Sirtuins: A homologous family of regulatory enzymes that are structurally related to the protein silent mating type information regulator 2 (Sir2) found in Saccharomyces cerevisiae. Sirtuins contain a central catalytic core region which binds NAD. Several of the sirtuins utilize NAD to deacetylate proteins such as HISTONES and are categorized as GROUP III HISTONE DEACETYLASES. Several other sirtuin members utilize NAD to transfer ADP-RIBOSE to proteins and are categorized as MONO ADP-RIBOSE TRANSFERASES, while a third group of sirtuins appears to have both deacetylase and ADP ribose transferase activities.Sirtuin 3: A sirtuin family member found primarily in MITOCHONDRIA. It is a multifunctional enzyme that contains a NAD-dependent deacetylase activity that is specific for HISTONES and a mono-ADP-ribosyltransferase activity.Group III Histone Deacetylases: A subclass of histone deacetylases that are NAD-dependent. Several members of the SIRTUINS family are included in this subclass.Sirtuin 1: A sirtuin family member found primarily in the CELL NUCLEUS. It is an NAD-dependent deacetylase with specificity towards HISTONES and a variety of proteins involved in gene regulation.Sirtuin 2: A sirtuin family member found primarily in the CYTOPLASM. It is a multifunctional enzyme that contains a NAD-dependent deacetylase activity that is specific for HISTONES and a mono-ADP-ribosyltransferase activity.Caloric Restriction: Reduction in caloric intake without reduction in adequate nutrition. In experimental animals, caloric restriction has been shown to extend lifespan and enhance other physiological variables.O-Acetyl-ADP-Ribose: An acetyl ester of ADENOSINE DIPHOSPHATE RIBOSE formed during NAD-dependent deacetylation of proteins by SIRTUINS. The acetate group resides on the ribose ring where nicotinamide was cleaved from NAD during the reaction. Several isomers of O-acetyl-ADP-ribose have been isolated from the reaction.NAD: A coenzyme composed of ribosylnicotinamide 5'-diphosphate coupled to adenosine 5'-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). (Dorland, 27th ed)Longevity: The normal length of time of an organism's life.Acetylation: Formation of an acetyl derivative. (Stedman, 25th ed)Acetate-CoA Ligase: An enzyme that catalyzes the formation of CoA derivatives from ATP, acetate, and CoA to form AMP, pyrophosphate, and acetyl CoA. It acts also on propionates and acrylates. EC 188.8.131.52.Stilbenes: Organic compounds that contain 1,2-diphenylethylene as a functional group.Histone Deacetylases: Deacetylases that remove N-acetyl groups from amino side chains of the amino acids of HISTONES. The enzyme family can be divided into at least three structurally-defined subclasses. Class I and class II deacetylases utilize a zinc-dependent mechanism. The sirtuin histone deacetylases belong to class III and are NAD-dependent enzymes.Enzyme Activators: Compounds or factors that act on a specific enzyme to increase its activity.Aging: The gradual irreversible changes in structure and function of an organism that occur as a result of the passage of time.Nicotinamide Phosphoribosyltransferase: An enzyme that catalyzes the formation of nicotinamide mononucleotide (NMN) from nicotinamide and 5-phosphoribosyl-1-pyrophosphate, the rate-limiting step in the biosynthesis of the NAD coenzyme. It is also known as a growth factor for early B-LYMPHOCYTES, or an ADIPOKINE with insulin-mimetic effects (visfatin).Naphthols: Naphthalene derivatives carrying one or more hydroxyl (-OH) groups at any ring position. They are often used in dyes and pigments, as antioxidants for rubber, fats, and oils, as insecticides, in pharmaceuticals, and in numerous other applications.Niacinamide: An important compound functioning as a component of the coenzyme NAD. Its primary significance is in the prevention and/or cure of blacktongue and PELLAGRA. Most animals cannot manufacture this compound in amounts sufficient to prevent nutritional deficiency and it therefore must be supplemented through dietary intake.Nervous System Physiological Processes: Biological actions and events that constitute the functions of the NERVOUS SYSTEM.Metabolic Diseases: Generic term for diseases caused by an abnormal metabolic process. It can be congenital due to inherited enzyme abnormality (METABOLISM, INBORN ERRORS) or acquired due to disease of an endocrine organ or failure of a metabolically important organ such as the liver. (Stedman, 26th ed)Mitochondria: Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed)Neurodegenerative Diseases: Hereditary and sporadic conditions which are characterized by progressive nervous system dysfunction. These disorders are often associated with atrophy of the affected central or peripheral nervous system structures.Energy Metabolism: The chemical reactions involved in the production and utilization of various forms of energy in cells.Mitochondrial Proteins: Proteins encoded by the mitochondrial genome or proteins encoded by the nuclear genome that are imported to and resident in the MITOCHONDRIA.Silent Information Regulator Proteins, Saccharomyces cerevisiae: A set of nuclear proteins in SACCHAROMYCES CEREVISIAE that are required for the transcriptional repression of the silent mating type loci. They mediate the formation of silenced CHROMATIN and repress both transcription and recombination at other loci as well. They are comprised of 4 non-homologous, interacting proteins, Sir1p, Sir2p, Sir3p, and Sir4p. Sir2p, an NAD-dependent HISTONE DEACETYLASE, is the founding member of the family of SIRTUINS.Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi).
Protein deacetylase: Protein deacetylase; any enzyme that removes acetyl groups from lysine amino acids in proteins.CALERIE: CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) is a trial currently underway in the U.S.Macro domain: In molecular biology, the Macro domain or A1pp domain is a module of about 180 amino acids which can bind ADP-ribose, an NAD metabolite, or related ligands. Binding to ADP-ribose can be either covalent or non-covalent: in certain cases it is believed to bind non-covalently, while in other cases (such as Aprataxin) it appears to bind both non-covalently through a zinc finger motif, and covalently through a separate region of the protein.Maximum life span: Maximum life span is a measure of the maximum amount of time one or more members of a population has been observed to survive between birth and death. The term can also denote an estimate of the maximum amount of time that a member of a given species could survive between life and death, provided circumstances that are optimal to their longevity.Compendium of protein lysine acetylation: The compendium of protein lysine acetylation (CPLA) database contains the sites of experimentally identified lysine acetylation sites.CO-methylating acetyl-CoA synthase: Acetyl-CoA Synthase (ACS), not to be confused with Acetyl-CoA Synthetase or Acetate-CoA Ligase (ADP forming), is a Nickel containing enzyme involved in the metabolic processes of cells. Together with Carbon monoxide dehydrogenase (CODH), it forms the bifunctional enzyme Acetyl-CoA Synthase/Carbon Monoxide Dehydrogenase (ACS/CODH) found in anaerobic organisms such as archaea and eubacteria.Vitisin B (stilbenoid): Vitisin B}}Histone deacetylaseNaphthol Green BIsonicotinamideMitochondrion: The mitochondrion (plural mitochondria) is a double membrane-bound organelle found in most eukaryotic cells. The word mitochondrion comes from the Greek , , i.Centre for Research in Neurodegenerative DiseasesIndex of energy articles: This is an index of energy articles.
(1/957) A genetic screen for ribosomal DNA silencing defects identifies multiple DNA replication and chromatin-modulating factors.
Transcriptional silencing in Saccharomyces cerevisiae occurs at several genetic loci, including the ribosomal DNA (rDNA). Silencing at telomeres (telomere position effect [TPE]) and the cryptic mating-type loci (HML and HMR) depends on the silent information regulator genes, SIR1, SIR2, SIR3, and SIR4. However, silencing of polymerase II-transcribed reporter genes integrated within the rDNA locus (rDNA silencing) requires only SIR2. The mechanism of rDNA silencing is therefore distinct from TPE and HM silencing. Few genes other than SIR2 have so far been linked to the rDNA silencing process. To identify additional non-Sir factors that affect rDNA silencing, we performed a genetic screen designed to isolate mutations which alter the expression of reporter genes integrated within the rDNA. We isolated two classes of mutants: those with a loss of rDNA silencing (lrs) phenotype and those with an increased rDNA silencing (irs) phenotype. Using transposon mutagenesis, lrs mutants were found in 11 different genes, and irs mutants were found in 22 different genes. Surprisingly, we did not isolate any genes involved in rRNA transcription. Instead, multiple genes associated with DNA replication and modulation of chromatin structure were isolated. We describe these two gene classes, and two previously uncharacterized genes, LRS4 and IRS4. Further characterization of the lrs and irs mutants revealed that many had alterations in rDNA chromatin structure. Several lrs mutants, including those in the cdc17 and rfc1 genes, caused lengthened telomeres, consistent with the hypothesis that telomere length modulates rDNA silencing. Mutations in the HDB (RPD3) histone deacetylase complex paradoxically increased rDNA silencing by a SIR2-dependent, SIR3-independent mechanism. Mutations in rpd3 also restored mating competence selectively to sir3Delta MATalpha strains, suggesting restoration of silencing at HMR in a sir3 mutant background. (+info)
(2/957) Net1, a Sir2-associated nucleolar protein required for rDNA silencing and nucleolar integrity.
The Sir2 protein mediates gene silencing and repression of recombination at the rDNA repeats in budding yeast. Here we show that Sir2 executes these functions as a component of a nucleolar complex designated RENT (regulator of nucleolar silencing and telophase exit). Net1, a core subunit of this complex, preferentially cross-links to the rDNA repeats, but not to silent DNA regions near telomeres or to active genes, and tethers the RENT complex to rDNA. Net1 is furthermore required for rDNA silencing and nucleolar integrity. During interphase, Net1 and Sir2 colocalize to a subdomain within the nucleous, but at the end of mitosis a fraction of Sir2 leaves the nucleolus and disperses as foci throughout the nucleus, suggesting that the structure of rDNA silent chromatin changes during the cell cycle. Our findings suggest that a protein complex shown to regulate exit from mitosis is also involved in gene silencing. (+info)
(3/957) Phenotypic switching in Candida albicans is controlled by a SIR2 gene.
We report the cloning of a gene from the human fungal pathogen Candida albicans with sequence and functional similarity to the Saccharomyces cerevisiae SIR2 gene. Deletion of the gene in C. albicans produces a dramatic phenotype: variant colony morphologies arise at frequencies as high as 1 in 10. The morphologies resemble those described previously as part of a phenotypic switching system proposed to contribute to pathogenesis. Deletion of SIR2 also produces a high frequency of karyotypic changes. These and other results are consistent with a model whereby Sir2 controls phenotypic switching and chromosome stability in C.albicans by organizing chromatin structure. (+info)
(4/957) Pch2 links chromatin silencing to meiotic checkpoint control.
The PCH2 gene of Saccharomyces cerevisiae is required for the meiotic checkpoint that prevents chromosome segregation when recombination and chromosome synapsis are defective. Mutation of PCH2 relieves the checkpoint-induced pachytene arrest of the zip1, zip2, and dmc1 mutants, resulting in chromosome missegregation and low spore viability. Most of the Pch2 protein localizes to the nucleolus, where it represses meiotic interhomolog recombination in the ribosomal DNA, apparently by excluding the meiosis-specific Hop1 protein. Nucleolar localization of Pch2 depends on the silencing factor Sir2, and mutation of SIR2 also bypasses the zip1 pachytene arrest. Under certain circumstances, Sir3-dependent localization of Pch2 to telomeres also provides checkpoint function. These unexpected findings link the nucleolus, chromatin silencing, and the pachytene checkpoint. (+info)
(5/957) MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks.
The yeast Sir2/3/4p complex is found in abundance at telomeres, where it participates in the formation of silent heterochromatin and telomere maintenance. Here, we show that Sir3p is released from telomeres in response to DNA double-strand breaks (DSBs), binds to DSBs, and mediates their repair, independent of cell mating type. Sir3p relocalization is S phase specific and, importantly, requires the DNA damage checkpoint genes MEC1 and RAD9. MEC1 is a homolog of ATM, mutations in which cause ataxia telangiectasia (A-T), a disease characterized by various neurologic and immunologic abnormalities, a predisposition for cancer, and a cellular defect in repair of DSBs. This novel mode by which preformed DNA repair machinery is mobilized by DNA damage sensors may have implications for human diseases resulting from defective DSB repair. (+info)
(6/957) A role for a replicator dominance mechanism in silencing.
The role of the natural HMR-E silencer in modulating replication initiation and silencing by the origin recognition complex (ORC) was examined. When natural HMR-E was the only silencer controlling HMR, the silencer's ORC-binding site (ACS) was dispensable for replication initiation but essential for silencing, indicating that a non-silencer chromosomal replicator(s) existed in close proximity to the silencer. Further analysis revealed that regions flanking both sides of HMR-E contained replicators. In contrast to replication initiation by the intact silencer, initiation by the non-silencer replicator(s) was abolished in an orc2-1 mutant, indicating that these replicators were extremely sensitive to defects in ORC. Remarkably, the activity of one of the non-silencer replicators correlated with reduced silencing; inactivation of these replicators caused by either the orc2-1 mutation or the deletion of flanking sequences enhanced silencing. These data were consistent with a role for the ORC bound to the HMR-E silencer ACS in suppressing the function of neighboring ORC molecules capable of inhibiting silencing, and indicated that differences in ORC-binding sites within HMR itself had profound effects on ORC function. Moreover, replication initiation by natural HMR-E was inefficient, suggesting that closely spaced replicators within HMR contributed to an inhibition of replication initiation. (+info)
(7/957) Role of yeast SIR genes and mating type in directing DNA double-strand breaks to homologous and non-homologous repair paths.
Eukaryotes have acquired many mechanisms to repair DNA double-strand breaks (DSBs) . In the yeast Saccharomyces cerevisiae, this damage can be repaired either by homologous recombination, which depends on the Rad52 protein, or by non-homologous end-joining (NHEJ), which depends on the proteins yKu70 and yKu80  . How do cells choose which repair pathway to use? Deletions of the SIR2, SIR3 and SIR4 genes - which are involved in transcriptional silencing at telomeres and HM mating-type loci (HMLalpha and HMRa) in yeast  - have been reported to reduce NHEJ as severely as deletions of genes encoding Ku proteins . Here, we report that the effect of deleting SIR genes is largely attributable to derepression of silent mating-type genes, although Sir proteins do play a minor role in end-joining. When DSBs were made on chromosomes in haploid cells that retain their mating type, sir Delta mutants reduced the frequency of NHEJ by twofold or threefold, although plasmid end-joining was not affected. In diploid cells, sir mutants showed a twofold reduction in the frequency of NHEJ in two assays. Mating type also regulated the efficiency of DSB-induced homologous recombination. In MATa/MATalpha diploid cells, a DSB induced by HO endonuclease was repaired 98% of the time by gene conversion with the homologous chromosome, whereas in diploid cells with an alpha mating type (matDelta/MATalpha) repair succeeded only 82% of the time. Mating-type regulation of genes specific to haploid or diploid cells plays a key role in determining which pathways are used to repair DSBs. (+info)
(8/957) The nucleolus: nucleolar space for RENT.
Recent studies indicate that the nucleolus is not just a site of ribosome biogenesis. Intriguing links have been found between nucleolar components and the machinery that regulates the cell cycle. (+info)