School and the founding director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard. He is the co-author of Lifespan: Why We Age – and Why We Don't Have To.

Histone deacetylase inhibitors are chemical compounds that inhibit histone deacetylases. Since deacetylation of histones produces transcriptionally silenced heterochromatin, HDIs can render chromatin more transcriptionally active and induce epigenomic changes.

<span class="mw-page-title-main">PARP1</span> Mammalian protein found in Homo sapiens

Poly [ADP-ribose] polymerase 1 (PARP-1) also known as NAD+ ADP-ribosyltransferase 1 or poly[ADP-ribose] synthase 1 is an enzyme that in humans is encoded by the PARP1 gene. It is the most abundant of the PARP family of enzymes, accounting for 90% of the NAD+ used by the family. PARP1 is mostly present in cell nucleus, but cytosolic fraction of this protein was also reported.

<span class="mw-page-title-main">Nicotinamide phosphoribosyltransferase</span> Human protein and coding gene

Nicotinamide phosphoribosyltransferase, formerly known as pre-B-cell colony-enhancing factor 1 (PBEF1) or visfatin for its extracellular form (eNAMPT), is an enzyme that in humans is encoded by the NAMPT gene. The intracellular form of this protein (iNAMPT) is the rate-limiting enzyme in the nicotinamide adenine dinucleotide (NAD+) salvage pathway that converts nicotinamide to nicotinamide mononucleotide (NMN) which is responsible for most of the NAD+ formation in mammals. iNAMPT can also catalyze the synthesis of NMN from phosphoribosyl pyrophosphate (PRPP) when ATP is present. eNAMPT has been reported to be a cytokine (PBEF) that activates TLR4, that promotes B cell maturation, and that inhibits neutrophil apoptosis.

<span class="mw-page-title-main">Sirtuin 2</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin 2 is an enzyme that in humans is encoded by the SIRT2 gene. SIRT2 is an NAD+ -dependent deacetylase. Studies of this protein have often been divergent, highlighting the dependence of pleiotropic effects of SIRT2 on cellular context. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status. Similar to other sirtuin family members, SIRT2 displays a ubiquitous distribution. SIRT2 is expressed in a wide range of tissues and organs and has been detected particularly in metabolically relevant tissues, including the brain, muscle, liver, testes, pancreas, kidney, and adipose tissue of mice. Of note, SIRT2 expression is much higher in the brain than all other organs studied, particularly in the cortex, striatum, hippocampus, and spinal cord.

<span class="mw-page-title-main">KIAA1967</span> Protein-coding gene in the species Homo sapiens

KIAA1967, also known as Deleted in Breast Cancer 1, is a protein which in humans is encoded by the KIAA1967 gene.

<span class="mw-page-title-main">Sirtuin 3</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase activity.

<span class="mw-page-title-main">Sirtuin 5</span> Protein-coding gene in the species Homo sapiens

Sirtuin 5 , also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the orthologous Sirt5 gene.

<span class="mw-page-title-main">Sirtuin 7</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin 7 is an enzyme that in humans is encoded by the SIRT7 gene. SIRT7 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.

<span class="mw-page-title-main">Sirtuin 6</span> Protein-coding gene in the species Homo sapiens

Sirtuin 6 is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene. In laboratory research, SIRT6 appears to function in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation. SIRT6 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.

<span class="mw-page-title-main">Sirtuin 4</span> Protein-coding gene in the species Homo sapiens

Sirtuin 4, also known as SIRT4, is a mitochondrial protein which in humans is encoded by the SIRT4 gene. SIRT4 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT4 exhibits NAD+-dependent deacetylase activity.

Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are caloric restriction mimetic compounds that may be helpful in treating various aging-related diseases.

<span class="mw-page-title-main">Genetics of aging</span> Overview of the genetics of aging

Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.

SilentInformationRegulator (SIR) proteins are involved in regulating gene expression. SIR proteins organize heterochromatin near telomeres, ribosomal DNA (rDNA), and at silent loci including hidden mating type loci in yeast. The SIR family of genes encodes catalytic and non-catalytic proteins that are involved in de-acetylation of histone tails and the subsequent condensation of chromatin around a SIR protein scaffold. Some SIR family members are conserved from yeast to humans.

<span class="mw-page-title-main">MIR34A</span> Non-coding RNA in the species Homo sapiens

MicroRNA 34a (miR-34a) is a microRNA that in humans is encoded by the MIR34A gene.

References

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  39. 1 2 Kaeberlein M, McVey M, Guarente L (October 1999). "The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms". Genes & Development. 13 (19): 2570–80. doi:10.1101/gad.13.19.2570. PMC   317077 . PMID   10521401.
  40. 1 2 EntrezGene 34708 Drosophila Sir2
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