Sir2
Encyclopedia
Sir2 was the first gene 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. 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
.
The name Sir2 is used for the enzyme in the yeast Saccharomyces cerevisiae
(where it was first discovered), in the fruit fly Drosophila melanogaster
, while in the roundworm, Caenorhabditis elegans
, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.
The various sirtuins in mammals are referred to as SIRT1-SIRT7 with SIRT1 being the mammalian ortholog closest in structure and function to Sir2.
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. They add the acetyl group from the protein to the ADP-ribose
component of NAD+ to form O-acetyl-ADP-ribose.
Sir2 is the only Class III histone deacetylase
(HDAC) in budding yeast.' 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%, 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. 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. 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.
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. Experiments in the nematode
Caenorhabditis elegans
and in the fruit fly Drosophila melanogaster
support these findings. , experiments in mice are underway.
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 Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.
In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.
Resveratrol
is a substance that has been shown through experiment to have a number of life-extending and health benefits in various species; it also increases the activity of Sir2, which is the postulated reason for its beneficial effects. Resveratrol is produced by plants when they are stressed, and it is possible that plants use the substance to increase their own Sir2 activity in order to survive periods of stress. Although there is mounting evidence for this hypothesis, its validity is debated.
In mammals, SIRT1 (the mammalian homolog of Sir2) has been shown to deacetylate and thereby deactivate the p53
protein. SIRT1 also stimulates autophagy by preventing acetylation of proteins required for autophagy in cultured cells and embryonic and neonatal tissues. This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction. 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.
In the fruit fly Drosophilia melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects. However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.
(also known as Sir2α) is the mammal homolog of Sir2. Mice that overexpress SIRT1 show eight properties of calorie restriction, including low cholesterol
, low blood glucose, and low insulin
levels. They also show increased numbers of mitochondria in their neuron
s. is expressed mainly in the brain
., , and are active in mitochondria, the energy-producing organelles that are a part of every cell. is active in the nucleus
of the cell. is active in the nucleolus
, a compartment of the nucleus reserved for the assembly of ribosome
s. Sirt7 has been shown to activate RNA Polymerase I transcription.
Sirtuin
Sirtuin or Sir2 proteins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes...
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. 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
Calorie restriction
Caloric restriction , or calorie restriction, is a dietary regimen that restricts calorie intake, where the baseline for the restriction varies, usually being the previous, unrestricted, intake of the subjects...
.
Nomenclature in various organisms
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. The term sirtuin is derived from Sir2 and stands for Silent Information Regulator Two (Sir2) protein.The name Sir2 is used for the enzyme in the yeast Saccharomyces cerevisiae
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
(where it was first discovered), in the fruit fly Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
, while in the roundworm, Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.
The various sirtuins in mammals are referred to as SIRT1-SIRT7 with SIRT1 being the mammalian ortholog closest in structure and function to Sir2.
Method of action and observed effects
Sirtuins act primarily by removing acetylAcetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...
groups from lysine residues within proteins in the presence of NAD+
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
; thus, they are classified as "NAD+-dependent deacetylases" and have EC number
EC number
The Enzyme Commission number is a numerical classification scheme for enzymes, based on the chemical reactions they catalyze....
3.5.1. They add the acetyl group from the protein to the ADP-ribose
Adenosine diphosphate ribose
Adenosine diphosphate ribose is a molecule formed into chains by the enzyme poly ADP ribose polymerase. It binds to and activates the TRPM2 ion channel....
component of NAD+ to form O-acetyl-ADP-ribose.
Sir2 is the only Class III histone deacetylase
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
(HDAC) in budding yeast.' The HDAC activity of Sir2 results in tighter packaging of chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
and a reduction in transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
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
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
DNA (rDNA) locus (RDN1) from which ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
is transcribed.
Limited overexpression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of the Sir2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
results in a lifespan extension of about 30%, 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. 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. 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
Homologous recombination
Homologous recombination is a type of genetic recombination in which nucleotide sequences are exchanged between two similar or identical molecules of DNA. It is most widely used by cells to accurately repair harmful breaks that occur on both strands of DNA, known as double-strand breaks...
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.
Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reduces nicotinamide
Nicotinamide
Nicotinamide, also known as niacinamide and nicotinic acid amide, is the amide of nicotinic acid . Nicotinamide is a water-soluble vitamin and is part of the vitamin B group...
, 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. Experiments in the nematode
Nematode
The nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
and in the fruit fly Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
support these findings. , experiments in mice are underway.
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 Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.
In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.
Resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
is a substance that has been shown through experiment to have a number of life-extending and health benefits in various species; it also increases the activity of Sir2, which is the postulated reason for its beneficial effects. Resveratrol is produced by plants when they are stressed, and it is possible that plants use the substance to increase their own Sir2 activity in order to survive periods of stress. Although there is mounting evidence for this hypothesis, its validity is debated.
In mammals, SIRT1 (the mammalian homolog of Sir2) has been shown to deacetylate and thereby deactivate the p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
protein. SIRT1 also stimulates autophagy by preventing acetylation of proteins required for autophagy in cultured cells and embryonic and neonatal tissues. This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction. Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha
PPARGC1A
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha is a protein that in humans is encoded by the PPARGC1A gene....
/ERR-alpha
Estrogen-related receptor alpha
Estrogen-related receptor alpha , also known as NR3B1 , is a nuclear receptor that in humans is encoded by the ESRRA gene.-Tissue distribution:...
complex, which are essential metabolic regulatory transcription factors.
In the fruit fly Drosophilia melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects. However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.
Mammal sirtuins
Seven sirtuins are known in mammals.(also known as Sir2α) is the mammal homolog of Sir2. Mice that overexpress SIRT1 show eight properties of calorie restriction, including low cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
, low blood glucose, and low insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
levels. They also show increased numbers of mitochondria in their neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. is expressed mainly in the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
., , and are active in mitochondria, the energy-producing organelles that are a part of every cell. is active in the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
of the cell. is active in the nucleolus
Nucleolus
The nucleolus is a non-membrane bound structure composed of proteins and nucleic acids found within the nucleus. Ribosomal RNA is transcribed and assembled within the nucleolus...
, a compartment of the nucleus reserved for the assembly of ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
s. Sirt7 has been shown to activate RNA Polymerase I transcription.
See also
- Histone deacetylaseHistone deacetylaseHistone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
s, the class of enzymes to which yeast Sir2 belongs - Longevity genes
- Life extensionLife extensionLife extension science, also known as anti-aging medicine, experimental gerontology, and biomedical gerontology, is the study of slowing down or reversing the processes of aging to extend both the maximum and average lifespan...
- SirtuinSirtuinSirtuin or Sir2 proteins are a class of proteins that possess either histone deacetylase or mono-ribosyltransferase activity. Sirtuins regulate important biological pathways in bacteria, archaea and eukaryotes...
s, the family of genes to which Sir2 genes are related.
External links
Human Sirt1- Human Sirt1 in the GenAge database
- Sirt1 in the iHOPInformation Hyperlinked over ProteinsInformation Hyperlinked over Proteins is an online service that provides a gene-guided network to access PubMed abstracts. By using genes and proteins as hyperlinks between sentences and abstracts, the information in PubMed can be converted into one navigable resource.Navigating across...
database