SIR2/YDL042C Summary Help

Standard Name SIR2 1
Systematic Name YDL042C
Alias MAR1 2
Feature Type ORF, Verified
Description Conserved NAD+ dependent histone deacetylase of the Sirtuin family; involved in regulation of lifespan; plays roles in silencing at HML, HMR, telomeres, and the rDNA locus; negatively regulates initiation of DNA replication; functions as a regulator of autophagy like mammalian homolog SIRT1, and also of mitophagy; SIR2 has a paralog, HST1, that arose from the whole genome duplication (1, 3, 4, 5, 6, 7 and see Summary Paragraph)
Name Description Silent Information Regulator 1
Chromosomal Location
ChrIV:378445 to 376757 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
Gbrowse
Genetic position: -16.03 cM
Gene Ontology Annotations All SIR2 GO evidence and references
  View Computational GO annotations for SIR2
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
Manually curated
Regulators 5 genes
Resources
Pathways
Classical genetics
conditional
null
overexpression
reduction of function
Large-scale survey
null
Resources
493 total interaction(s) for 294 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 51
  • Affinity Capture-Western: 50
  • Biochemical Activity: 14
  • Co-crystal Structure: 1
  • Co-localization: 11
  • Co-purification: 5
  • Protein-peptide: 2
  • Protein-RNA: 1
  • Reconstituted Complex: 14
  • Two-hybrid: 25

Genetic Interactions
  • Dosage Lethality: 1
  • Dosage Rescue: 22
  • Phenotypic Enhancement: 38
  • Phenotypic Suppression: 74
  • Synthetic Growth Defect: 152
  • Synthetic Lethality: 5
  • Synthetic Rescue: 27

Resources
Expression Summary
histogram
Resources
Length (a.a.) 562
Molecular Weight (Da) 63,261
Isoelectric Point (pI) 8.58
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrIV:378445 to 376757 | ORF Map | GBrowse
Note: this feature is encoded on the Crick strand.
SGD ORF map
Genetic position: -16.03 cM
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..1689 378445..376757 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | E.C. | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000002200
SUMMARY PARAGRAPH for SIR2

SIR2 encodes an NAD+-dependent deacetylase involved in chromatin silencing (8 and reviewed in 9 and 10). Sir2p facilitates transcriptional silencing at cryptic mating type loci HML and HMR, at telomeres, and at the rDNA locus RDN1, and this silencing regulates the processes of recombination, genomic stability, and aging (1, 11, 2, 12, 13, 14, 15). SIR2 is one of four Silent Information Regulator genes in yeast but is the only one that is highly conserved from archaea to humans (16 and reviewed in 17). Although SIR2 is not essential for viability, absence of Sir2p function does result in a complete loss of transcriptional silencing, increases the rate of rDNA repeat recombination, decreases chromosome stability, causes defects in the meiotic pachytene checkpoint, and decreases yeast lifespan (18, 1, 4, 14, 19, 15). Overexpression of Sir2p has been shown to extend the lifespan of yeast in a dose-dependant manner but highly overexpressed SIR2 can be toxic to the cells (15, 14). Additionally, caloric restriction increases the activity of Sir2p while nicotinamide, a degradation product of NAD, inhibits it (20, 21).

Silencing at HML, HMR, and heterochromatic telomeres is mediated by the Sir complex, comprised of the two structural proteins Sir3p and Sir4p, as well as Sir2p which is the enzymatic component (22). The Sir complex does not bind DNA directly, instead it is recruited to regulatory chromosomal domains bound by Rap1p, Abf1p and the Origin Recognition Complex (via Sir1p) (23, 24, 25 and reviewed in 9). Once a silencing complex is bound to a nucleosome, Sir2p deacetylates the histone tails of H3 and H4 of the adjacent nucleosome. Because the Sir proteins have a higher affinity for H3 and H4 with reduced acetylation, deacetylation creates a binding site for an additional silencing complex. This process repeats until Sir complexes are spread across the entire chromatin region to be silenced (reviewed in 9, 10, and 26).

Sir2p also localizes to the nucleolus (27). Sir2p (but not the other Sir proteins) along with Net1p and the Cdc14p phosphatase comprise the nucleolar complex called RENT, a regulator of nucleolar silencing and telophase exit (28, 29). The association of Sir2p to rDNA is dependent on Net1p, and RENT is recruited to rDNA through interaction with Fob1p and RNA polymerase I (30). As a component of RENT, Sir2p represses mitotic and meiotic recombination between rDNA arrays, and affects rDNA chromatin structure and silencing in a dose-dependent manner (4, 31, 32). Sir2p may play a role in slowing the aging of yeast cells by preventing the formation of extrachromosomal rDNA circles (ercs) that form through homologous recombination within rDNA arrays, and that seem to be one cause of yeast cell aging (33, 15)

About NAD biosynthesis -- de novo and salvage pathways

Nicotinamide adenine dinucleotide (NAD) is an essential cofactor for cellular redox reactions and energy metabolism. NAD also has been shown to be an important substrate in a variety of biological processes, including transcriptional regulation, DNA repair, calcium-dependent signaling pathways, calorie-restriction-mediated life-span extension and age-associated diseases (34, 35). NAD appears to affect these processes by regulating the Sir2p family of NAD-dependent deacetylases (Sirtuins) (35).

There are a number of pathways for NAD biosynthesis. In yeast and most other organisms, the two major pathways are de novo synthesis of NAD (the de novo pathway) and regeneration of NAD from its nicotinamide degradation products (the NAD salvage pathway) (36, 35). NAD is synthesized de novo from tryptophan via kynurenine (36). In this pathway tryptophan is converted to nicotinic acid mononucleotide (NaMN) in 6 enzymatic steps (catalyzed by Bna1-2p, and Bna4-7p) and one non-enzymatic step (36). At NaMN the de novo pathway converges with the NAD salvage pathway and the last two steps to NAD are shared (36, 35). In the yeast NAD salvage pathway, the vitamin precursors nicotinamide and nicotinic acid are converted to NaMN, the point of convergence with the de novo pathway (35). The steps from nicotinic acid to NAD were elucidated by Preiss and Handler and are sometimes referred to as the Preiss-Handler pathway (as reviewed in 37). Yeast can also import extracellular nicotinic acid into the cell by the permease Tna1p and then convert it to NAD via the Preiss-Handler pathway (35).

There are four additional pathways for synthesizing NAD in yeast: two salvage pathways from the vitamin precursor nicotinamide riboside (NR) and two salvage pathways from nicotinic acid riboside (NaR) (37, 38, 39). Only one of these pathways, the NR salvage pathway I, is independent of the NAD salvage pathway. In the NR salvage pathway I, NR is phosphorylated to nicotinamide mononucleotide by the kinase Nrk1p, and then adenylated to NAD by Nma1p or Nma2p (37). In the NR salvage pathway II, the hydrolase Urh1p or the phosphorylase Pnp1p split NR into a ribosyl product and nicotinamide, which subsequently is converted to NAD via the NAD salvage pathway (38). The initial steps in the NaR salvage pathways I and II are similar to those of the NR salvage pathways I and II and are catalyzed by the same enzymes, respectively. In the NaR salvage pathway I, Nrk1p phosphorylates NaR to NaMN, which subsequently is converted to NAD via the enzymes shared by the de novo and NAD salvage pathways (39). In the NaR salvage pathway II, Urh1p or Pnp1p split NR into a ribosyl product and nicotinic acid, which is first converted to NaMN and then is converted similarly to NAD (39).

Last updated: 2006-02-14 Contact SGD

References cited on this page View Complete Literature Guide for SIR2
1) Rine J and Herskowitz I  (1987) Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics 116(1):9-22
2) Klar AJ, et al.  (1979) MAR1-a Regulator of the HMa and HMalpha Loci in SACCHAROMYCES CEREVISIAE. Genetics 93(1):37-50
3) Landry J, et al.  (2000) The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci U S A 97(11):5807-11
4) Gottlieb S and Esposito RE  (1989) A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell 56(5):771-6
5) Pappas DL Jr, et al.  (2004) The NAD(+)-dependent Sir2p histone deacetylase is a negative regulator of chromosomal DNA replication. Genes Dev 18(7):769-81
6) Byrne KP and Wolfe KH  (2005) The Yeast Gene Order Browser: combining curated homology and syntenic context reveals gene fate in polyploid species. Genome Res 15(10):1456-61
7) Sampaio-Marques B, et al.  (2012) SNCA (a-synuclein)-induced toxicity in yeast cells is dependent on sirtuin 2 (Sir2)-mediated mitophagy. Autophagy 8(10):1494-509
8) Imai S, et al.  (2000) Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403(6771):795-800
9) Rusche LN, et al.  (2003) The establishment, inheritance, and function of silenced chromatin in Saccharomyces cerevisiae. Annu Rev Biochem 72():481-516
10) Blander G and Guarente L  (2004) The Sir2 family of protein deacetylases. Annu Rev Biochem 73():417-35
11) Aparicio OM, et al.  (1991) Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Cell 66(6):1279-87
12) Rine J, et al.  (1979) A suppressor of mating-type locus mutations in Saccharomyces cerevisiae: evidence for and identification of cryptic mating-type loci. Genetics 93(4):877-901
13) Smith JS and Boeke JD  (1997) An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev 11(2):241-54
14) Holmes SG, et al.  (1997) Hyperactivation of the silencing proteins, Sir2p and Sir3p, causes chromosome loss. Genetics 145(3):605-14
15) Kaeberlein M, et al.  (1999) The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13(19):2570-80
16) Brachmann CB, et al.  (1995) The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. Genes Dev 9(23):2888-902
17) Dutnall RN and Pillus L  (2001) Deciphering NAD-dependent deacetylases. Cell 105(2):161-4
18) Ivy JM, et al.  (1986) Cloning and characterization of four SIR genes of Saccharomyces cerevisiae. Mol Cell Biol 6(2):688-702
19) San-Segundo PA and Roeder GS  (1999) Pch2 links chromatin silencing to meiotic checkpoint control. Cell 97(3):313-24
20) Lin SJ, et al.  (2000) Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289(5487):2126-8
21) Bitterman KJ, et al.  (2002) Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J Biol Chem 277(47):45099-107
22) Moazed D, et al.  (1997) Silent information regulator protein complexes in Saccharomyces cerevisiae: a SIR2/SIR4 complex and evidence for a regulatory domain in SIR4 that inhibits its interaction with SIR3. Proc Natl Acad Sci U S A 94(6):2186-91
23) Kimmerly W, et al.  (1988) Roles of two DNA-binding factors in replication, segregation and transcriptional repression mediated by a yeast silencer. EMBO J 7(7):2241-53
24) Gardner KA, et al.  (1999) A region of the Sir1 protein dedicated to recognition of a silencer and required for interaction with the Orc1 protein in saccharomyces cerevisiae. Genetics 151(1):31-44
25) Triolo T and Sternglanz R  (1996) Role of interactions between the origin recognition complex and SIR1 in transcriptional silencing. Nature 381(6579):251-3
26) Buck SW, et al.  (2004) Diversity in the Sir2 family of protein deacetylases. J Leukoc Biol 75(6):939-50
27) Gotta M, et al.  (1997) Localization of Sir2p: the nucleolus as a compartment for silent information regulators. EMBO J 16(11):3243-55
28) Straight AF, et al.  (1999) Net1, a Sir2-associated nucleolar protein required for rDNA silencing and nucleolar integrity. Cell 97(2):245-56
29) Shou W, et al.  (1999) Exit from mitosis is triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex. Cell 97(2):233-44
30) Huang J and Moazed D  (2003) Association of the RENT complex with nontranscribed and coding regions of rDNA and a regional requirement for the replication fork block protein Fob1 in rDNA silencing. Genes Dev 17(17):2162-76
31) Fritze CE, et al.  (1997) Direct evidence for SIR2 modulation of chromatin structure in yeast rDNA. EMBO J 16(21):6495-509
32) Smith JS, et al.  (1998) Distribution of a limited Sir2 protein pool regulates the strength of yeast rDNA silencing and is modulated by Sir4p. Genetics 149(3):1205-19
33) Park PU, et al.  (1999) Effects of mutations in DNA repair genes on formation of ribosomal DNA circles and life span in Saccharomyces cerevisiae. Mol Cell Biol 19(5):3848-56
34) Anderson RM, et al.  (2003) Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature 423(6936):181-5
35) Lin SJ and Guarente L  (2003) Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease. Curr Opin Cell Biol 15(2):241-6
36) Bedalov A, et al.  (2003) NAD+-dependent deacetylase Hst1p controls biosynthesis and cellular NAD+ levels in Saccharomyces cerevisiae. Mol Cell Biol 23(19):7044-54
37) Bieganowski P and Brenner C  (2004) Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans. Cell 117(4):495-502
38) Belenky P, et al.  (2007) Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell 129(3):473-84
39) Tempel W, et al.  (2007) Nicotinamide Riboside Kinase Structures Reveal New Pathways to NAD(+). PLoS Biol 5(10):e263