HST3

id: P53687
gene_symbol: HST3
aliases:
  - YOR025W
  - OR26.15
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: 'NAD-dependent histone deacetylase HST3, a member of the sirtuin family.
  Catalyzes deacetylation of histone H3 lysine 56 (H3K56), a critical residue in nucleosome
  assembly during DNA replication and repair. Functions redundantly with HST4 in regulating
  transcription, sister chromatid recombination, DNA damage checkpoint control, and
  genome stability.'
core_functions:
  - molecular_function:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    description: 'NAD-dependent deacetylation of histone H3 lysine 56, catalyzed during
      S/G2 phase transition. Essential cofactor in cell cycle checkpoint control and
      proper nucleosome assembly during DNA replication.'
    directly_involved_in:
      - id: GO:0006351
        label: DNA-templated transcription
      - id: GO:1990414
        label: replication-born double-strand break repair via sister chromatid 
          exchange
  - molecular_function:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    description: 'Parent term for histone lysine deacetylation activity. Critical
      for maintaining proper histone acetylation states and transcription regulation.'
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'HST3 localizes to the nucleus where it functions as a histone deacetylase.
        UniProt subcellular localization states both cytoplasm and nucleus. This IBA
        annotation is supported by phylogenetic inference from orthologs. IC evidence
        from PMID:12242223 also confirms nuclear localization, which is essential
        for its function in histone deacetylation and transcriptional regulation.'
      action: ACCEPT
      reason: 'HST3 is a nuclear protein required for histone H3K56 deacetylation
        during S/G2 phase transitions (PMID:17977840). IBA annotation is well-supported
        by orthologous relationships across sirtuins and confirmed experimentally.'
      supported_by:
        - reference_id: PMID:12242223
          supporting_text: 'Furthermore, Hst3 was physically present at 2mu ARS in
            a silencing context as well as at the endogenous 2mu plasmid'
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'This is the core enzymatic activity of HST3. It catalyzes NAD-dependent
        deacetylation of histone H3 lysine 56. Multiple experimental lines of evidence
        confirm this activity: direct biochemical assays showing NAD-dependent deacetylase
        activity in vitro (PMID:17977840), and functional studies demonstrating H3K56
        deacetylation during S phase/G2 transition (PMID:23357952, PMID:31167142).
        IBA phylogenetic evidence is very well supported.'
      action: ACCEPT
      reason: 'This is the canonical and well-established primary catalytic function
        of HST3. The protein contains the sirtuin domain (InterPro: IPR003000, IPR050134)
        and demonstrates NAD-dependent histone deacetylase activity experimentally.
        Core function of gene.'
      supported_by:
        - reference_id: PMID:17977840
          supporting_text: 'Hst3 has NAD-dependent histone deacetylase activity in
            vitro and that it functions during S phase to deacetylate the core domain
            of histone H3 at lysine 56 (H3K56)'
        - reference_id: PMID:23357952
          supporting_text: 'These functions are necessary for the repair of replication-born
            DSBs by SCR'
  - term:
      id: GO:0000183
      label: rDNA heterochromatin formation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: 'HST3 contributes to rDNA heterochromatin formation through its NAD-dependent
        histone deacetylase activity. However, this term appears somewhat over-specific
        compared to the broader silencing roles. UniProt documents roles in histone
        H3K56 deacetylation and telomeric silencing. The rDNA-specific annotation
        is less well-established than general transcriptional silencing.'
      action: KEEP_AS_NON_CORE
      reason: 'While HST3 participates in silencing processes that may include rDNA,
        this is not explicitly demonstrated as a core function. The primary characterized
        substrate is histone H3K56, which affects broader transcription and genome
        stability. The rDNA-specific function is an inferred application of the deacetylase
        activity rather than a primary function.'
      additional_reference_ids:
        - PMID:7498786
        - PMID:31167142
      supported_by:
        - reference_id: PMID:7498786
          supporting_text: The SIR2 gene family, conserved from bacteria to 
            humans, functions in silencing, cell cycle progression, and 
            chromosome stability.
        - reference_id: PMID:31167142
          supporting_text: Yeast Sirtuin Family Members Maintain Transcription 
            Homeostasis to Ensure Genome Stability.
  - term:
      id: GO:0000781
      label: chromosome, telomeric region
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: 'This is a localization annotation indicating HST3 associates with
        telomeric regions of chromosomes. Evidence shows HST3 and HST4 contribute
        to telomeric silencing (PMID:7498786), but this is inferred primarily from
        functional effects rather than direct localization studies. The IEA inference
        from GO:0031509 (subtelomeric heterochromatin formation) is logically sound.'
      action: KEEP_AS_NON_CORE
      reason: 'HST3 function at telomeric regions is secondary to its core H3K56 deacetylase
        activity. The localization annotation is supported by functional genomics
        (silencing phenotypes) but this is not a primary function description. Better
        captured under heterochromatin formation processes.'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'Duplicate of annotation 1 (same GO term, different evidence code).
        UniProtKB subcellular location vocabulary explicitly states HST3 is localized
        to nucleus and cytoplasm. This IEA annotation from UniProt is consistent with
        the IBA annotation.'
      action: ACCEPT
      reason: 'Redundant but valid annotation. Multiple evidence types (IEA from subcellular
        location mapping and IBA from phylogenetics) support nuclear localization.'
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: 'UniProtKB subcellular location states "Cytoplasm. Nucleus." HST3 is
        documented in both compartments, though primary function is nuclear. Cytoplasmic
        localization is less characterized but appears to be a minor component of
        HST3 localization.'
      action: KEEP_AS_NON_CORE
      reason: 'HST3 has documented cytoplasmic localization in UniProt, but its characterized
        functions (H3K56 deacetylation, transcription regulation, DNA repair) are
        nuclear. Cytoplasmic localization may represent transit or peripheral functions.'
  - term:
      id: GO:0006351
      label: DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'HST3 involvement in transcription is experimentally confirmed. PMID:31167142
        demonstrates that Hst3 and Hst4 regulate transcription homeostasis by repressing
        nascent RNA transcription at many loci. This prevents excessive transcription-associated
        R-loops that cause DNA damage. The function is broader than suggested by general
        "DNA-templated transcription" term.'
      action: ACCEPT
      reason: 'HST3 is documented as regulating transcription through H3K56 deacetylation.
        IEA from UniProt keywords (Transcription) is supported by experimental evidence
        (PMID:31167142 shows HST3 regulates nascent transcription). This is a core
        regulatory function.'
      supported_by:
        - reference_id: PMID:31167142
          supporting_text: 'Hst3 and Hst4 are required to repress transcription of
            coding and non-coding RNAs'
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'Transferase activity is an extremely broad parent term for enzyme
        activities that transfer chemical groups. However, HST3 is a deacetylase (removes
        acetyl groups), not a transferase. The EC number (2.3.1.286) is unusual notation
        for this annotation. UniProt keyword "Transferase" may be a legacy annotation.
        This term is mechanistically misleading.'
      action: REMOVE
      reason: 'HST3 catalyzes NAD-dependent deacetylation (removal of acetyl groups),
        not transfer of groups to other molecules. While deacetylation is technically
        a hydrolysis/removal reaction rather than transfer, it is explicitly classified
        as NAD-dependent deacetylase activity (GO:0017136, GO:0034979). The term "transferase
        activity" (GO:0016740) is not appropriate and would mislead about the molecular
        mechanism.'
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'Duplicate annotation (same GO term as annotation 2 and 18). This is
        the same enzymatic activity annotated by IEA using ARBA machine learning rules.
        Multiple evidence codes (IBA, IEA/ARBA, IDA, IMP) converge on the same core
        catalytic function.'
      action: ACCEPT
      reason: 'Redundant but valid. Multiple independent lines of evidence support
        this core enzymatic function.'
  - term:
      id: GO:0031507
      label: heterochromatin formation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: 'HST3 contributes to heterochromatin formation through histone deacetylation.
        PMID:7498786 shows hst3 hst4 double mutants are defective in telomeric silencing.
        However, PMID:31167142 suggests the primary mechanism is regulation of transcription
        homeostasis rather than structural heterochromatin formation. The term is
        somewhat over-general for the more specific H3K56 deacetylation function.'
      action: KEEP_AS_NON_CORE
      reason: 'While HST3 participates in silencing and heterochromatin-associated
        processes, its primary characterized function is H3K56 deacetylation and transcription
        regulation. Heterochromatin formation is an inferred downstream consequence
        rather than direct function.'
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: 'This is a more general parent term for histone deacetylase activity.
        HST3 catalyzes NAD-dependent deacetylation of histone lysine residues (primarily
        H3K56). This is correctly inferred from the EC number (2.3.1.286) which is
        mapped to the RHEA reaction for NAD-dependent protein lysine deacetylation.
        This is an appropriate superclass annotation.'
      action: ACCEPT
      reason: 'Correct parent-term annotation. HST3 activity is a specific instance
        of NAD-dependent protein lysine deacetylase activity. IEA from EC number mapping
        is appropriate.'
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: 'HST3 contains zinc-binding sites. UniProt specifically documents that
        HST3 binds 1 zinc ion per subunit, with 4 zinc-coordinating residues in the
        catalytic sirtuin domain (positions 195, 198, 220, 223). The annotation is
        inferred from UniProt keyword "Zinc" (GO_REF:0000043 is UniProt-KW mapping).
        PMID:30358795 on yeast zinc proteome may provide additional validation.'
      action: ACCEPT
      reason: 'HST3 contains a zinc cofactor essential for sirtuin catalytic activity.
        The annotation is well-supported by UniProt feature annotations identifying
        zinc-binding residues.'
  - term:
      id: GO:0070403
      label: NAD+ binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: 'HST3 is an NAD-dependent deacetylase and must bind NAD+ cofactor.
        UniProt documents multiple NAD+-binding residues (positions 60-79, 151-154,
        282-284, 312-314, 333) in the characteristic sirtuin NAD+ binding domain.
        The inference from InterPro IPR003000 (sirtuin domain) is appropriate. This
        is a required cofactor binding activity.'
      action: ACCEPT
      reason: 'Essential cofactor binding for catalytic activity. HST3 catalytic mechanism
        absolutely requires NAD+ binding. The annotation is correctly inferred from
        the sirtuin domain structure.'
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: RCA
    original_reference_id: PMID:30358795
    review:
      summary: 'Zinc ion binding is specifically documented by UniProt with four coordinating
        residues identified through structure. RCA (Reviewed Computational Analysis)
        using PMID:30358795 (yeast zinc proteome characterization) is appropriate
        evidence. This is equivalent to the metal ion binding annotation but more
        specific.'
      action: ACCEPT
      reason: 'Specific instance of the broader metal ion binding annotation. Zinc
        is specifically required for sirtuin catalytic activity. RCA evidence from
        zinc proteome characterization is valid.'
      supported_by:
        - reference_id: PMID:30358795
          supporting_text: The cellular economy of the Saccharomyces cerevisiae 
            zinc proteome.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IC
    original_reference_id: PMID:12242223
    review:
      summary: 'Third annotation of nuclear localization. PMID:12242223 provides experimental
        evidence that HST3 is physically present at the 2mu ARS silencer element in
        a silencing context, inferred curated evidence (IC) of nuclear localization.
        Redundant with annotations 1 and 5.'
      action: ACCEPT
      reason: 'Valid experimental evidence of nuclear localization through physical
        presence at genomic elements. Redundant with other nuclear localization annotations
        but valid.'
      supported_by:
        - reference_id: PMID:12242223
          supporting_text: 'Furthermore, Hst3 was physically present at 2mu ARS in
            a silencing context as well as at the endogenous 2mu plasmid'
  - term:
      id: GO:0031509
      label: subtelomeric heterochromatin formation
    evidence_type: IGI
    original_reference_id: PMID:7498786
    review:
      summary: 'PMID:7498786 shows that hst3 hst4 double mutants are defective in
        telomeric silencing, establishing that HST3 and HST4 contribute together to
        subtelomeric silencing. IGI (Inferred from Genetic Interaction) is appropriate
        evidence code, using HST4 as the interacting gene. This demonstrates HST3
        function in telomeric silencing.'
      action: ACCEPT
      reason: 'Experimental evidence demonstrates HST3 requirement for subtelomeric
        silencing. The function is well-characterized even if redundant with HST4.
        This is a core genomic stability function.'
      supported_by:
        - reference_id: PMID:7498786
          supporting_text: 'hst3 hst4 double mutants are defective in telomeric silencing'
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:17977840
    review:
      summary: 'Fourth annotation of NAD-dependent histone deacetylase activity. IDA
        (Inferred from Direct Assay) using PMID:17977840 is excellent evidence. The
        paper demonstrates Hst3 has NAD-dependent histone deacetylase activity in
        vitro and specifically deacetylates histone H3 at lysine 56. Redundant with
        annotations 2, 8, and 9 but strongest evidence type.'
      action: ACCEPT
      reason: 'Directly demonstrates NAD-dependent histone deacetylase activity through
        biochemical assays. IDA is the strongest experimental evidence code. Core
        function.'
      supported_by:
        - reference_id: PMID:17977840
          supporting_text: 'Hst3 has NAD-dependent histone deacetylase activity in
            vitro and that it functions during S phase to deacetylate the core domain
            of histone H3 at lysine 56 (H3K56)'
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IMP
    original_reference_id: PMID:17977840
    review:
      summary: 'Fifth annotation of NAD-dependent histone deacetylase activity. IMP
        (Inferred from Mutant Phenotype) using PMID:17977840 shows that loss of Hst3
        function results in failure to deacetylate H3K56, demonstrating its role.
        This creates a functional annotation rather than direct activity assay. Redundant
        with annotations 2, 8, and 18.'
      action: ACCEPT
      reason: 'Demonstrates function through loss-of-function phenotype. Loss of Hst3
        results in failure to deacetylate H3K56 and downstream phenotypes (S phase
        checkpoint defect, sister chromatid cohesion impairment). Valid functional
        evidence.'
      supported_by:
        - reference_id: PMID:17977840
          supporting_text: 'Loss of Hst3-mediated regulation of H3K56 acetylation
            results in a defect in the S phase DNA damage checkpoint'
  - term:
      id: GO:0006351
      label: DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:31167142
    review:
      summary: 'IDA evidence from PMID:31167142 shows comprehensive transcriptomic
        analysis demonstrating HST3 directly regulates transcription. Using NET-seq
        (native elongating transcript sequencing), the authors show that loss of Hst3
        and Hst4 leads to global increases in nascent transcription at ~1,000 genes.
        This is direct measurement of transcription dynamics, not merely inference.
        Highly specific to H3K56-mediated regulation.'
      action: ACCEPT
      reason: 'Robust experimental evidence of direct involvement in transcription
        regulation. NET-seq provides genome-wide transcription measurement. HST3 specifically
        regulates transcription of coding and non-coding RNAs. Core regulatory function.'
      supported_by:
        - reference_id: PMID:31167142
          supporting_text: 'Loss of Hst3 and Hst4 led to a global shift in the nascent
            RNA transcriptome, with an average fold increase of ~1.4'
  - term:
      id: GO:0009299
      label: mRNA transcription
    evidence_type: IDA
    original_reference_id: PMID:31167142
    review:
      summary: 'Specific child term of DNA-templated transcription. PMID:31167142
        demonstrates that HST3 regulates mRNA transcription specifically: metagene
        analysis shows higher nascent transcript levels throughout genic regions,
        especially near transcription start sites. This is more specific than the
        parent term.'
      action: ACCEPT
      reason: 'Directly measured via NET-seq showing mRNA-coding regions are specifically
        affected. HST3 acts as transcription repressor to maintain transcription homeostasis.
        Valid specific annotation.'
      supported_by:
        - reference_id: PMID:31167142
          supporting_text: 'Metagene plots of mean nascent transcript levels, representative
            genome browser views of NET-seq data, and a heatmap of the log2-fold change
            between the hst4Δ HST3-FRB mutant and WT confirmed higher levels of transcription
            throughout genic regions'
  - term:
      id: GO:1990414
      label: replication-born double-strand break repair via sister chromatid 
        exchange
    evidence_type: IMP
    original_reference_id: PMID:23357952
    review:
      summary: 'PMID:23357952 provides comprehensive evidence that HST3 is required
        for sister chromatid recombination (SCR) of replication-born double-strand
        breaks. The authors identify hst3 among 12 mutants consistently impaired in
        SCR using physical assay of recombination. Loss of HST3 (and HST4) severely
        impairs the ability to repair DSBs with the sister chromatid, with 50-fold
        decrease in intrachromosomal SCR. This is a major genome stability function
        dependent on H3K56 acetylation state.'
      action: ACCEPT
      reason: 'HST3 is a critical factor for proper DSB repair template choice (sister
        chromatid preference). Loss results in genome instability and increased recombination
        with homologs instead of sister chromatids. Core function in genome stability.'
      supported_by:
        - reference_id: PMID:23357952
          supporting_text: 'The hst3Δ mutation is strongly affected in intrachromosomal
            SCR repeat recombination (50-fold decrease)'
  - term:
      id: GO:0046459
      label: short-chain fatty acid metabolic process
    evidence_type: IMP
    original_reference_id: PMID:12618394
    review:
      summary: 'PMID:12618394 shows that growth on short-chain fatty acids (acetate,
        propionate) is severely impaired in quintuple sir2 hst1 hst2 hst3 hst4 mutant
        strain, with HST3 and HST4 identified as most important for growth on these
        substrates. However, this is not the primary function of HST3. The mechanism
        appears to involve SIR2 family proteins controlling acetyl-CoA synthetase
        (Acs) enzyme activity, suggesting an indirect metabolic role rather than direct
        involvement in lipid metabolism.'
      action: MARK_AS_OVER_ANNOTATED
      reason: 'While HST3 contributes to growth on short-chain fatty acids through
        its requirement for Acs activity regulation, this is not a primary enzymatic
        function. HST3 is a histone deacetylase whose role in fatty acid metabolism
        is indirect, mediated through NAD-dependent regulation of Acs protein acetylation.
        The annotation overstates HST3s direct involvement in metabolic process. Better
        annotated as a regulatory cofactor effect than a metabolic process function.'
      additional_reference_ids:
        - PMID:12618394
      supported_by:
        - reference_id: PMID:12618394
          supporting_text: Short-chain fatty acid activation by acyl-coenzyme A 
            synthetases requires SIR2 protein function in Salmonella enterica 
            and Saccharomyces cerevisiae.
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:0000108
    title: Automatic assignment of GO terms using logical inference, based on on
      inter-ontology links
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:12242223
    title: A novel yeast silencer. the 2mu origin of Saccharomyces cerevisiae 
      has HST3-, MIG1- and SIR-dependent silencing activity.
    findings: []
  - id: PMID:12618394
    title: Short-chain fatty acid activation by acyl-coenzyme A synthetases 
      requires SIR2 protein function in Salmonella enterica and Saccharomyces 
      cerevisiae.
    findings: []
  - id: PMID:17977840
    title: Hst3 is regulated by Mec1-dependent proteolysis and controls the S 
      phase checkpoint and sister chromatid cohesion by deacetylating histone H3
      at lysine 56.
    findings: []
  - id: PMID:23357952
    title: Histone H3K56 acetylation, Rad52, and non-DNA repair factors control 
      double-strand break repair choice with the sister chromatid.
    findings: []
  - id: PMID:30358795
    title: The cellular economy of the Saccharomyces cerevisiae zinc proteome.
    findings: []
  - id: PMID:31167142
    title: Yeast Sirtuin Family Members Maintain Transcription Homeostasis to 
      Ensure Genome Stability.
    findings: []
  - id: PMID:7498786
    title: The SIR2 gene family, conserved from bacteria to humans, functions in
      silencing, cell cycle progression, and chromosome stability.
    findings: []