SIR3

id: P06701
gene_symbol: SIR3
aliases:
  - CMT1
  - MAR2
  - STE8
  - YLR442C
  - L9753.10
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: Structural protein and core component of the Sir2-3-4 silent 
  chromatin complex. SIR3 functions as a nucleosome-binding protein critical for
  heterochromatin formation and maintenance at mating-type loci, telomeres, and 
  rDNA. Unlike SIR2 (the catalytic deacetylase), SIR3 provides the structural 
  scaffold through direct binding to histones and DNA. Forms homodimers and 
  interacts with SIR2 and SIR4 to establish transcriptional repression through 
  chromatin compaction and formation of condensed higher-order chromatin 
  structure. Also directly localizes to euchromatic origins where it 
  participates in modulating origin function through nucleosome binding without 
  requiring its catalytic activity.
existing_annotations:
  - term:
      id: GO:0006270
      label: DNA replication initiation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA-seeded from phylogenetic inference. SIR3 directly localizes 
        to euchromatic origins but suppresses MCM loading (negative regulation),
        not initiation.
      action: REMOVE
      reason: SIR3 does not participate in DNA replication initiation. SIR3 
        suppresses MCM loading and origin activity (GO:0008156), which is 
        negative regulation, not initiation itself. Core machinery includes ORC,
        CDC6, CDT1, MCM2-7, not SIR3.
      additional_reference_ids:
        - PMID:29795547
      supported_by:
        - reference_id: PMID:29795547
          supporting_text: Sir2 and Sir3 were physically associated with 
            nucleosomes adjacent to origins
  - term:
      id: GO:0003688
      label: DNA replication origin binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation. SIR3 binds nucleosomes at origins, not origins 
        themselves. Origins are DNA sequences recognized by ORC.
      action: REMOVE
      reason: SIR3 binds chromatin/nucleosomes near origins, not the origin DNA 
        itself. Origin binding is attributed to ORC (origin recognition 
        complex). This confuses SIR3 nucleosome binding with origin recognition.
      additional_reference_ids:
        - PMID:29795547
      supported_by:
        - reference_id: PMID:29795547
          supporting_text: eCollection 2018 May.
  - term:
      id: GO:0033314
      label: mitotic DNA replication checkpoint signaling
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IBA annotation with no supporting evidence. SIR3 has no known 
        role in checkpoint signaling.
      action: REMOVE
      reason: SIR3 functions in heterochromatin formation and chromatin 
        structure, not DNA damage or replication checkpoints. This is a spurious
        IBA inference.
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: SIR3 directly binds DNA. Experimentally validated with both ds 
        and ssDNA binding (PMID:19099415). More specific molecular functions 
        exist (GO:0003690, GO:0003697) but DNA binding is also appropriate.
      action: ACCEPT
      reason: SIR3 is experimentally shown to bind both double-stranded 
        (PMID:19099415) and single-stranded DNA (PMID:19099415). This is a core 
        molecular function supporting its role in chromatin structure and 
        transcriptional regulation.
      additional_reference_ids:
        - PMID:19099415
        - PMID:17176117
      supported_by:
        - reference_id: PMID:19099415
          supporting_text: Role of nucleic acid binding in Sir3p-dependent 
            interactions with chromatin
        - reference_id: PMID:17176117
          supporting_text: Domain organization and quaternary structure of the 
            Saccharomyces cerevisiae silent information regulator 3 protein, 
            Sir3p.
  - term:
      id: GO:0003682
      label: chromatin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Critical molecular function. SIR3 binds chromatin and nucleosomes
        (PMID:19217406, PMID:18195043). Direct experimental evidence with IDA 
        code also available (PMID:18195043).
      action: ACCEPT
      reason: SIR3 directly binds to chromatin and nucleosomes, which is central
        to its function in heterochromatin formation. This is a core molecular 
        mechanism.
      additional_reference_ids:
        - PMID:19217406
        - PMID:18195043
      supported_by:
        - reference_id: PMID:19217406
          supporting_text: 'Reconstitution of yeast silent chromatin: multiple contact
            sites and O-AADPR binding load SIR complexes onto nucleosomes in vitro.'
        - reference_id: PMID:18195043
          supporting_text: Jan 14. Long-range communication between the 
            silencers of HMR.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: SIR3 localizes to the nucleus where it functions in 
        heterochromatin formation at mating-type loci, telomeres, and 
        euchromatic origins.
      action: ACCEPT
      reason: SIR3 is exclusively nuclear, functioning at HML, HMR, telomeres, 
        rDNA, and euchromatic origins. Correct cellular localization annotation.
  - term:
      id: GO:0005694
      label: chromosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: SIR3 is a chromosomal protein functioning at multiple chromosomal
        loci.
      action: ACCEPT
      reason: SIR3 localizes to chromosomes including telomeres, mating-type 
        loci, rDNA, and euchromatic origins. Correct annotation.
  - term:
      id: GO:0006351
      label: DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: SIR3 is not involved in the transcription process itself. SIR3s 
        role is in transcriptional repression through heterochromatin formation 
        (GO:0006354 or GO:0030466 are more accurate).
      action: MODIFY
      reason: GO:0006351 refers to the core transcription machinery. SIR3 is not
        involved in RNA synthesis. Instead, SIR3 negatively regulates 
        transcription by forming repressive heterochromatin. More specific and 
        accurate terms are GO:0006354 (negative regulation) or GO:0030466 
        (mating-type silencing).
      proposed_replacement_terms:
        - id: GO:0006354
          label: negative regulation of transcription, DNA-templated
        - id: GO:0030466
          label: silent mating-type cassette heterochromatin formation
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11689698
    review:
      summary: SIR3 binds RAP1 protein (PMID:11689698). However, protein binding
        is too vague - more specific binding terms exist.
      action: KEEP_AS_NON_CORE
      reason: GO:0005515 (protein binding) is uninformative per curation 
        guidelines. SIR3 binds specific partners (SIR2, SIR4, RAP1, histones). 
        These are better captured by identical protein binding (GO:0042802), 
        nucleosome binding (GO:0031491), and chromatin binding (GO:0003682).
      additional_reference_ids:
        - PMID:11689698
      supported_by:
        - reference_id: PMID:11689698
          supporting_text: Multiple interactions in Sir protein recruitment by 
            Rap1p at silencers and telomeres in yeast.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:11805837
    review:
      summary: Protein complex membership by mass spectrometry. Too vague 
        compared to specific binding partners and complex membership 
        annotations.
      action: KEEP_AS_NON_CORE
      reason: Generic protein binding obscures the specific complex and binding 
        partners documented in this study.
      additional_reference_ids:
        - PMID:11805837
      supported_by:
        - reference_id: PMID:11805837
          supporting_text: Systematic identification of protein complexes in 
            Saccharomyces cerevisiae by mass spectrometry.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16554755
    review:
      summary: Protein complex annotation. Vague annotation.
      action: KEEP_AS_NON_CORE
      reason: Generic protein binding is less informative than specific binding 
        partner and complex annotations.
      supported_by:
        - reference_id: PMID:16554755
          supporting_text: Global landscape of protein complexes in the yeast 
            Saccharomyces cerevisiae.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16717101
    review:
      summary: SIR3 domain structure and interactions (PMID:16717101). SIR3 
        binding to SIR4 and other partners. Generic term.
      action: KEEP_AS_NON_CORE
      reason: Uninformative without specifying the actual binding partners and 
        interactions.
      additional_reference_ids:
        - PMID:16717101
      supported_by:
        - reference_id: PMID:16717101
          supporting_text: Domain structure and protein interactions of the 
            silent information regulator Sir3 revealed by screening a nested 
            deletion library of protein fragments.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21217703
    review:
      summary: RAP1 binding. Generic annotation.
      action: KEEP_AS_NON_CORE
      reason: Protein binding is too vague. The specific RAP1 interaction should
        be documented elsewhere.
      supported_by:
        - reference_id: PMID:21217703
          supporting_text: A conserved motif within RAP1 has diversified roles 
            in telomere protection and regulation in different organisms.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:16717101
    review:
      summary: SIR3 forms homodimers through nested deletion and biochemical 
        analysis (PMID:16717101). Essential structural feature.
      action: ACCEPT
      reason: SIR3 self-associates to form oligomers and homodimers. This is a 
        core structural feature essential for heterochromatin formation. 
        Directly supports GO:0005677 complex formation.
      additional_reference_ids:
        - PMID:17176117
      supported_by:
        - reference_id: PMID:17176117
          supporting_text: Sir3p self-associates extensively in moderate 
            salt...producing a broad range of oligomers
        - reference_id: PMID:16717101
          supporting_text: 2006 May 22. Domain structure and protein 
            interactions of the silent information regulator Sir3 revealed by 
            screening a nested deletion library of protein fragments.
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:21179020
    review:
      summary: SIR3 homodimer formation confirmed by chromatin-associated 
        interactome mapping (PMID:21179020).
      action: ACCEPT
      reason: Multiple independent experimental approaches confirm SIR3 
        homodimerization is essential for function.
      supported_by:
        - reference_id: PMID:21179020
          supporting_text: Defining the budding yeast chromatin-associated 
            interactome
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:23299941
    review:
      summary: SIR3 C-terminal winged helix domain mediates homodimerization, 
        essential for heterochromatin formation (PMID:23299941).
      action: ACCEPT
      reason: Structural evidence shows SIR3 WH domain dimerizes and this is 
        required for silencing. Core structural function.
      additional_reference_ids:
        - PMID:23299941
      supported_by:
        - reference_id: PMID:23299941
          supporting_text: Dimerization of Sir3 via its C-terminal winged helix 
            domain is essential for yeast heterochromatin formation
  - term:
      id: GO:0031507
      label: heterochromatin formation
    evidence_type: NAS
    original_reference_id: PMID:15282295
    review:
      summary: SIR3 is essential for heterochromatin formation. Core function 
        documented in budding yeast silencing complexes review.
      action: ACCEPT
      reason: SIR3 is a core component of the Sir2-3-4 complex required for 
        heterochromatin formation at mating-type loci, telomeres, and rDNA. This
        is the defining function of SIR3.
      additional_reference_ids:
        - PMID:15282295
      supported_by:
        - reference_id: PMID:15282295
          supporting_text: Budding yeast silencing complexes and regulation of 
            Sir2 activity by protein-protein interactions.
  - term:
      id: GO:0003676
      label: nucleic acid binding
    evidence_type: EXP
    original_reference_id: PMID:17176117
    review:
      summary: Direct experimental evidence of nucleic acid binding through 
        domain organization and biochemical characterization (PMID:17176117).
      action: ACCEPT
      reason: EXP evidence from biochemical studies. SIR3 directly binds nucleic
        acids. Experimentally validated.
      additional_reference_ids:
        - PMID:17176117
      supported_by:
        - reference_id: PMID:17176117
          supporting_text: Domain organization and quaternary structure of the 
            Saccharomyces cerevisiae silent information regulator 3 protein
  - term:
      id: GO:0003688
      label: DNA replication origin binding
    evidence_type: IDA
    original_reference_id: PMID:29795547
    review:
      summary: SIR3 localizes to origin-adjacent nucleosomes but does not bind 
        origins themselves. Origins are DNA sequences bound by ORC.
      action: REMOVE
      reason: SIR3 binds nucleosomes that are located near origins 
        (PMID:29795547), not the origin DNA itself. The origin DNA is recognized
        and bound by ORC (origin recognition complex). This annotation confuses 
        nucleosome binding with origin binding.
      additional_reference_ids:
        - PMID:29795547
      supported_by:
        - reference_id: PMID:29795547
          supporting_text: Yeast heterochromatin regulators Sir2 and Sir3 act 
            directly at euchromatic DNA replication origins.
  - term:
      id: GO:0005677
      label: chromatin silencing complex
    evidence_type: IDA
    original_reference_id: PMID:9122169
    review:
      summary: SIR3 is an integral component of the chromatin silencing complex 
        (Sir2-SIR3-SIR4). Both is_active_in and part_of relations exist in GOA.
      action: ACCEPT
      reason: SIR3 is a core structural component of the Sir2-3-4 silent 
        chromatin complex documented by co-immunoprecipitation and biochemical 
        studies.
      additional_reference_ids:
        - PMID:9122169
      supported_by:
        - reference_id: PMID:9122169
          supporting_text: Silent information regulator protein complexes in 
            Saccharomyces cerevisiae
  - term:
      id: GO:0008156
      label: negative regulation of DNA replication
    evidence_type: IMP
    original_reference_id: PMID:29795547
    review:
      summary: SIR3 suppresses MCM loading at euchromatic origins and maintains 
        repression at heterochromatic origins. Core negative regulatory 
        function.
      action: ACCEPT
      reason: SIR3 directly suppresses MCM complex loading at the majority of 
        euchromatic origins and negatively regulates rDNA and telomeric origin 
        function. This is a key SIR3 function distinguishing it from initiation 
        role.
      additional_reference_ids:
        - PMID:29795547
      supported_by:
        - reference_id: PMID:29795547
          supporting_text: heterochromatin proteins directly modify the local 
            chromatin environment of euchromatic DNA replication origins
  - term:
      id: GO:0031509
      label: subtelomeric heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:1913809
    review:
      summary: SIR3 is required for silencing at telomeres and subtelomeric 
        regions. Classic position-effect data.
      action: ACCEPT
      reason: SIR3 is essential for telomeric and subtelomeric heterochromatin. 
        Core function of SIR complex.
      additional_reference_ids:
        - PMID:1913809
      supported_by:
        - reference_id: PMID:1913809
          supporting_text: Modifiers of position effect are shared between 
            telomeric and silent mating-type loci in S. cerevisiae.
  - term:
      id: GO:0031509
      label: subtelomeric heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:31599702
    review:
      summary: SIR3 role in telomeric silencing in context of lifespan and 
        aging.
      action: ACCEPT
      reason: Multiple genetic studies confirm SIR3 requirement for telomeric 
        silencing and its connection to aging phenotypes.
      additional_reference_ids:
        - PMID:31599702
      supported_by:
        - reference_id: PMID:31599702
          supporting_text: Reciprocal interactions between mtDNA and lifespan 
            control in budding yeast
  - term:
      id: GO:0031509
      label: subtelomeric heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:9501103
    review:
      summary: SIR3 mutation effects on telomeric silencing and NHEJ processes.
      action: ACCEPT
      reason: SIR3 is required for telomeric silencing and maintenance.
      additional_reference_ids:
        - PMID:9501103
      supported_by:
        - reference_id: PMID:9501103
          supporting_text: Components of the Ku-dependent non-homologous 
            end-joining pathway are involved in telomeric length maintenance and
            telomeric silencing.
  - term:
      id: GO:0000781
      label: chromosome, telomeric region
    evidence_type: IMP
    original_reference_id: PMID:27122604
    review:
      summary: SIR3 localizes to telomeric regions and is required for telomere 
        clustering in quiescent cells.
      action: ACCEPT
      reason: SIR3 directly localizes to and functions at telomeres. Documented 
        localization via ChIP.
      additional_reference_ids:
        - PMID:27122604
      supported_by:
        - reference_id: PMID:27122604
          supporting_text: Quiescent Saccharomyces cerevisiae forms telomere 
            hyperclusters
  - term:
      id: GO:0000781
      label: chromosome, telomeric region
    evidence_type: IDA
    original_reference_id: PMID:9710643
    review:
      summary: Direct experimental evidence of SIR3 binding at telomeres by 
        ChIP.
      action: ACCEPT
      reason: ChIP evidence documenting SIR3 at telomeric chromatin.
      additional_reference_ids:
        - PMID:9710643
      supported_by:
        - reference_id: PMID:9710643
          supporting_text: Sir proteins, Rif proteins, and Cdc13p bind 
            Saccharomyces telomeres in vivo.
  - term:
      id: GO:0000792
      label: heterochromatin
    evidence_type: IDA
    original_reference_id: PMID:20176978
    review:
      summary: SIR3 is a component of heterochromatin. Required for formation 
        and maintenance.
      action: ACCEPT
      reason: SIR3 localizes to and is integral part of heterochromatin at all 
        silenced loci.
      supported_by:
        - reference_id: PMID:20176978
          supporting_text: An auxiliary silencer and a boundary element maintain
            high levels of silencing proteins at HMR in Saccharomyces 
            cerevisiae.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HDA
    original_reference_id: PMID:14576278
    review:
      summary: HDA from mitochondrial proteomics study. SIR3 is not 
        mitochondrial.
      action: REMOVE
      reason: SIR3 is a nuclear protein with no known mitochondrial function or 
        localization. HDA from mitochondrial proteomics is a false positive, 
        likely from contamination in the MS sample.
      supported_by:
        - reference_id: PMID:14576278
          supporting_text: The proteome of Saccharomyces cerevisiae 
            mitochondria.
  - term:
      id: GO:0005739
      label: mitochondrion
    evidence_type: HDA
    original_reference_id: PMID:16823961
    review:
      summary: HDA from mitochondrial proteomics. Spurious annotation.
      action: REMOVE
      reason: SIR3 is exclusively nuclear. This HDA is likely experimental 
        artifact.
      supported_by:
        - reference_id: PMID:16823961
          supporting_text: "Toward the complete yeast mitochondrial proteome: multidimensional
            separation techniques for mitochondrial proteomics."
  - term:
      id: GO:0006303
      label: double-strand break repair via nonhomologous end joining
    evidence_type: IMP
    original_reference_id: PMID:9501103
    review:
      summary: SIR3 has been implicated in NHEJ through studies with Ku complex,
        but this is likely indirect through telomere maintenance.
      action: REMOVE
      reason: SIR3 itself is not a NHEJ component or catalyst. The association 
        appears to be indirect through telomeric regulation - SIR3 represses 
        telomeric origins and helps maintain telomere structure, which affects 
        DSB signaling. SIR3 has no role in core NHEJ machinery (Ku70/80, Lig IV,
        XLF).
      additional_reference_ids:
        - PMID:9501103
      supported_by:
        - reference_id: PMID:9501103
          supporting_text: Components of the Ku-dependent non-homologous 
            end-joining pathway are involved in telomeric length maintenance and
            telomeric silencing.
  - term:
      id: GO:0030466
      label: silent mating-type cassette heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:3297920
    review:
      summary: Classic position-effect data. SIR3 is essential for HML and HMR 
        silencing. Founding function of the SIR genes.
      action: ACCEPT
      reason: SIR3 is required for mating-type silencing at HML and HMR loci. 
        This is a core function defined in the original SIR studies.
      additional_reference_ids:
        - PMID:3297920
      supported_by:
        - reference_id: PMID:3297920
          supporting_text: Four genes responsible for a position effect on 
            expression from HML and HMR in Saccharomyces cerevisiae.
  - term:
      id: GO:0097695
      label: establishment of protein-containing complex localization to 
        telomere
    evidence_type: IMP
    original_reference_id: PMID:26218225
    review:
      summary: SIR3 is part of the Sir complex that localizes to telomeres. Ku 
        complex recruitment involves SIR4.
      action: ACCEPT
      reason: SIR3 as part of the Sir complex is required for complex 
        localization to telomeres for telomerase recruitment and telomere 
        maintenance.
      additional_reference_ids:
        - PMID:26218225
      supported_by:
        - reference_id: PMID:26218225
          supporting_text: The Ku subunit of telomerase binds Sir4 to recruit 
            telomerase to lengthen telomeres
  - term:
      id: GO:0034398
      label: telomere tethering at nuclear periphery
    evidence_type: IMP
    original_reference_id: PMID:26399229
    review:
      summary: SIR3 participates in telomere clustering and nuclear 
        organization.
      action: ACCEPT
      reason: SIR3 as component of Sir complex participates in telomere 
        tethering and clustering at nuclear periphery.
      additional_reference_ids:
        - PMID:26399229
      supported_by:
        - reference_id: PMID:26399229
          supporting_text: Spatial reorganization of telomeres in long-lived 
            quiescent cells
  - term:
      id: GO:0034398
      label: telomere tethering at nuclear periphery
    evidence_type: IMP
    original_reference_id: PMID:27122604
    review:
      summary: SIR3 required for telomere hyperclustering and nuclear 
        organization in quiescent cells.
      action: ACCEPT
      reason: Additional evidence for SIR3s role in telomere organization.
      additional_reference_ids:
        - PMID:27122604
      supported_by:
        - reference_id: PMID:27122604
          supporting_text: Quiescent Saccharomyces cerevisiae forms telomere 
            hyperclusters
  - term:
      id: GO:0000781
      label: chromosome, telomeric region
    evidence_type: IDA
    original_reference_id: PMID:16956377
    review:
      summary: SIR3 localization at telomeres documented.
      action: ACCEPT
      reason: Confirms telomeric localization of SIR3 at functional loci.
      supported_by:
        - reference_id: PMID:16956377
          supporting_text: The nuclear GTPase Gsp1p can affect proper telomeric 
            function through the Sir4 protein
  - term:
      id: GO:0003682
      label: chromatin binding
    evidence_type: IDA
    original_reference_id: PMID:18195043
    review:
      summary: Long-range communication and chromatin structure study. SIR3 
        directly binds chromatin.
      action: ACCEPT
      reason: Experimental evidence for chromatin binding in HMR silencer 
        analysis.
      additional_reference_ids:
        - PMID:18195043
      supported_by:
        - reference_id: PMID:18195043
          supporting_text: Long-range communication between the silencers of 
            HMR.
  - term:
      id: GO:0003690
      label: double-stranded DNA binding
    evidence_type: IDA
    original_reference_id: PMID:19099415
    review:
      summary: SIR3 binds double-stranded DNA in vitro. Direct biochemical 
        evidence.
      action: ACCEPT
      reason: SIR3 directly binds dsDNA. Core molecular function.
      additional_reference_ids:
        - PMID:19099415
      supported_by:
        - reference_id: PMID:19099415
          supporting_text: Role of nucleic acid binding in Sir3p-dependent 
            interactions with chromatin fibers
  - term:
      id: GO:0003697
      label: single-stranded DNA binding
    evidence_type: IDA
    original_reference_id: PMID:19099415
    review:
      summary: SIR3 binds single-stranded DNA in vitro. Direct biochemical 
        evidence.
      action: ACCEPT
      reason: SIR3 binds both ss and dsDNA. Core molecular function.
      additional_reference_ids:
        - PMID:19099415
      supported_by:
        - reference_id: PMID:19099415
          supporting_text: Role of nucleic acid binding in Sir3p-dependent 
            interactions with chromatin fibers.
  - term:
      id: GO:0005730
      label: nucleolus
    evidence_type: IDA
    original_reference_id: PMID:9150138
    review:
      summary: SIR3 redistributes from telomeres to nucleolus in long-lived 
        yeast strains. Reflects differential regulation in aging.
      action: ACCEPT
      reason: SIR3 can localize to nucleolus where rDNA silencing occurs. 
        Secondary but documented localization site. Important for aging 
        phenotypes.
      additional_reference_ids:
        - PMID:9150138
      supported_by:
        - reference_id: PMID:9150138
          supporting_text: Redistribution of silencing proteins from telomeres 
            to the nucleolus is associated with extension of life span in S. 
            cerevisiae.
  - term:
      id: GO:0030466
      label: silent mating-type cassette heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:16581798
    review:
      summary: SIR3 BAH domain structure and function essential for HM 
        silencing.
      action: ACCEPT
      reason: Structural basis of SIR3 function in mating-type silencing 
        documented.
      additional_reference_ids:
        - PMID:16581798
      supported_by:
        - reference_id: PMID:16581798
          supporting_text: Structure and function of the Saccharomyces 
            cerevisiae Sir3 BAH domain.
  - term:
      id: GO:0030466
      label: silent mating-type cassette heterochromatin formation
    evidence_type: IGI
    original_reference_id: PMID:16581798
    review:
      summary: Genetic interaction studies showing SIR3-SIR1 relationship in 
        silencing.
      action: ACCEPT
      reason: Genetic interactions confirm SIR3s role in mating-type silencing.
      additional_reference_ids:
        - PMID:16581798
      supported_by:
        - reference_id: PMID:16581798
          supporting_text: Structure and function of the Saccharomyces 
            cerevisiae Sir3 BAH domain.
  - term:
      id: GO:0031491
      label: nucleosome binding
    evidence_type: IDA
    original_reference_id: PMID:19217406
    review:
      summary: SIR3 binds nucleosomes in vitro. Histone H4 tail and H3K79 are 
        contact sites. Core mechanism of action.
      action: ACCEPT
      reason: SIR3 directly binds nucleosomes through multiple histone contact 
        sites. Core mechanism. Biochemically validated.
      additional_reference_ids:
        - PMID:19217406
      supported_by:
        - reference_id: PMID:19217406
          supporting_text: 'Reconstitution of yeast silent chromatin: multiple contact
            sites...load SIR complexes onto nucleosomes'
  - term:
      id: GO:0031507
      label: heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:16908543
    review:
      summary: SIR3 C-terminal domain involvement in heterochromatin initiation 
        and spreading.
      action: ACCEPT
      reason: Functional analysis of SIR3 domains in heterochromatin formation 
        and maintenance.
      additional_reference_ids:
        - PMID:16908543
      supported_by:
        - reference_id: PMID:16908543
          supporting_text: Sir3 C-terminal domain involvement in the initiation 
            and spreading of heterochromatin.
  - term:
      id: GO:0070481
      label: nuclear-transcribed mRNA catabolic process, non-stop decay
    evidence_type: IMP
    original_reference_id: PMID:17660569
    review:
      summary: SIR3 identified in genomic screen for nonstop mRNA decay factors.
        Mechanism unclear and likely indirect.
      action: REMOVE
      reason: SIR3 was recovered in a genomic screen (PMID:17660569) but SIR3s 
        primary functions are in chromatin and heterochromatin formation, not 
        mRNA surveillance. Association is likely indirect through secondary 
        effects on gene expression or cell stress responses, not a core function
        in mRNA decay pathway.
      additional_reference_ids:
        - PMID:17660569
      supported_by:
        - reference_id: PMID:17660569
          supporting_text: A genomic screen in yeast reveals novel aspects of 
            nonstop mRNA metabolism.
core_functions:
  - molecular_function:
      id: GO:0003682
      label: chromatin binding
    directly_involved_in:
      - id: GO:0031507
        label: heterochromatin formation
    description: SIR3 is a structural component that binds chromatin and 
      nucleosomes to establish and maintain heterochromatin domains. This is the
      primary molecular mechanism by which SIR3 functions.
  - molecular_function:
      id: GO:0042802
      label: identical protein binding
    directly_involved_in:
      - id: GO:0030466
        label: silent mating-type cassette heterochromatin formation
    description: SIR3 forms homodimers and interacts with SIR2 and SIR4 to 
      assemble the Sir2-3-4 silent chromatin complex. Homodimerization through 
      the C-terminal winged helix domain is essential for silencing function.
  - molecular_function:
      id: GO:0031491
      label: nucleosome binding
    directly_involved_in:
      - id: GO:0008156
        label: negative regulation of DNA replication
    description: SIR3 directly binds to histone octamers and nucleosomes at 
      mating-type loci, telomeres, rDNA, and euchromatic origins. This 
      nucleosome binding is critical for both establishing transcriptional 
      silencing and suppressing DNA replication initiation at origins.
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: PMID:1913809
    title: Modifiers of position effect are shared between telomeric and silent 
      mating-type loci in S. cerevisiae.
    findings: []
  - id: PMID:3297920
    title: Four genes responsible for a position effect on expression from HML 
      and HMR in Saccharomyces cerevisiae.
    findings: []
  - id: PMID:9122169
    title: Silent information regulator protein complexes in Saccharomyces 
      cerevisiae.
    findings: []
  - id: PMID:9150138
    title: Redistribution of silencing proteins from telomeres to the nucleolus 
      is associated with extension of life span in S. cerevisiae.
    findings: []
  - id: PMID:9501103
    title: Components of the Ku-dependent non-homologous end-joining pathway are
      involved in telomeric length maintenance and telomeric silencing.
    findings: []
  - id: PMID:9710643
    title: Sir proteins, Rif proteins, and Cdc13p bind Saccharomyces telomeres 
      in vivo.
    findings: []
  - id: PMID:11689698
    title: Multiple interactions in Sir protein recruitment by Rap1p at 
      silencers and telomeres in yeast.
    findings: []
  - id: PMID:11805837
    title: Systematic identification of protein complexes in Saccharomyces 
      cerevisiae by mass spectrometry.
    findings: []
  - id: PMID:14576278
    title: The proteome of Saccharomyces cerevisiae mitochondria.
    findings: []
  - id: PMID:15282295
    title: Budding yeast silencing complexes and regulation of Sir2 activity by 
      protein-protein interactions.
    findings: []
  - id: PMID:16554755
    title: Global landscape of protein complexes in the yeast Saccharomyces 
      cerevisiae.
    findings: []
  - id: PMID:16581798
    title: Structure and function of the Saccharomyces cerevisiae Sir3 BAH 
      domain.
    findings: []
  - id: PMID:16717101
    title: Domain structure and protein interactions of the silent information 
      regulator Sir3 revealed by screening a nested deletion library of protein 
      fragments.
    findings: []
  - id: PMID:16823961
    title: Toward the complete yeast mitochondrial proteome.
    findings: []
  - id: PMID:16908543
    title: Sir3 C-terminal domain involvement in the initiation and spreading of
      heterochromatin.
    findings: []
  - id: PMID:16956377
    title: The nuclear GTPase Gsp1p can affect proper telomeric function through
      the Sir4 protein in Saccharomyces cerevisiae.
    findings: []
  - id: PMID:17176117
    title: Domain organization and quaternary structure of the Saccharomyces 
      cerevisiae silent information regulator 3 protein, Sir3p.
    findings: []
  - id: PMID:17660569
    title: A genomic screen in yeast reveals novel aspects of nonstop mRNA 
      metabolism.
    findings: []
  - id: PMID:18195043
    title: Long-range communication between the silencers of HMR.
    findings: []
  - id: PMID:19099415
    title: Role of nucleic acid binding in Sir3p-dependent interactions with 
      chromatin fibers.
    findings: []
  - id: PMID:19217406
    title: Reconstitution of yeast silent chromatin multiple contact sites and 
      O-AADPR binding load SIR complexes onto nucleosomes in vitro.
    findings: []
  - id: PMID:20176978
    title: An auxiliary silencer and a boundary element maintain high levels of 
      silencing proteins at HMR in Saccharomyces cerevisiae.
    findings: []
  - id: PMID:21179020
    title: Defining the budding yeast chromatin-associated interactome.
    findings: []
  - id: PMID:21217703
    title: A conserved motif within RAP1 has diversified roles in telomere 
      protection and regulation in different organisms.
    findings: []
  - id: PMID:23299941
    title: Dimerization of Sir3 via its C-terminal winged helix domain is 
      essential for yeast heterochromatin formation.
    findings: []
  - id: PMID:26218225
    title: The Ku subunit of telomerase binds Sir4 to recruit telomerase to 
      lengthen telomeres in S. cerevisiae.
    findings: []
  - id: PMID:26399229
    title: Spatial reorganization of telomeres in long-lived quiescent cells.
    findings: []
  - id: PMID:27122604
    title: Quiescent Saccharomyces cerevisiae forms telomere hyperclusters at 
      the nuclear membrane vicinity through a multifaceted mechanism involving 
      Esc1, the Sir complex, and chromatin condensation.
    findings: []
  - id: PMID:29795547
    title: Yeast heterochromatin regulators Sir2 and Sir3 act directly at 
      euchromatic DNA replication origins.
    findings: []
  - id: PMID:31599702
    title: Reciprocal interactions between mtDNA and lifespan control in budding
      yeast.
    findings: []