saccharomyces cerevisiae silent information regulator proteins

Summary

Summary: 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.

Top Publications

  1. Maillet L, Gaden F, Brevet V, Fourel G, Martin S, Dubrana K, et al. Ku-deficient yeast strains exhibit alternative states of silencing competence. EMBO Rep. 2001;2:203-10 pubmed
    ..These findings indicate the existence of a yKu-independent pathway of telomere clustering and Sir localization. Interestingly, this pathway appears to be under epigenetic control. ..
  2. Kennedy B, Smith E, Kaeberlein M. The enigmatic role of Sir2 in aging. Cell. 2005;123:548-50 pubmed
    ..In contrast to measurements of aging for mitotic cells, cell survival in the nonmitotic state is decreased by Sir2 activity under conditions that mimic calorie restriction. ..
  3. Kaeberlein M, Andalis A, Fink G, Guarente L. High osmolarity extends life span in Saccharomyces cerevisiae by a mechanism related to calorie restriction. Mol Cell Biol. 2002;22:8056-66 pubmed
    ..This metabolic shift likely increases NAD levels, thereby activating Sir2p and promoting longevity. ..
  4. van Welsem T, Frederiks F, Verzijlbergen K, Faber A, Nelson Z, Egan D, et al. Synthetic lethal screens identify gene silencing processes in yeast and implicate the acetylated amino terminus of Sir3 in recognition of the nucleosome core. Mol Cell Biol. 2008;28:3861-72 pubmed publisher
    ..Our results suggest that the BAH domain of Sir3 binds to histone H3K79 and that acetylation of the BAH domain is required for the binding specificity of Sir3 for nucleosomes unmethylated at H3K79. ..
  5. Venkatasubrahmanyam S, Hwang W, Meneghini M, Tong A, Madhani H. Genome-wide, as opposed to local, antisilencing is mediated redundantly by the euchromatic factors Set1 and H2A.Z. Proc Natl Acad Sci U S A. 2007;104:16609-14 pubmed
    ..Antisilencing mechanisms may therefore cooperate to play a considerably broader role in regulating genome-wide transcription than previously thought. ..
  6. Hecht A, Strahl Bolsinger S, Grunstein M. Spreading of transcriptional repressor SIR3 from telomeric heterochromatin. Nature. 1996;383:92-6 pubmed
    ..Thus SIR3 is a structural component of yeast heterochromatin, repressing adjacent genes as it spreads along the chromosome. ..
  7. Anderson R, Latorre Esteves M, Neves A, Lavu S, Medvedik O, Taylor C, et al. Yeast life-span extension by calorie restriction is independent of NAD fluctuation. Science. 2003;302:2124-2126 pubmed publisher
    ..Moreover, the activity of Sir2 and its human homologue SIRT1 are not affected by physiological alterations in the NAD+:NADH ratio. These data implicate alternate mechanisms of Sir2 regulation by CR. ..
  8. Frye R. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun. 1999;260:273-9 pubmed
    ..These results suggest that the sirtuins may function via mono-ADP-ribosylation of proteins. ..
  9. Hecht A, Laroche T, Strahl Bolsinger S, Gasser S, Grunstein M. Histone H3 and H4 N-termini interact with SIR3 and SIR4 proteins: a molecular model for the formation of heterochromatin in yeast. Cell. 1995;80:583-92 pubmed
    ..Based on these interactions, we propose a model for heterochromatin-mediated transcriptional silencing in yeast, which may serve as a paradigm for other eukaryotic organisms as well. ..

More Information

Publications62

  1. Howitz K, Bitterman K, Cohen H, Lamming D, Lavu S, Wood J, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425:191-6 pubmed
    ..We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators. ..
  2. Andrulis E, Zappulla D, Alexieva Botcheva K, Evangelista C, Sternglanz R. One-hybrid screens at the Saccharomyces cerevisiae HMR locus identify novel transcriptional silencing factors. Genetics. 2004;166:631-5 pubmed
    ..Here, we report results of screening a Gal4 DNA-binding domain hybrid library for proteins that cause silencing when targeted to a silencer-defective HMR locus. ..
  3. Straight A, Shou W, Dowd G, Turck C, Deshaies R, Johnson A, et al. Net1, a Sir2-associated nucleolar protein required for rDNA silencing and nucleolar integrity. Cell. 1999;97:245-56 pubmed
    ..Our findings suggest that a protein complex shown to regulate exit from mitosis is also involved in gene silencing. ..
  4. Park Y, Hanish J, Lustig A. Sir3p domains involved in the initiation of telomeric silencing in Saccharomyces cerevisiae. Genetics. 1998;150:977-86 pubmed
    ..These data suggest that the CTD "active" site is under both positive and negative control mediated by multiple Sir3p domains. ..
  5. Yang B, Kirchmaier A. Bypassing the catalytic activity of SIR2 for SIR protein spreading in Saccharomyces cerevisiae. Mol Biol Cell. 2006;17:5287-97 pubmed
    ..These results also provide genetic evidence for the existence of additional critical substrates of Sir2p for silencing in vivo. ..
  6. Kaeberlein M, Powers R. Sir2 and calorie restriction in yeast: a skeptical perspective. Ageing Res Rev. 2007;6:128-40 pubmed
    ..These shortcomings must be considered along with evidence supporting a role for Sir2 in CR in order to fully evaluate the validity of this model. ..
  7. Strahl Bolsinger S, Hecht A, Luo K, Grunstein M. SIR2 and SIR4 interactions differ in core and extended telomeric heterochromatin in yeast. Genes Dev. 1997;11:83-93 pubmed
    ..RAP1 binding at the core region is unaffected by SIR3 overproduction and RAP1 shows no evidence of spreading. Thus, we propose that the structure of core telomeric heterochromatin differs from that extended by SIR3. ..
  8. Xu E, Bi X, Holland M, Gottschling D, Broach J. Mutations in the nucleosome core enhance transcriptional silencing. Mol Cell Biol. 2005;25:1846-59 pubmed
    ..We propose that these mutations use distinct mechanisms to affect the dynamic interplay between activation and repression at the boundary between active and silent chromatin. ..
  9. Piper P. Long-lived yeast as a model for ageing research. Yeast. 2006;23:215-26 pubmed
    ..This review addresses these issues and describes the ongoing studies that are now attempting to address ageing in yeast cells of maximal replicative or chronological longevity. ..
  10. North B, Marshall B, Borra M, Denu J, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003;11:437-44 pubmed
    ..These observations establish SIRT2 as a bona fide tubulin deacetylase. ..
  11. Kimura A, Umehara T, Horikoshi M. Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing. Nat Genet. 2002;32:370-7 pubmed
    ..Thus, the Sas2p and Sir2p function in concert to regulate transcription in yeast, by acetylating and deacetylating H4-Lys16 in a mechanism that may be common to all eukaryotes. ..
  12. Moretti P, Freeman K, Coodly L, Shore D. Evidence that a complex of SIR proteins interacts with the silencer and telomere-binding protein RAP1. Genes Dev. 1994;8:2257-69 pubmed
    ..These data are consistent with a model in which SIR3 and SIR4 play a structural role in the maintenance of silent chromatin and indicate that their action is initiated at the silencer itself. ..
  13. Suka N, Luo K, Grunstein M. Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin. Nat Genet. 2002;32:378-83 pubmed
    ..These data indicate that opposing effects of Sir2p and Sas2p on acetylation of H4-Lys16 maintain the boundary at telomeric heterochromatin. ..
  14. Kobayashi T, Horiuchi T, Tongaonkar P, Vu L, Nomura M. SIR2 regulates recombination between different rDNA repeats, but not recombination within individual rRNA genes in yeast. Cell. 2004;117:441-53 pubmed
    ..From these and other experiments, we conclude that SIR2 prevents unequal sister-chromatid recombination, probably by forming special cohesin structures, without significant effects on recombinational events within individual rRNA genes. ..
  15. Meneghini M, Wu M, Madhani H. Conserved histone variant H2A.Z protects euchromatin from the ectopic spread of silent heterochromatin. Cell. 2003;112:725-36 pubmed
    ..Thus, euchromatin and heterochromatin each contains components that antagonize switching to the opposite chromatin state...
  16. Paetkau D, Riese J, MacMorran W, Woods R, Gietz R. Interaction of the yeast RAD7 and SIR3 proteins: implications for DNA repair and chromatin structure. Genes Dev. 1994;8:2035-45 pubmed
    ..Expression of a telomeric copy of the URA3 gene was stimulated in a rad7-delta mutant, suggesting that repair of lesions in the absence of Rad7 can result in the activation of transcriptionally silenced genes. ..
  17. Gasser S, Cockell M. The molecular biology of the SIR proteins. Gene. 2001;279:1-16 pubmed
    ..Nonetheless, there have been many recent insights into their molecular structures. This review examines the impact of these results on our understanding of silencing function in budding yeast. ..
  18. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408:255-62 pubmed
    ..Intriguing similarities in the phenotypes of many of these mutants indicate that the mutations may also perturb regulatory systems that control ageing in higher organisms. ..
  19. Imai S, Armstrong C, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403:795-800 pubmed
    ..These findings provide a molecular framework of NAD-dependent histone deacetylation that connects metabolism, genomic silencing and ageing in yeast and, perhaps, in higher eukaryotes. ..
  20. Lustig A. Mechanisms of silencing in Saccharomyces cerevisiae. Curr Opin Genet Dev. 1998;8:233-9 pubmed
    ..The past year of investigations has led to a clearer understanding of the nature of nucleation and spreading of heterochromatin, as well as uncovering a fascinating link between silencing, the nucleolus and aging. ..
  21. Jackson M, Denu J. Structural identification of 2'- and 3'-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+-dependent histone/protein deacetylases. J Biol Chem. 2002;277:18535-44 pubmed
    ..Possible mechanisms for the generation of 2'-O-acetyl-ADP-ribose are discussed. ..
  22. Johzuka K, Horiuchi T. Replication fork block protein, Fob1, acts as an rDNA region specific recombinator in S. cerevisiae. Genes Cells. 2002;7:99-113 pubmed
    ..In addition, FOB1 may also play a role in the copy number regulation of rDNA tandem repeats. ..
  23. Cioci F, Vogelauer M, Camilloni G. Acetylation and accessibility of rDNA chromatin in Saccharomyces cerevisiae in (Delta)top1 and (Delta)sir2 mutants. J Mol Biol. 2002;322:41-52 pubmed
    ..Here, we show that the absence of Top1p causes increased histone acetylation at the rDNA locus. Moreover, rDNA chromatin becomes more accessible in a similar manner in both top1 and sir2 mutant strains. ..
  24. Ghidelli S, Donze D, Dhillon N, Kamakaka R. Sir2p exists in two nucleosome-binding complexes with distinct deacetylase activities. EMBO J. 2001;20:4522-35 pubmed
    ..Finally, we demonstrate that the Sir2p-containing complexes bind nucleosomes efficiently and partially restrict accessibility of the linker DNA to enzymatic probes. ..
  25. Muth V, Nadaud S, Grummt I, Voit R. Acetylation of TAF(I)68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription. EMBO J. 2001;20:1353-62 pubmed
  26. Kirchmaier A, Rine J. DNA replication-independent silencing in S. cerevisiae. Science. 2001;291:646-50 pubmed
    ..Thus, in contrast to the prevailing view, the establishment of silencing occurred in the absence of passage of the DNA replication fork through or near the HMR locus, but retained a cell cycle dependence. ..
  27. Smith J, Boeke J. An unusual form of transcriptional silencing in yeast ribosomal DNA. Genes Dev. 1997;11:241-54 pubmed
    ..Deletion of SIR2 resulted in increased psoralen cross-linking of the rDNA in vivo, suggesting that a specific chromatin structure in rDNA down-regulates polymerase II promoters. ..
  28. Rudner A, Hall B, Ellenberger T, Moazed D. A nonhistone protein-protein interaction required for assembly of the SIR complex and silent chromatin. Mol Cell Biol. 2005;25:4514-28 pubmed
  29. Ray A, Hector R, Roy N, Song J, Berkner K, Runge K. Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan. Nat Genet. 2003;33:522-6 pubmed
    ..Lifespan extension occurs by a mechanism that is independent of suppressing rDNA recombination. Thus, Slt2p is an enzymatic regulator of silencing function that couples commitment to cell growth and shorter lifespan. ..
  30. Fabrizio P, Gattazzo C, Battistella L, Wei M, Cheng C, McGrew K, et al. Sir2 blocks extreme life-span extension. Cell. 2005;123:655-67 pubmed
    ..Our results demonstrate that effects of SIR2 on chronological life span are opposite to replicatve life span and suggest that the relevant activities of Sir2-like deacetylases may also be complex in higher eukaryotes. ..
  31. Bystricky K, Laroche T, van Houwe G, Blaszczyk M, Gasser S. Chromosome looping in yeast: telomere pairing and coordinated movement reflect anchoring efficiency and territorial organization. J Cell Biol. 2005;168:375-87 pubmed
    ..These mutations do not, however, eliminate coordinated movement of telomere (Tel) 6R and Tel6L, which we propose stems from the territorial organization of yeast chromosomes. ..
  32. Ravindra A, Weiss K, Simpson R. High-resolution structural analysis of chromatin at specific loci: Saccharomyces cerevisiae silent mating-type locus HMRa. Mol Cell Biol. 1999;19:7944-50 pubmed
    ..Features of the chromatin structure of this silent locus compared to the previously studied HMLalpha locus suggest differences in the mechanisms of silencing and may relate to donor selection during mating-type interconversion. ..
  33. Enomoto S, Berman J. Chromatin assembly factor I contributes to the maintenance, but not the re-establishment, of silencing at the yeast silent mating loci. Genes Dev. 1998;12:219-32 pubmed
    ..We propose a model to explain the distinctions between the establishment and the maintenance of silent chromatin. ..
  34. Tompa R, Madhani H. Histone H3 lysine 36 methylation antagonizes silencing in Saccharomyces cerevisiae independently of the Rpd3S histone deacetylase complex. Genetics. 2007;175:585-93 pubmed
    ..Thus, antagonism of silencing is independent of the only known effector of this conserved histone modification. ..
  35. McBryant S, Krause C, Woodcock C, Hansen J. The silent information regulator 3 protein, SIR3p, binds to chromatin fibers and assembles a hypercondensed chromatin architecture in the presence of salt. Mol Cell Biol. 2008;28:3563-72 pubmed publisher
    ..Collectively, these results define how SIR3p may function as a chromatin architectural protein and provide new insight into the interplay between endogenous and protein-mediated chromatin fiber condensation pathways. ..
  36. Yang B, Britton J, Kirchmaier A. Insights into the impact of histone acetylation and methylation on Sir protein recruitment, spreading, and silencing in Saccharomyces cerevisiae. J Mol Biol. 2008;381:826-44 pubmed publisher
  37. Laroche T, Martin S, Tsai Pflugfelder M, Gasser S. The dynamics of yeast telomeres and silencing proteins through the cell cycle. J Struct Biol. 2000;129:159-74 pubmed
    ..Using live GFP fluorescence we show that the diffuse mitotic distribution of GFP-Rap1p is restored to the interphase pattern of foci in early G1-phase. ..
  38. Frye R. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun. 2000;273:793-8 pubmed
    ..The seven human sirtuin genes include all four classes: SIRT1, SIRT2, and SIRT3 are class I, SIRT4 is class II, SIRT5 is class III, and SIRT6 and SIRT7 are class IV. ..
  39. Santos Rosa H, Bannister A, Dehe P, Geli V, Kouzarides T. Methylation of H3 lysine 4 at euchromatin promotes Sir3p association with heterochromatin. J Biol Chem. 2004;279:47506-12 pubmed
    ..The inability of Sir3p to bind methylated H3 Lys-4 tails suggests a model whereby H3 Lys-4 methylation prevents Sir3p association at euchromatic sites and therefore concentrates Sir3p at unmodified, heterochromatic regions of the genome...
  40. Dhillon N, Kamakaka R. A histone variant, Htz1p, and a Sir1p-like protein, Esc2p, mediate silencing at HMR. Mol Cell. 2000;6:769-80 pubmed
  41. Matecic M, Stuart S, Holmes S. SIR2-induced inviability is suppressed by histone H4 overexpression. Genetics. 2002;162:973-6 pubmed
    ..These results suggest a direct and specific interaction between Sir2 and H4 in the silencing mechanism. ..
  42. Sperling A, Grunstein M. Histone H3 N-terminus regulates higher order structure of yeast heterochromatin. Proc Natl Acad Sci U S A. 2009;106:13153-9 pubmed publisher
    ..These findings indicate an altered chromatin structure. We propose that Sir proteins recruited by the H4 tail then interact with the H3 tail to form a higher order silent chromatin structure. ..
  43. Emre N, Ingvarsdottir K, Wyce A, Wood A, Krogan N, Henry K, et al. Maintenance of low histone ubiquitylation by Ubp10 correlates with telomere-proximal Sir2 association and gene silencing. Mol Cell. 2005;17:585-94 pubmed
    ..Our results suggest that these H2B-deubiquitylating enzymes have distinct genomic functions. ..
  44. Pappas D, Frisch R, Weinreich M. The NAD(+)-dependent Sir2p histone deacetylase is a negative regulator of chromosomal DNA replication. Genes Dev. 2004;18:769-81 pubmed
  45. Rusche L, Kirchmaier A, Rine J. Ordered nucleation and spreading of silenced chromatin in Saccharomyces cerevisiae. Mol Biol Cell. 2002;13:2207-22 pubmed
    ..This model suggests mechanisms for boundary formation, and for maintenance and inheritance of silenced chromatin. The principles are generalizable to other types of heritable chromatin states. ..
  46. Keogh M, Kurdistani S, Morris S, Ahn S, Podolny V, Collins S, et al. Cotranscriptional set2 methylation of histone H3 lysine 36 recruits a repressive Rpd3 complex. Cell. 2005;123:593-605 pubmed
    ..This pathway apparently acts to negatively regulate transcription because deleting the genes for Set2 or Rpd3C(S) bypasses the requirement for the positive elongation factor Bur1/Bur2. ..
  47. Tsukamoto Y, Kato J, Ikeda H. Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae. Nature. 1997;388:900-3 pubmed
    ..We propose that Sir proteins act with Hdf1 to alter broken DNA ends to create an inactivated chromatin structure that is essential for the rejoining of DNA ends. ..
  48. Aguilaniu H, Gustafsson L, Rigoulet M, Nystrom T. Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science. 2003;299:1751-3 pubmed
    ..These findings suggest that a genetically determined, Sir2p-dependent asymmetric inheritance of oxidatively damaged proteins may contribute to free-radical defense and the fitness of newborn cells. ..
  49. Maillet L, Boscheron C, Gotta M, Marcand S, Gilson E, Gasser S. Evidence for silencing compartments within the yeast nucleus: a role for telomere proximity and Sir protein concentration in silencer-mediated repression. Genes Dev. 1996;10:1796-811 pubmed
    ..Efficient silencer function thus seems to require either proximity to a pool of concentrated Sir proteins, that is, proximity to telomeres, or delocalization of the silencing factors. ..
  50. Triolo T, Sternglanz R. Role of interactions between the origin recognition complex and SIR1 in transcriptional silencing. Nature. 1996;381:251-3 pubmed
    ..Here we report that SIR1 can bind directly to ORC1, the largest of the ORC subunits, and that targeting of SIR1 to ORC1 at a silencer is sufficient to establish a silenced state. ..
  51. Connelly J, Yuan P, Hsu H, Li Z, Xu R, Sternglanz R. Structure and function of the Saccharomyces cerevisiae Sir3 BAH domain. Mol Cell Biol. 2006;26:3256-65 pubmed
    ..The structure of the Sir3 BAH domain has been determined. In the crystal, the molecule multimerizes in the form of a left-handed superhelix. This superhelix may be relevant to the function of the BAH domain of Sir3 in silencing. ..
  52. Taddei A, Hediger F, Neumann F, Bauer C, Gasser S. Separation of silencing from perinuclear anchoring functions in yeast Ku80, Sir4 and Esc1 proteins. EMBO J. 2004;23:1301-12 pubmed
    ..These data provide the first unambiguous identification of protein interactions that are both necessary and sufficient to localize chromatin to the nuclear envelope. ..
  53. Mills K, Sinclair D, Guarente L. MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks. Cell. 1999;97:609-20 pubmed
    ..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. ..