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

• Overproduced SIR3 also could restore silencing at HMR in sir1 delta cells [5].

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

• Silent information regulator two ortholog 1 (SIRT1) is the human ortholog of the yeast sir2 protein; one of the most important regulators of lifespan extension by caloric restriction in several organisms [20].

References