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Gene Review

SIR1  -  Sir1p

Saccharomyces cerevisiae S288c

 
 
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High impact information on SIR1

  • We have identified the Saccharomyces cerevisiae genes SAS2 and SAS3 through a screen for enhancers of sir1 epigenetic silencing defects [1].
  • Here we show that a GAL4 DNA-binding domain-SIR1 hybrid protein (GBD-SIR1), when targeted to an HMR locus containing GAL4-binding sites (UASG), can establish silencing and bypass the requirement for the silencer element HMR-E [2].
  • Previous studies suggest that the yeast SIR1 protein is involved in the establishment of transcriptional silencing at the HM mating-type loci [2].
  • Telomeric silencing, which does not require SIR1 and is normally unstable, is greatly improved by tethering GBD-SIR1 to the telomere [2].
  • Sir2 and Sir3, but not Sir1, were also found to participate in these processes [3].
 

Biological context of SIR1

  • However, there were differences between transcriptional silencing at telomeres and the HM loci, as demonstrated by suppressor analysis and the lack of involvement of SIR1 in telomeric silencing [4].
  • In contrast, SIR1 in a multicopy plasmid relieved the telomere position effect, especially in a gal11 delta mutant [5].
  • These mutants are dependent on SIR1 for silencing function at the HM silent mating-type loci, display distinct phenotypes at the rDNA, and have dominant silencing defects at the telomeres [6].
  • An unusual collection of sir3 mutant alleles was identified in a genetic screen for enhancers of the sir1 mutant mating-defective phenotype [7].
  • SIR1, one of several genes required for repression of yeast silent mating type loci, has a unique role in repression of the HML alpha locus [8].
 

Anatomical context of SIR1

 

Physical interactions of SIR1

  • These data suggest that the HAT activity and ASF1-dependent localization of the SAS complex are required for SIR1-dependent HMLalpha silencing [9].
  • Previous experiments suggested that SIR1 might be localized to the silencers by binding to ORC and/or RAP1 [10].
  • Sir1 bound to Cac1, a subunit of chromatin assembly factor I (CAF-I), and helped to retain Cac1 at centromeric loci [11].
  • Sir1p binds the N-terminal region of Orc1p encompassing a Bromo-adjacent homology (BAH) domain found in various chromatin-associated proteins [12].
  • The structure reveals two key features that can account for Sir3p-BAH domain's inability to interact with Sir1p [13].
 

Regulatory relationships of SIR1

  • Consistent with this proposal we find that deletion of MGA2 or SPT23 also suppresses the silencing defects caused by deletion of the SIR1 gene or by mutations in the HMR silencer sequences [14].
  • Two classes of sir3 mutants enhance the sir1 mutant mating defect and abolish telomeric silencing in Saccharomyces cerevisiae [7].
 

Other interactions of SIR1

  • MATa cac- sir1 double mutants have a synergistic mating defect, suggesting that the two silencing mechanisms, establishment and maintenance, function cooperatively [15].
  • Repression is restored by creation of a new telomere 13 kb from the integrated reporter or by elevated expression of SIR1, SIR3, and/or SIR4 [16].
  • However, GBD/RAP1-mediated silencing is independent of SIR1, whose product is normally required for the establishment of repression at HMR [17].
  • Silencing in the rDNA occurs by a novel mechanism that depends on a single Silent Information Regulator (SIR) gene, SIR2 [18].
  • FKH1 was isolated as a gene that, when expressed in multiple copies, could substitute for the function of SIR1 in silencing HMRa [19].
 

Analytical, diagnostic and therapeutic context of SIR1

References

  1. Yeast SAS silencing genes and human genes associated with AML and HIV-1 Tat interactions are homologous with acetyltransferases. Reifsnyder, C., Lowell, J., Clarke, A., Pillus, L. Nat. Genet. (1996) [Pubmed]
  2. Targeting of SIR1 protein establishes transcriptional silencing at HM loci and telomeres in yeast. Chien, C.T., Buck, S., Sternglanz, R., Shore, D. Cell (1993) [Pubmed]
  3. Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae. Tsukamoto, Y., Kato, J., Ikeda, H. Nature (1997) [Pubmed]
  4. Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Aparicio, O.M., Billington, B.L., Gottschling, D.E. Cell (1991) [Pubmed]
  5. The yeast GAL11 protein is involved in regulation of the structure and the position effect of telomeres. Suzuki, Y., Nishizawa, M. Mol. Cell. Biol. (1994) [Pubmed]
  6. A unique class of conditional sir2 mutants displays distinct silencing defects in Saccharomyces cerevisiae. Garcia, S.N., Pillus, L. Genetics (2002) [Pubmed]
  7. Two classes of sir3 mutants enhance the sir1 mutant mating defect and abolish telomeric silencing in Saccharomyces cerevisiae. Stone, E.M., Reifsnyder, C., McVey, M., Gazo, B., Pillus, L. Genetics (2000) [Pubmed]
  8. Epigenetic inheritance of transcriptional states in S. cerevisiae. Pillus, L., Rine, J. Cell (1989) [Pubmed]
  9. Chromatin assembly factor Asf1p-dependent occupancy of the SAS histone acetyltransferase complex at the silent mating-type locus HMLalpha. Osada, S., Kurita, M., Nishikawa, J., Nishihara, T. Nucleic Acids Res. (2005) [Pubmed]
  10. Role of interactions between the origin recognition complex and SIR1 in transcriptional silencing. Triolo, T., Sternglanz, R. Nature (1996) [Pubmed]
  11. The budding yeast silencing protein Sir1 is a functional component of centromeric chromatin. Sharp, J.A., Krawitz, D.C., Gardner, K.A., Fox, C.A., Kaufman, P.D. Genes Dev. (2003) [Pubmed]
  12. Structural basis for origin recognition complex 1 protein-silence information regulator 1 protein interaction in epigenetic silencing. Hsu, H.C., Stillman, B., Xu, R.M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. Structure of the Sir3 protein bromo adjacent homology (BAH) domain from S. cerevisiae at 1.95 A resolution. Hou, Z., Danzer, J.R., Fox, C.A., Keck, J.L. Protein Sci. (2006) [Pubmed]
  14. MGA2 and SPT23 are modifiers of transcriptional silencing in yeast. Dula, M.L., Holmes, S.G. Genetics (2000) [Pubmed]
  15. Chromatin assembly factor I contributes to the maintenance, but not the re-establishment, of silencing at the yeast silent mating loci. Enomoto, S., Berman, J. Genes Dev. (1998) [Pubmed]
  16. Evidence for silencing compartments within the yeast nucleus: a role for telomere proximity and Sir protein concentration in silencer-mediated repression. Maillet, L., Boscheron, C., Gotta, M., Marcand, S., Gilson, E., Gasser, S.M. Genes Dev. (1996) [Pubmed]
  17. Action of a RAP1 carboxy-terminal silencing domain reveals an underlying competition between HMR and telomeres in yeast. Buck, S.W., Shore, D. Genes Dev. (1995) [Pubmed]
  18. Distribution of a limited Sir2 protein pool regulates the strength of yeast rDNA silencing and is modulated by Sir4p. Smith, J.S., Brachmann, C.B., Pillus, L., Boeke, J.D. Genetics (1998) [Pubmed]
  19. Forkhead genes in transcriptional silencing, cell morphology and the cell cycle. Overlapping and distinct functions for FKH1 and FKH2 in Saccharomyces cerevisiae. Hollenhorst, P.C., Bose, M.E., Mielke, M.R., Müller, U., Fox, C.A. Genetics (2000) [Pubmed]
  20. SIRT1 stimulation by polyphenols is affected by their stability and metabolism. de Boer, V.C., de Goffau, M.C., Arts, I.C., Hollman, P.C., Keijer, J. Mech. Ageing Dev. (2006) [Pubmed]
 
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