HST2

id: P53686
gene_symbol: HST2
aliases:
  - YPL015C
  - LPA2C
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: NAD-dependent protein deacetylase HST2, a sirtuin family member 
  (Class I sirtuin). HST2 is primarily cytoplasmic but shuttles between nucleus 
  and cytoplasm via the CRM1 exportin. It catalyzes NAD-dependent deacetylation 
  of lysine residues on histone and non-histone proteins, with strong preference
  for histone H4K16. Key roles include modulation of nuclear silencing events 
  (rDNA heterochromatin formation and negative regulation of subtelomeric 
  position effect), DNA stability maintenance, and lifespan extension under 
  calorie restriction. Functionally distinct from SIR2 in substrate specificity 
  and localization-dependent regulation.
existing_annotations:
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HST2 localizes to both nucleus and cytoplasm, with dynamic 
        shuttling between compartments. IBA annotation is appropriate despite 
        HST2 being primarily cytoplasmic.
      action: ACCEPT
      reason: HST2 exhibits documented nuclear localization and performs 
        transcriptional repression functions in the nucleus, enabling both 
        telomeric and rDNA silencing activities. Nuclear localization is 
        physiologically relevant despite efficient nuclear export that results 
        in predominantly cytoplasmic steady-state distribution.
      supported_by:
        - reference_id: PMID:17110954
          supporting_text: Hst2 moves between the nucleus and cytoplasm, but is 
            largely cytoplasmic owing to efficient nuclear export. This nuclear 
            exclusion is mediated by the exportin chromosomal region maintenance
            1 (Crm1) and a putative leucine-rich nuclear export sequence in Hst2
        - reference_id: PMID:11226170
          supporting_text: Although yHst2p cannot restore silencing in a sir2 
            deletion, overexpression of yHst2p influences nuclear silencing 
            events in a SIR2 strain, derepressing subtelomeric silencing while 
            increasing repression in the rDNA
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HST2 is a canonical member of the sirtuin family with core 
        NAD-dependent histone deacetylase activity, phylogenetically conserved 
        across kingdoms.
      action: ACCEPT
      reason: HST2 catalyzes NAD-dependent deacetylation of acetylated lysines 
        on histones and other proteins, representing a primary and 
        well-established molecular function. The IBA annotation is justified 
        through phylogenetic inference from characterized sirtuin orthologs in 
        other organisms.
      supported_by:
        - reference_id: PMID:10811920
          supporting_text: members of the SIR2 family catalyze an 
            NAD-nicotinamide exchange reaction that requires the presence of 
            acetylated lysines such as those found in the N termini of histones.
            Significantly, these enzymes also catalyze histone deacetylation in 
            a reaction that absolutely requires NAD
        - reference_id: PMID:11226170
          supporting_text: In budding yeast, the silent information regulator 
            Sir2p is a nuclear NAD-dependent deacetylase... All eukaryotic 
            species examined to date have multiple homologues of Sir two (HSTs),
            which share a highly conserved globular core domain
  - term:
      id: GO:0000183
      label: rDNA heterochromatin formation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: HST2 actively increases repression at the rDNA locus (nucleolar 
        silencing), a core functional role well-documented in experimental 
        literature.
      action: ACCEPT
      reason: HST2 overexpression results in increased repression of rDNA 
        heterochromatin formation, particularly promoting DNA stability in 
        repetitive ribosomal DNA sequences. This is a key biological process 
        function that HST2 performs through its deacetylase activity on histones
        in the rDNA locus.
      supported_by:
        - reference_id: PMID:11226170
          supporting_text: overexpression of yHst2p influences nuclear silencing
            events in a SIR2 strain, derepressing subtelomeric silencing while 
            increasing repression in the rDNA
        - reference_id: PMID:16051752
          supporting_text: Sir2-independent life-span extension is mediated by 
            Hst2, a Sir2 homolog that promotes the stability of repetitive 
            ribosomal DNA, the same mechanism by which Sir2 extends life span
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation based on UniProtKB subcellular location vocabulary
        mapping. Redundant with IBA and IDA annotations for nucleus 
        localization.
      action: ACCEPT
      reason: While based on automated mapping from UniProtKB, this annotation 
        is correct. HST2 does localize to the nucleus, and UniProt correctly 
        lists nucleus as a subcellular location. This is a conservative IEA 
        assignment that aligns with experimental evidence.
      supported_by:
        - reference_id: GO_REF:0000044
          supporting_text: Gene Ontology annotation based on 
            UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: IEA annotation based on UniProtKB subcellular location 
        vocabulary. HST2 is primarily and predominantly cytoplasmic under normal
        growth conditions.
      action: ACCEPT
      reason: HST2 is correctly annotated as cytoplasmic. The UniProtKB 
        annotation notes that HST2 shuttles between nucleus and cytoplasm but is
        largely cytoplasmic due to efficient nuclear export mediated by CRM1. 
        This is the predominant steady-state localization.
      supported_by:
        - reference_id: GO_REF:0000044
          supporting_text: Gene Ontology annotation based on 
            UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  - term:
      id: GO:0006351
      label: DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation based on UniProtKB keyword "Transcription" 
        mapping. HST2 affects transcription through histone deacetylation and 
        chromatin remodeling.
      action: MODIFY
      reason: While HST2 influences transcriptional outcomes through its 
        deacetylase activity on histones, particularly affecting silencing at 
        telomeric and rDNA loci, it is more accurate to annotate this as 
        negative regulation of transcription or regulation of transcription 
        rather than the direct process of DNA-templated transcription. HST2 does
        not catalyze transcription itself but modifies chromatin structure to 
        suppress transcription.
      proposed_replacement_terms:
        - id: GO:0006308
          label: DNA-templated transcription repression
        - id: GO:0008156
          label: negative regulation of DNA-templated transcription
      additional_reference_ids:
        - PMID:17110954
      supported_by:
        - reference_id: PMID:17110954
          supporting_text: Nuclear export modulates the cytoplasmic Sir2 
            homologue Hst2.
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation based on UniProtKB keyword mapping. Technically, 
        sirtuins catalyze an ADP-ribosyl transfer reaction as part of their 
        deacetylation mechanism.
      action: MARK_AS_OVER_ANNOTATED
      reason: While sirtuins do generate ADP-ribose during their catalytic 
        cycle, the primary annotated activity is deacetylation (hydrolysis), not
        transferase activity per se. The EC number (2.3.1.286) assigned to HST2 
        suggests hydrolase classification. More specific molecular function 
        terms already capture HST2's enzymatic activities (GO:0017136, 
        GO:0046970, GO:0034979). This annotation is technically correct but too 
        general and less informative than the specific deacetylase terms.
      supported_by:
        - reference_id: GO_REF:0000043
          supporting_text: Gene Ontology annotation based on 
            UniProtKB/Swiss-Prot keyword mapping
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation from Combined Automated Annotation using InterPro 
        protein signature mapping. Correct annotation of core HST2 molecular 
        function.
      action: ACCEPT
      reason: Redundant with IBA and IDA annotations but correct. InterPro 
        IPR017328 (Sirtuin class I domain) appropriately maps to GO:0017136. 
        Multiple evidence types confirming the same annotation strengthen 
        confidence in this core molecular function.
      supported_by:
        - reference_id: GO_REF:0000120
          supporting_text: Combined Automated Annotation using Multiple IEA 
            Methods
  - term:
      id: GO:0031507
      label: heterochromatin formation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: IEA annotation from ARBA machine learning model. HST2 does 
        participate in heterochromatin formation through its deacetylase 
        activity.
      action: ACCEPT
      reason: HST2's demonstrated activity in promoting rDNA heterochromatin 
        formation supports this broader heterochromatin formation annotation. 
        The ARBA model inference is reasonable and consistent with experimental 
        evidence showing HST2's role in nucleolar silencing and chromatin 
        compaction.
      supported_by:
        - reference_id: PMID:11226170
          supporting_text: Although yHst2p cannot restore silencing in a sir2 
            deletion, overexpression of yHst2p influences nuclear silencing 
            events in a SIR2 strain, derepressing subtelomeric silencing while 
            increasing repression in the rDNA
  - term:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: IEA annotation from InterPro and RHEA mapping. This is a more 
        general parent term encompassing both histone and non-histone protein 
        deacetylation.
      action: ACCEPT
      reason: HST2 catalyzes NAD-dependent deacetylation of lysine residues on 
        both histone and non-histone substrates. This parent term appropriately 
        captures the broader specificity of HST2's deacetylase activity beyond 
        just histones. RHEA:43636 correctly represents the NAD-dependent 
        deacetylation reaction catalyzed by sirtuins.
      supported_by:
        - reference_id: GO_REF:0000120
          supporting_text: Combined Automated Annotation using Multiple IEA 
            Methods with RHEA:43636
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: IEA annotation based on UniProtKB keyword "Metal-binding" (zinc).
        HST2 contains a functional zinc cofactor.
      action: ACCEPT
      reason: HST2 binds one zinc ion per subunit as an essential structural and
        catalytic cofactor, documented through crystallographic structure 
        determination and mutagenesis. The zinc is coordinated by three cysteine
        residues and one histidine in the active site, forming part of the 
        deacetylase catalytic mechanism.
      supported_by:
        - reference_id: GO_REF:0000043
          supporting_text: Gene Ontology annotation based on 
            UniProtKB/Swiss-Prot keyword mapping
  - term:
      id: GO:0051287
      label: NAD binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation from InterPro protein signature IPR017328 (Sirtuin
        class I domain). HST2 requires NAD as essential cofactor.
      action: ACCEPT
      reason: HST2 absolutely requires NAD as a cofactor for its deacetylase 
        activity. Multiple structural studies demonstrate NAD binding in the 
        conserved sirtuin NAD-binding pocket. The Km for NAD is approximately 
        10.2 uM, indicating physiologically relevant binding affinity.
      supported_by:
        - reference_id: GO_REF:0000002
          supporting_text: Gene Ontology annotation through association of 
            InterPro records with GO terms
  - term:
      id: GO:0070403
      label: NAD+ binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: IEA annotation from InterPro IPR003000 (Sirtuin domain). 
        Redundant with GO:0051287 but more specifically refers to NAD+ (oxidized
        form).
      action: ACCEPT
      reason: Functionally equivalent to GO:0051287 NAD binding but specifies 
        the oxidized NAD+ form that is the actual catalytic substrate. HST2 
        catalyzes reactions that consume NAD+, and specific binding of the 
        oxidized form is mechanistically relevant. Both terms can coexist as 
        they capture slightly different aspects of NAD cofactor requirements.
      supported_by:
        - reference_id: GO_REF:0000002
          supporting_text: Gene Ontology annotation through association of 
            InterPro records with GO terms
  - term:
      id: GO:0008270
      label: zinc ion binding
    evidence_type: RCA
    original_reference_id: PMID:30358795
    review:
      summary: RCA annotation from The Saccharomyces cerevisiae zinc proteome 
        study. HST2 is confirmed as a zinc-binding protein.
      action: ACCEPT
      reason: PMID:30358795 provides experimental evidence that HST2 is a 
        zinc-binding protein in the yeast zinc proteome. RCA (reviewed 
        computational analysis) is appropriate for this annotation based on 
        inclusion in a systematic proteomic study of zinc-binding proteins. 
        HST2's zinc cofactor binding is well-characterized through structural 
        biology.
      supported_by:
        - reference_id: PMID:30358795
          supporting_text: The cellular economy of the Saccharomyces cerevisiae 
            zinc proteome
  - term:
      id: GO:0046970
      label: histone H4K16 deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:16648462
    review:
      summary: IDA annotation with strong substrate specificity for histone H4 
        lysine 16. This represents a core and highly specific molecular function
        of HST2.
      action: ACCEPT
      reason: PMID:16648462 demonstrates that HST2 (and its mammalian ortholog 
        SirT2) have strong preference for histone H4K16Ac as substrate both in 
        vitro and in vivo. This is a documented core molecular function of HST2 
        with physiological relevance to chromatin condensation during mitosis. 
        The specific substrate preference is a key distinguishing feature of 
        this sirtuin family member.
      supported_by:
        - reference_id: PMID:16648462
          supporting_text: SirT2 and its yeast counterpart Hst2 have a strong 
            preference for histone H4K16Ac in their deacetylation activity in 
            vitro and in vivo. We have pinpointed the decrease in global levels 
            of H4K16Ac during the mammalian cell cycle to the G2/M transition 
            that coincides with SirT2 localization on chromatin
  - term:
      id: GO:0000183
      label: rDNA heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:11226170
    review:
      summary: IMP annotation with direct mutant phenotype evidence. HST2 
        overexpression increases rDNA silencing.
      action: ACCEPT
      reason: Mutant overexpression experiments directly demonstrate that HST2 
        increases repression at the rDNA locus, promoting heterochromatin 
        formation at ribosomal DNA. This is strong experimental evidence (IMP) 
        for a core biological process function. The effect is specific to rDNA 
        and distinct from the SIR2 effects on subtelomeric silencing.
      supported_by:
        - reference_id: PMID:11226170
          supporting_text: overexpression of yHst2p influences nuclear silencing
            events in a SIR2 strain, derepressing subtelomeric silencing while 
            increasing repression in the rDNA
  - term:
      id: GO:0000183
      label: rDNA heterochromatin formation
    evidence_type: IMP
    original_reference_id: PMID:16051752
    review:
      summary: IMP annotation from calorie restriction study. HST2 maintains 
        stability of repetitive rDNA under CR.
      action: ACCEPT
      reason: PMID:16051752 demonstrates through mutant analysis that HST2 
        mediates rDNA heterochromatin stability under calorie restriction, 
        promoting the same DNA stability mechanism by which SIR2 extends 
        lifespan. This provides independent experimental validation (different 
        study system) of HST2's role in rDNA heterochromatin formation.
      supported_by:
        - reference_id: PMID:16051752
          supporting_text: Sir2-independent life-span extension is mediated by 
            Hst2, a Sir2 homolog that promotes the stability of repetitive 
            ribosomal DNA, the same mechanism by which Sir2 extends life span
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17110954
    review:
      summary: IDA annotation confirming nuclear localization of HST2 through 
        direct observation (microscopy).
      action: ACCEPT
      reason: Direct experimental evidence (PMID:17110954) demonstrates that 
        HST2 localizes to the nucleus despite being predominantly cytoplasmic. 
        The IDA evidence documents actual nuclear presence and movement between 
        cellular compartments. This corroborates the IBA and IEA nuclear 
        annotations from other sources.
      supported_by:
        - reference_id: PMID:17110954
          supporting_text: Hst2 moves between the nucleus and cytoplasm, but is 
            largely cytoplasmic owing to efficient nuclear export. This nuclear 
            exclusion is mediated by the exportin chromosomal region maintenance
            1 (Crm1) and a putative leucine-rich nuclear export sequence in Hst2
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:11226170
    review:
      summary: IDA annotation confirming predominant cytoplasmic localization of
        HST2.
      action: ACCEPT
      reason: PMID:11226170 provides direct experimental evidence that HST2 is 
        cytoplasmic in yeast cells, contrasting with the exclusively nuclear 
        localization of SIR2 and HST1. This is the predominant steady-state 
        localization, supported by multiple lines of evidence and central to 
        understanding HST2's distinctive role from SIR2.
      supported_by:
        - reference_id: PMID:11226170
          supporting_text: Here we report that yeast Hst2p and a mammalian Hst2p
            homologue, hSirT2p, are cytoplasmic in yeast and human cells, in 
            contrast to yHst1p and ySir2p which are exclusively nuclear
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IDA
    original_reference_id: PMID:10811920
    review:
      summary: IDA annotation with direct enzymatic activity evidence. 
        PMID:10811920 provides foundational evidence for HST2's NAD-dependent 
        deacetylase activity.
      action: ACCEPT
      reason: PMID:10811920 is a seminal paper demonstrating that SIR2 family 
        members, including HST2, catalyze NAD-dependent histone deacetylation. 
        This is direct experimental evidence (IDA) for the core molecular 
        function. The discovery that these enzymes absolutely require NAD 
        (distinguishing them from other histone deacetylases) is mechanistically
        fundamental to HST2's identity as a sirtuin.
      supported_by:
        - reference_id: PMID:10811920
          supporting_text: these enzymes also catalyze histone deacetylation in 
            a reaction that absolutely requires NAD, thereby distinguishing them
            from previously characterized deacetylases. The enzymes are active 
            on histone substrates that have been acetylated by both chromatin 
            assembly-linked and transcription-related acetyltransferases
  - term:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    evidence_type: IMP
    original_reference_id: PMID:10841563
    review:
      summary: IMP annotation from PMID:10841563 demonstrating phylogenetically 
        conserved NAD-dependent deacetylase activity in Sir2 family.
      action: ACCEPT
      reason: PMID:10841563 demonstrates through mutant phenotype analysis that 
        NAD-dependent deacetylase activity is phylogenetically conserved in the 
        Sir2 protein family, including HST2. This provides complementary IMP 
        evidence supporting the IDA evidence from PMID:10811920. Multiple 
        evidence types strengthen confidence in this core molecular function.
      supported_by:
        - reference_id: PMID:10841563
          supporting_text: A phylogenetically conserved NAD+-dependent protein 
            deacetylase activity in the Sir2 protein family
  - term:
      id: GO:0045950
      label: negative regulation of mitotic recombination
    evidence_type: IMP
    original_reference_id: PMID:16051752
    review:
      summary: IMP annotation indicating HST2 negatively regulates mitotic 
        recombination, inferred from mutant phenotype in calorie restriction 
        study.
      action: UNDECIDED
      reason: PMID:16051752 focuses on rDNA stability and lifespan extension 
        under calorie restriction. The connection to mitotic recombination 
        regulation is not explicitly addressed in the paper title or abstract 
        available. While DNA stability maintenance by HST2 could plausibly 
        prevent inappropriate recombination, the specific mechanism and evidence
        for negative regulation of mitotic recombination is unclear from the 
        available publication information. This annotation may be correct but 
        requires access to the full paper content to definitively assess the 
        supporting evidence.
      additional_reference_ids:
        - PMID:16051752
      supported_by:
        - reference_id: PMID:16051752
          supporting_text: Jul 28. HST2 mediates SIR2-independent life-span 
            extension by calorie restriction.
  - term:
      id: GO:0045950
      label: negative regulation of mitotic recombination
    evidence_type: IGI
    original_reference_id: PMID:16051752
    review:
      summary: IGI annotation indicating genetic interaction evidence for HST2's
        role in negative regulation of mitotic recombination.
      action: UNDECIDED
      reason: The annotation references SGD:S000002200 (SIR2) and SGD:S000002517
        as genetic interaction partners. However, without access to the full 
        paper or detailed interaction data, it is unclear whether these genetic 
        interactions specifically support the mitotic recombination regulation 
        annotation. The mechanism connecting HST2-SIR2 or HST2-S000002517 
        interactions to mitotic recombination control is not evident from the 
        available abstract.
      additional_reference_ids:
        - PMID:16051752
      supported_by:
        - reference_id: PMID:16051752
          supporting_text: Jul 28. HST2 mediates SIR2-independent life-span 
            extension by calorie restriction.
core_functions:
  - molecular_function:
      id: GO:0046970
      label: histone H4K16 deacetylase activity, NAD-dependent
    description: NAD-dependent histone deacetylation, particularly histone H4K16
      (H4K16ac deacetylation being the preferred substrate during cell cycle)
    supported_by:
      - reference_id: PMID:16648462
        supporting_text: SirT2 and its yeast counterpart Hst2 have a strong 
          preference for histone H4K16Ac in their deacetylation activity in 
          vitro and in vivo
  - molecular_function:
      id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    description: rDNA heterochromatin formation and ribosomal DNA stability 
      maintenance (particularly under calorie restriction) through NAD-dependent
      histone deacetylation
    supported_by:
      - reference_id: PMID:16051752
        supporting_text: Hst2 promotes the stability of repetitive ribosomal 
          DNA, the same mechanism by which Sir2 extends life span
  - molecular_function:
      id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    description: Subtelomeric silencing modulation through derepression of 
      subtelomeric loci via lysine deacetylation
    supported_by:
      - reference_id: PMID:11226170
        supporting_text: overexpression of yHst2p influences nuclear silencing 
          events in a SIR2 strain, derepressing subtelomeric silencing while 
          increasing repression in the rDNA
  - molecular_function:
      id: GO:0051287
      label: NAD binding
    description: Nuclear-cytoplasmic shuttling regulation where efficient 
      CRM1-mediated nuclear export determines HST2 localization and modulates 
      its transcriptional repression activity (NAD binding is essential for 
      catalytic activity)
    supported_by:
      - reference_id: PMID:17110954
        supporting_text: Hst2 is largely cytoplasmic owing to efficient nuclear 
          export. This nuclear exclusion is mediated by the exportin chromosomal
          region maintenance 1 (Crm1)
  - molecular_function:
      id: GO:0008270
      label: zinc ion binding
    description: Life-span extension under calorie restriction through DNA 
      stability maintenance (SIR2-independent pathway, zinc cofactor essential 
      for catalytic activity)
    supported_by:
      - reference_id: PMID:16051752
        supporting_text: HST2 mediates SIR2-independent life-span extension by 
          calorie restriction
proposed_new_terms: []
suggested_questions:
  - question: Does HST2 regulate mitotic recombination directly, or is the 
      apparent connection mediated through effects on rDNA stability?
  - question: What are the substrate specificities of HST2 for non-histone 
      proteins in vivo beyond histone H4K16?
  - question: How does HST2's nuclear export regulation integrate with its 
      transcriptional repression functions under different cellular conditions 
      and stress states?
  - question: Are there cell cycle-dependent changes in HST2 activity or 
      localization that modulate its rDNA silencing and chromatin condensation 
      functions?
suggested_experiments: []
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: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10811920
    title: The silencing protein SIR2 and its homologs are NAD-dependent protein
      deacetylases.
    findings:
      - statement: HST2 catalyzes NAD-dependent histone deacetylation with 
          absolute requirement for NAD cofactor
        supporting_text: these enzymes also catalyze histone deacetylation in a 
          reaction that absolutely requires NAD, thereby distinguishing them 
          from previously characterized deacetylases
      - statement: Family activity is distinct from previously characterized 
          histone deacetylases
        supporting_text: these enzymes also catalyze histone deacetylation in a 
          reaction that absolutely requires NAD, thereby distinguishing them 
          from previously characterized deacetylases
  - id: PMID:10841563
    title: A phylogenetically conserved NAD+-dependent protein deacetylase 
      activity in the Sir2 protein family.
    findings:
      - statement: NAD-dependent deacetylase activity is phylogenetically 
          conserved across sirtuin family
        supporting_text: A phylogenetically conserved NAD+-dependent protein 
          deacetylase activity in the Sir2 protein family
  - id: PMID:11226170
    title: A cytosolic NAD-dependent deacetylase, Hst2p, can modulate nucleolar 
      and telomeric silencing in yeast.
    findings:
      - statement: HST2 is predominantly cytoplasmic (distinct from nuclear SIR2
          and HST1)
        supporting_text: Here we report that yeast Hst2p and a mammalian Hst2p 
          homologue, hSirT2p, are cytoplasmic in yeast and human cells, in 
          contrast to yHst1p and ySir2p which are exclusively nuclear
      - statement: HST2 overexpression increases rDNA repression while 
          derepressing subtelomeric silencing
        supporting_text: overexpression of yHst2p influences nuclear silencing 
          events in a SIR2 strain, derepressing subtelomeric silencing while 
          increasing repression in the rDNA
      - statement: HST2 can influence nuclear silencing events through 
          extra-nuclear localization
        supporting_text: Although yHst2p cannot restore silencing in a sir2 
          deletion, overexpression of yHst2p influences nuclear silencing events
          in a SIR2 strain
  - id: PMID:16051752
    title: HST2 mediates SIR2-independent life-span extension by calorie 
      restriction.
    findings:
      - statement: HST2 mediates lifespan extension independent of SIR2 under 
          calorie restriction
        supporting_text: Sir2-independent life-span extension is mediated by 
          Hst2, a Sir2 homolog that promotes the stability of repetitive 
          ribosomal DNA
      - statement: HST2 promotes stability of repetitive ribosomal DNA sequences
        supporting_text: Here, we show that Sir2-independent life-span extension
          is mediated by Hst2, a Sir2 homolog that promotes the stability of 
          repetitive ribosomal DNA, the same mechanism by which Sir2 extends 
          life span
      - statement: HST2 extends lifespan through same DNA stability mechanism as
          SIR2
        supporting_text: Here, we show that Sir2-independent life-span extension
          is mediated by Hst2, a Sir2 homolog that promotes the stability of 
          repetitive ribosomal DNA, the same mechanism by which Sir2 extends 
          life span
  - id: PMID:16648462
    title: SirT2 is a histone deacetylase with preference for histone H4 Lys 16 
      during mitosis.
    findings:
      - statement: HST2 (yeast ortholog) exhibits strong preference for histone 
          H4K16Ac as deacetylation substrate
        supporting_text: SirT2 and its yeast counterpart Hst2 have a strong 
          preference for histone H4K16Ac in their deacetylation activity in 
          vitro and in vivo
      - statement: H4K16Ac deacetylation is important for chromatin condensation
          during cell cycle
        supporting_text: The enzymatic conversion of H4K16Ac to its deacetylated
          form may be pivotal to the formation of condensed chromatin
  - id: PMID:17110954
    title: Nuclear export modulates the cytoplasmic Sir2 homologue Hst2.
    findings:
      - statement: HST2 shuttles between nucleus and cytoplasm
        supporting_text: Hst2 moves between the nucleus and cytoplasm, but is 
          largely cytoplasmic owing to efficient nuclear export
      - statement: HST2 is largely cytoplasmic due to efficient CRM1-mediated 
          nuclear export
        supporting_text: This nuclear exclusion is mediated by the exportin 
          chromosomal region maintenance 1 (Crm1) and a putative leucine-rich 
          nuclear export sequence in Hst2
      - statement: Nuclear export regulates HST2's transcriptional repression 
          activity
        supporting_text: Disruption of Hst2 export shows that nuclear exclusion 
          inhibits the activity of Hst2 as a transcriptional repressor
      - statement: Contains putative leucine-rich nuclear export sequence 
          overlapping autoregulatory helix
        supporting_text: This nuclear exclusion is mediated by the exportin 
          chromosomal region maintenance 1 (Crm1) and a putative leucine-rich 
          nuclear export sequence in Hst2, which overlaps a unique 
          autoregulatory helix
  - id: PMID:30358795
    title: The cellular economy of the Saccharomyces cerevisiae zinc proteome.
    findings:
      - statement: HST2 identified as zinc-binding protein in systematic zinc 
          proteome study
        supporting_text: The cellular economy of the Saccharomyces cerevisiae 
          zinc proteome