Disease relevance of SIR3

• Mutation of SGS1 is shown to cause premature aging in yeast mother cells on the basis of a shortened life-span and the aging-induced phenotypes of sterility and redistribution of the Sir3 silencing protein from telomeres to the nucleolus [1].
• A strain disrupted in CMT1 was generated in C. neoformans; this had no effect on virulence in an animal model of cryptococcosis [2].

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

• Overproduced SIR3 also could restore silencing at HMR in sir1 delta cells [11].
• The positioning of yeast telomeres depends on SIR3, SIR4, and the integrity of the nuclear membrane [12].
• Sir3 hyperphosphorylation is correlated with reduced subtelomeric silencing, increased subtelomeric cell wall gene expression, and stress resistance to chlorpromazine, but does not affect the silent HML and rDNA loci [13].

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

• Using protein affinity chromatography, we show that SIR2, SIR3, and two proteins of 69 and 110 kDa tightly associate with SIR4 [28].
• Binding of H4 peptide (residues 1-34) acetylated at lysines Lys-5, Lys-8, Lys-12, and Lys-16 to an immobilized SIR3 protein fragment (residues 510-970) was investigated using surface plasmon resonance [29].
• We show by indirect immunofluorescence that Sir3p and Sir4p are redirected to the nucleolus in the SIR4-42 mutant [30].
• Reactivation of unstably repressed rings was blocked by overexpression of silencing proteins Sir3p and Sir4p, and chromatin immunoprecipitation studies showed that overexpressed Sir3p was incorporated into silent chromatin [31].
• In wild-type cells the immunostaining of Sir3p, Sir4p and Rap1 colocalizes with Y' subtelomeric sequences detected by in situ hybridization [32].

References