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Gene Review

SIR3  -  Sir3p

Saccharomyces cerevisiae S288c

Synonyms: CMT1, L9753.10, MAR2, Regulatory protein SIR3, STE8, ...
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Disease relevance of SIR3


High impact information on SIR3

  • Moreover, AAR itself promotes the association of multiple copies of Sir3 with Sir2/Sir4 and induces a dramatic structural rearrangement in the SIR complex [3].
  • Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan [4].
  • In htz1Delta cells, Sir2 and Sir3 spread into flanking euchromatic regions, producing changes in histone H4 acetylation and H3 4-methylation indicative of ectopic heterochromatin formation [5].
  • Elimination of the Sir3p phosphorylation site at Ser275 extended lifespan by 38% [4].
  • Loss of hyperacetylation is accompanied by an increase in localization of the telomere protein Sir3p and the inactivation of gene expression in telomere-distal regions [6].

Biological context of SIR3

  • SIR3 and SIR4 proteins are required for the positioning and integrity of yeast telomeres [7].
  • Interaction of the yeast RAD7 and SIR3 proteins: implications for DNA repair and chromatin structure [8].
  • A screen of a yeast genomic DNA-GAL4 activation domain (GAD) fusion gene library allowed the isolation of plasmids containing sequences corresponding to the 3' end of the SIR3 gene [8].
  • Within the resolution of these immunodetection techniques, we show that proteins encoded by the SIR3, SIR4, and RAP1 genes colocalize in a statistically significant manner with Y' telomere-associated DNA sequences [9].
  • In wild-type budding yeast strains, the proteins encoded by SIR3, SIR4 and RAP1 co-localize with telomeric DNA in a limited number of foci in interphase nuclei [10].

Anatomical context of SIR3


Associations of SIR3 with chemical compounds

  • Deacetylation of lysine 16 of H4 is necessary for binding the silencing protein, Sir3 [14].
  • The N-terminal alanine residues of the silencing protein Sir3 and of Orc1 are acetylated by the NatA Nalpha-acetyltransferase [15].

Physical interactions of SIR3

  • Rap1p initiates silencing at telomeres by interacting through its carboxy-terminal domain with Sir3p and Sir4p, both of which are required for repression [16].
  • This evidence suggests that the Sir3 protein interacts with the Rad7 protein to allow the nucleotide excision repair complex access to transcriptionally inactive chromatin [8].
  • At HM loci and telomeres, Sir2p forms a complex with Sir3p and Sir4p [17].
  • The structure reveals two key features that can account for Sir3p-BAH domain's inability to interact with Sir1p [18].
  • When the assembly of Sir3 into this complex is disrupted by a specific mutation on the surface of the C-terminal coiled-coil domain of Sir4, Sir3 is no longer recruited to chromatin and silencing is disrupted [19].

Regulatory relationships of SIR3

  • Two classes of sir3 mutants enhance the sir1 mutant mating defect and abolish telomeric silencing in Saccharomyces cerevisiae [20].
  • Furthermore, mutations in MCM10 inhibit the ability of GBD-SIR3 to restore silencing when tethered to a defective HMR-E [21].
  • Using the cloned genes, we showed that SIR3 at a high copy number is able to suppress mutations of SIR4 [22].
  • Overexpression of Sir3p completely suppressed the reduction in TPE observed with expression of Rap1 delta BBp, but did not restore high levels of TPE to cells with extra telomeres [23].
  • Sir3p is a target of mitogen-activated protein (MAP) kinase cascade regulation and has significant similarity to the Orc1p subunit of the DNA replication origin recognition complex [24].

Other interactions of SIR3

  • In strains deficient for either SIR3 or SIR4, telomeres lose their perinuclear localization, as monitored by RAP1 immunofluorescence [7].
  • Sir2 and Sir3, but not Sir1, were also found to participate in these processes [25].
  • In contrast, when SIR3 is reintroduced into cac1 sir3 cells, silencing is restored to HML, indicating that CAF-I is not required for the re-establishment of silencing [26].
  • Mutations in the HDB (RPD3) histone deacetylase complex paradoxically increased rDNA silencing by a SIR2-dependent, SIR3-independent mechanism [27].
  • Mutations in rpd3 also restored mating competence selectively to sir3Delta MATalpha strains, suggesting restoration of silencing at HMR in a sir3 mutant background [27].

Analytical, diagnostic and therapeutic context of SIR3


  1. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Sinclair, D.A., Mills, K., Guarente, L. Science (1997) [Pubmed]
  2. An alpha-1,3-mannosyltransferase of Cryptococcus neoformans. Sommer, U., Liu, H., Doering, T.L. J. Biol. Chem. (2003) [Pubmed]
  3. Assembly of the SIR complex and its regulation by O-acetyl-ADP-ribose, a product of NAD-dependent histone deacetylation. Liou, G.G., Tanny, J.C., Kruger, R.G., Walz, T., Moazed, D. Cell (2005) [Pubmed]
  4. Sir3p phosphorylation by the Slt2p pathway effects redistribution of silencing function and shortened lifespan. Ray, A., Hector, R.E., Roy, N., Song, J.H., Berkner, K.L., Runge, K.W. Nat. Genet. (2003) [Pubmed]
  5. Conserved histone variant H2A.Z protects euchromatin from the ectopic spread of silent heterochromatin. Meneghini, M.D., Wu, M., Madhani, H.D. Cell (2003) [Pubmed]
  6. Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing. Kimura, A., Umehara, T., Horikoshi, M. Nat. Genet. (2002) [Pubmed]
  7. SIR3 and SIR4 proteins are required for the positioning and integrity of yeast telomeres. Palladino, F., Laroche, T., Gilson, E., Axelrod, A., Pillus, L., Gasser, S.M. Cell (1993) [Pubmed]
  8. Interaction of the yeast RAD7 and SIR3 proteins: implications for DNA repair and chromatin structure. Paetkau, D.W., Riese, J.A., MacMorran, W.S., Woods, R.A., Gietz, R.D. Genes Dev. (1994) [Pubmed]
  9. The clustering of telomeres and colocalization with Rap1, Sir3, and Sir4 proteins in wild-type Saccharomyces cerevisiae. Gotta, M., Laroche, T., Formenton, A., Maillet, L., Scherthan, H., Gasser, S.M. J. Cell Biol. (1996) [Pubmed]
  10. Localization of Sir2p: the nucleolus as a compartment for silent information regulators. Gotta, M., Strahl-Bolsinger, S., Renauld, H., Laroche, T., Kennedy, B.K., Grunstein, M., Gasser, S.M. EMBO J. (1997) [Pubmed]
  11. 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]
  12. The positioning of yeast telomeres depends on SIR3, SIR4, and the integrity of the nuclear membrane. Palladino, F., Laroche, T., Gilson, E., Pillus, L., Gasser, S.M. Cold Spring Harb. Symp. Quant. Biol. (1993) [Pubmed]
  13. Regulation of subtelomeric silencing during stress response. Ai, W., Bertram, P.G., Tsang, C.K., Chan, T.F., Zheng, X.F. Mol. Cell (2002) [Pubmed]
  14. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Imai, S., Armstrong, C.M., Kaeberlein, M., Guarente, L. Nature (2000) [Pubmed]
  15. Importance of the Sir3 N terminus and its acetylation for yeast transcriptional silencing. Wang, X., Connelly, J.J., Wang, C.L., Sternglanz, R. Genetics (2004) [Pubmed]
  16. A novel Rap1p-interacting factor, Rif2p, cooperates with Rif1p to regulate telomere length in Saccharomyces cerevisiae. Wotton, D., Shore, D. Genes Dev. (1997) [Pubmed]
  17. Locus specificity determinants in the multifunctional yeast silencing protein Sir2. Cuperus, G., Shafaatian, R., Shore, D. EMBO J. (2000) [Pubmed]
  18. 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]
  19. A nonhistone protein-protein interaction required for assembly of the SIR complex and silent chromatin. Rudner, A.D., Hall, B.E., Ellenberger, T., Moazed, D. Mol. Cell. Biol. (2005) [Pubmed]
  20. 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]
  21. Mcm10 is required for the maintenance of transcriptional silencing in Saccharomyces cerevisiae. Liachko, I., Tye, B.K. Genetics (2005) [Pubmed]
  22. Cloning and characterization of four SIR genes of Saccharomyces cerevisiae. Ivy, J.M., Klar, A.J., Hicks, J.B. Mol. Cell. Biol. (1986) [Pubmed]
  23. Extra telomeres, but not internal tracts of telomeric DNA, reduce transcriptional repression at Saccharomyces telomeres. Wiley, E.A., Zakian, V.A. Genetics (1995) [Pubmed]
  24. Silent chromatin in yeast: an orchestrated medley featuring Sir3p [corrected]. Stone, E.M., Pillus, L. Bioessays (1998) [Pubmed]
  25. Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae. Tsukamoto, Y., Kato, J., Ikeda, H. Nature (1997) [Pubmed]
  26. 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]
  27. A genetic screen for ribosomal DNA silencing defects identifies multiple DNA replication and chromatin-modulating factors. Smith, J.S., Caputo, E., Boeke, J.D. Mol. Cell. Biol. (1999) [Pubmed]
  28. A deubiquitinating enzyme interacts with SIR4 and regulates silencing in S. cerevisiae. Moazed, D., Johnson, D. Cell (1996) [Pubmed]
  29. Acetylation of the yeast histone H4 N terminus regulates its binding to heterochromatin protein SIR3. Carmen, A.A., Milne, L., Grunstein, M. J. Biol. Chem. (2002) [Pubmed]
  30. Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Kennedy, B.K., Gotta, M., Sinclair, D.A., Mills, K., McNabb, D.S., Murthy, M., Pak, S.M., Laroche, T., Gasser, S.M., Guarente, L. Cell (1997) [Pubmed]
  31. Yeast heterochromatin is a dynamic structure that requires silencers continuously. Cheng, T.H., Gartenberg, M.R. Genes Dev. (2000) [Pubmed]
  32. Nuclear organization and transcriptional silencing in yeast. Gotta, M., Gasser, S.M. Experientia (1996) [Pubmed]
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