HST2 encodes a class I sirtuin NAD-dependent protein lysine deacetylase that is predominantly cytoplasmic but shuttles into the nucleus. Its best-supported catalytic specificity is histone H4K16 deacetylation, with broader NAD-dependent lysine deacetylase/deacylase activity supported by sirtuin enzymology and structure. Hst2 modulates chromatin states, including increased rDNA repression and mitotic chromatin compaction, while subtelomeric and lifespan phenotypes are context-dependent consequences of this regulated deacetylase activity rather than separate core molecular functions.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: HST2 localizes to both nucleus and cytoplasm, with dynamic shuttling between compartments. IBA annotation is appropriate despite HST2 being primarily cytoplasmic. Reason: HST2 has documented nuclear access despite its predominantly cytoplasmic steady-state localization, and nuclear Hst2 can modulate chromatin-dependent repression, including increased rDNA repression on overexpression. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008492176 SUPPORTS TRANSFER This broad sirtuin PAINT node correctly transfers nuclear localization to Hst2, whose nuclear shuttling and nuclear repression activity are directly supported in budding yeast. Supporting Evidence: PMID:17110954 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 PMID:11226170 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 |
| GO:0017136 histone deacetylase activity, NAD-dependent | IBA GO_REF:0000033 | ACCEPT | Summary: HST2 is a canonical member of the sirtuin family with core NAD-dependent histone deacetylase activity, phylogenetically conserved across kingdoms. Reason: HST2 catalyzes NAD-dependent deacetylation of acetylated histone lysines, representing a primary and well-established molecular function. The IBA annotation is justified through phylogenetic inference from characterized sirtuin orthologs and from direct yeast Hst2 experimental evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008718612 SUPPORTS TRANSFER Hst2 descends from the current broad sirtuin histone-deacetylase node and has direct yeast evidence for NAD-dependent histone deacetylase activity. Supporting Evidence: PMID:10811920 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 PMID:10841563 This HDA activity is also displayed by purified yeast Sir2p and homologous Archaeal, eubacterial, and human proteins, and depends completely on NAD(+) in all species tested. file:yeast/HST2/HST2-deep-research-falcon.md Hst2 is a Sir2-family sirtuin enzyme that catalyzes NAD-dependent removal of acyl groups from lysine residues. |
| GO:0000183 rDNA heterochromatin formation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: HST2 actively increases repression at the rDNA locus (nucleolar silencing), but this appears secondary to its sirtuin deacetylase and chromatin-compaction function. Reason: HST2 overexpression can increase rDNA repression, but the strongest current synthesis places the core biological role at H4K16 deacetylation during mitotic chromatin compaction rather than rDNA heterochromatin formation as the primary process. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000119247 SUPPORTS TRANSFER The eukaryotic rDNA-heterochromatin node is seeded by Hst2 itself and by fission-yeast Hst4, so the transfer is defensible while remaining secondary to Hst2's catalytic H4K16 deacetylase activity. Supporting Evidence: PMID:11226170 overexpression of yHst2p influences nuclear silencing events in a SIR2 strain, derepressing subtelomeric silencing while increasing repression in the rDNA PMID:16051752 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 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProtKB subcellular location vocabulary mapping. Redundant with IBA and IDA annotations for nucleus localization. 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. Supporting Evidence: GO_REF:0000044 Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProtKB subcellular location vocabulary. HST2 is primarily and predominantly cytoplasmic under normal growth conditions. 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. Supporting Evidence: GO_REF:0000044 Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | MODIFY | Summary: IEA annotation based on UniProtKB keyword "Transcription" mapping. HST2 affects transcription through histone deacetylation and chromatin remodeling. Reason: While HST2 influences transcriptional outcomes through its deacetylase activity on histones, the stale keyword-derived DNA-templated transcription row overstated a core polymerase process. The PMID:17110954 nuclear-export assay would fit a negative-regulation term better, but a new BP annotation should be asserted directly from the transcriptional-repressor evidence rather than through this retired keyword row. Proposed replacements: negative regulation of DNA-templated transcription Supporting Evidence: PMID:17110954 Disruption of Hst2 export shows that nuclear exclusion inhibits the activity of Hst2 as a transcriptional repressor |
| GO:0016740 transferase activity | IEA GO_REF:0000043 | MODIFY | Summary: IEA annotation based on UniProtKB keyword mapping. Technically, sirtuins catalyze an ADP-ribosyl transfer reaction as part of their deacetylation mechanism. 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. Because the proposed replacement terms are already present as accepted annotations in this file, this review is effectively removing the redundant generic transferase IEA rather than proposing novel deacetylase annotations. Proposed replacements: NAD-dependent protein lysine deacetylase activity histone deacetylase activity, NAD-dependent Supporting Evidence: GO_REF:0000043 Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping |
| GO:0017136 histone deacetylase activity, NAD-dependent | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from Combined Automated Annotation using InterPro protein signature mapping. Correct annotation of core HST2 molecular function. 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. Supporting Evidence: GO_REF:0000120 Combined Automated Annotation using Multiple IEA Methods |
| GO:0031507 heterochromatin formation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: IEA annotation from ARBA machine learning model. HST2 can influence rDNA heterochromatin, but the generic parent term is not the clearest core HST2 process. Reason: HST2 has accepted rDNA heterochromatin formation rows, which are descendants of this broader term, so heterochromatin formation is not wrong. The generic parent should remain non-core relative to Hst2's direct NAD-dependent H4K16 deacetylase activity and the better-resolved mitotic chromatin-compaction pathway. Supporting Evidence: PMID:11226170 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 |
| GO:0034979 NAD-dependent protein lysine deacetylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from InterPro and RHEA mapping. This is a valid parent term for HST2's NAD-dependent protein lysine deacetylase chemistry. Reason: HST2 catalyzes NAD-dependent deacetylation of lysine residues in proteins. This parent term is less specific than the H4K16 histone deacetylase term, but RHEA:43636 correctly represents the NAD-dependent deacetylation reaction catalyzed by sirtuins. Supporting Evidence: GO_REF:0000120 Combined Automated Annotation using Multiple IEA Methods with RHEA:43636 |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | TOO GENERAL | Summary: IEA annotation based on UniProtKB keyword "Metal-binding" (zinc). HST2 contains a functional zinc cofactor, but the specific zinc ion binding annotation is already present. Reason: The generic metal ion binding assertion is redundant with the retained GO:0008270 zinc ion binding annotation, which captures Hst2's structurally supported zinc cofactor more precisely. This exact UniProt keyword row is also no longer live in GOA. TOO_GENERAL rather than REMOVE: zinc ion binding, kept in this review, entails this term, so the claim is true but less informative. Supporting Evidence: GO_REF:0000043 Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping |
| GO:0051287 NAD binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA annotation from InterPro protein signature IPR017328 (Sirtuin class I domain). HST2 requires NAD as essential cofactor. 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. This is a valid cofactor binding annotation but the core molecular function is NAD-dependent lysine deacetylation. Supporting Evidence: GO_REF:0000002 Gene Ontology annotation through association of InterPro records with GO terms |
| GO:0070403 NAD+ binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA annotation from InterPro IPR003000 (Sirtuin domain). Redundant with GO:0051287 but more specifically refers to NAD+ (oxidized form). 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. This is mechanistically valid but should remain non-core relative to the deacetylase activity. Supporting Evidence: GO_REF:0000002 Gene Ontology annotation through association of InterPro records with GO terms |
| GO:0008270 zinc ion binding | RCA PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc pr... | KEEP AS NON CORE | Summary: RCA annotation from The Saccharomyces cerevisiae zinc proteome study. HST2 is confirmed as a zinc-binding protein. 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, but zinc binding is a cofactor requirement rather than the core function. Supporting Evidence: UniProt:P53686 Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Note=Binds 1 zinc ion per subunit. |
| GO:0046970 histone H4K16 deacetylase activity, NAD-dependent | IDA PMID:16648462 SirT2 is a histone deacetylase with preference for histone H... | ACCEPT | Summary: IDA annotation with strong substrate specificity for histone H4 lysine 16. This represents a core and highly specific molecular function of HST2. 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. Supporting Evidence: PMID:16648462 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 |
| GO:0000183 rDNA heterochromatin formation | IMP PMID:11226170 A cytosolic NAD-dependent deacetylase, Hst2p, can modulate n... | KEEP AS NON CORE | Summary: IMP annotation with direct mutant phenotype evidence. HST2 overexpression increases rDNA silencing. Reason: Overexpression evidence supports an HST2 effect on rDNA repression, but this is a context-dependent chromatin outcome rather than the best core biological process for the enzyme. Supporting Evidence: PMID:11226170 overexpression of yHst2p influences nuclear silencing events in a SIR2 strain, derepressing subtelomeric silencing while increasing repression in the rDNA |
| GO:0000183 rDNA heterochromatin formation | IMP PMID:16051752 HST2 mediates SIR2-independent life-span extension by calori... | KEEP AS NON CORE | Summary: IMP annotation from calorie restriction study. HST2 maintains stability of repetitive rDNA under CR. Reason: The accessible abstract links HST2 to rDNA stability and lifespan under calorie restriction, so the rDNA term can be retained as a non-core context. It should not be treated as the primary HST2 biological process. Supporting Evidence: PMID:16051752 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 |
| GO:0005634 nucleus | IDA PMID:17110954 Nuclear export modulates the cytoplasmic Sir2 homologue Hst2... | ACCEPT | Summary: IDA annotation confirming nuclear localization of HST2 through direct observation (microscopy). 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. Supporting Evidence: PMID:17110954 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 |
| GO:0005737 cytoplasm | IDA PMID:11226170 A cytosolic NAD-dependent deacetylase, Hst2p, can modulate n... | ACCEPT | Summary: IDA annotation confirming predominant cytoplasmic localization of HST2. 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. Supporting Evidence: PMID:11226170 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 |
| GO:0017136 histone deacetylase activity, NAD-dependent | IDA PMID:10811920 The silencing protein SIR2 and its homologs are NAD-dependen... | ACCEPT | Summary: IDA annotation with direct enzymatic activity evidence. PMID:10811920 provides foundational evidence for HST2's NAD-dependent deacetylase activity. 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. Supporting Evidence: PMID:10811920 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 |
| GO:0017136 histone deacetylase activity, NAD-dependent | IMP PMID:10841563 A phylogenetically conserved NAD+-dependent protein deacetyl... | ACCEPT | Summary: IMP annotation from PMID:10841563 demonstrating phylogenetically conserved NAD-dependent deacetylase activity in Sir2 family. 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. Supporting Evidence: PMID:10841563 A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family |
| GO:0045950 negative regulation of mitotic recombination | IMP PMID:16051752 HST2 mediates SIR2-independent life-span extension by calori... | KEEP AS NON CORE | Summary: IMP annotation from the calorie-restriction lifespan study. The abstract states that Hst2 promotes the stability of the repetitive rDNA array, the same mechanism by which Sir2 extends lifespan; in yeast rDNA, repeat instability is recombination between tandem repeats (marker loss, extrachromosomal rDNA circle formation), so the claim that hst2 loss raises mitotic recombination is directly what the abstract reports. SGD curated the same paper to HST1 as well as HST2 for this term (SGD GO detail consulted 2026-10-16 at https://www.yeastgenome.org/backend/reference/16051752/go_details). Reason: The curator read the full text; the abstract-level claim (Hst2 promotes rDNA stability under calorie restriction) is consistent with the term, so there is no basis to doubt the annotation. GO has no narrower regulation term for recombination within rDNA repeats (GO:0045458 has no regulation children), so GO:0045950 is as precise as the ontology allows. It is kept as non-core for the same reason as the sibling GO:0000183 rDNA heterochromatin formation row from this paper - the rDNA effect is condition-dependent (calorie restriction), while the core HST2 biology is NAD-dependent H4K16 deacetylation and mitotic chromatin compaction. Supporting Evidence: PMID:16051752 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 |
| GO:0045950 negative regulation of mitotic recombination | IGI PMID:16051752 HST2 mediates SIR2-independent life-span extension by calori... | KEEP AS NON CORE | Summary: IGI annotation (with SIR2) from the same calorie-restriction study. The abstract frames HST2 as mediating the Sir2-independent arm of lifespan extension through rDNA stability, so the genetic test of HST2 in relation to SIR2 is the paper's central experiment. Reason: Same claim as the IMP row for GO:0045950 from PMID:16051752 and given the same action for consistency. The SIR2 genetic interaction is what the abstract describes (Sir2-independent rDNA stabilisation by Hst2); the exact assay sits in the full text, which the SGD curator read, and nothing visible contradicts it. Non-core because the rDNA recombination effect is condition-dependent rather than the main HST2 activity. Supporting Evidence: PMID:16051752 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 |
| GO:0045950 negative regulation of mitotic recombination | IGI PMID:16051752 HST2 mediates SIR2-independent life-span extension by calori... | KEEP AS NON CORE | Summary: IGI annotation (with FOB1, the rDNA replication-fork-barrier protein that drives rDNA recombination and ERC formation) from the same calorie-restriction study. Reason: Same claim as the IMP and SIR2-IGI rows for GO:0045950 from PMID:16051752 and given the same action for consistency. FOB1 is the standard genetic tool for separating rDNA recombination from other effects, which fits a recombination readout for HST2; the specific assay is in the full text that the SGD curator read, and nothing visible contradicts it. Non-core because the effect is condition-dependent. Supporting Evidence: PMID:16051752 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 |
| GO:0030261 chromosome condensation | TAS PMID:33187982 14-3-3 Protein Bmh1 triggers short-range compaction of mitot... | NEW | Summary: Proposed broad chromosome-condensation annotation for HST2's role in short-range mitotic chromatin compaction. Reason: Jain, Janning, and Neumann describe the yeast mitotic cascade in which H3S10 phosphorylation recruits Hst2, Hst2 removes H4K16 acetylation, and the unmasked H4 tails drive short-range compaction through neighboring nucleosomes. The broad parent GO:0030261 captures this Hst2-dependent compaction role without over-asserting the narrower chromosome-segregation context of mitotic chromosome condensation. Supporting Evidence: PMID:33187982 Aurora B kinase elicits a cascade of events starting with phosphorylation of histone H3 serine 10 (H3S10ph), which signals the recruitment of lysine deacetylase Hst2 and the removal of lysine 16 acetylation in histone 4. The unmasked histone 4 tails interact with the acidic patch of neighboring nucleosomes to drive short-range compaction of chromatin |
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Download this section (compressed HTML)Q: The rDNA-stability readout in PMID:16051752 is a recombination readout, so HST2 negatively regulates mitotic recombination at the rDNA. Does Hst2 act on the recombination machinery or the replication-fork-barrier pathway directly, or only through H4K16 deacetylation and silencing of rDNA chromatin?
Q: Should GO add a regulation term under GO:0045458 recombination within rDNA repeats (for example negative regulation of recombination within rDNA repeats)? Sirtuin rDNA-stability annotations such as the HST2 and HST1 rows from PMID:16051752 currently have to use the broader GO:0045950 negative regulation of mitotic recombination.
Q: What are the substrate specificities of HST2 for non-histone proteins in vivo beyond histone H4K16?
Q: How does HST2's nuclear export regulation integrate with its transcriptional repression functions under different cellular conditions and stress states?
Q: Are there cell cycle-dependent changes in HST2 activity or localization that modulate its rDNA silencing and chromatin condensation functions?
Experiment: Compare acetyl-lysine and broader acyl-lysine proteomes in wild-type, hst2 deletion, catalytically inactive Hst2, and nuclear-export mutants, separating cytoplasmic and nuclear fractions before mass spectrometry.
Hypothesis: Hst2 has a limited set of non-histone yeast substrates that explain its cytoplasmic steady-state localization.
Type: substrate proteomics
Experiment: Measure Hst2 chromatin occupancy, H4K16Ac levels, rDNA silencing, and chromosome compaction in Hst2 S320/S324 phosphosite mutants and Bmh1 binding mutants across synchronized cell-cycle stages.
Hypothesis: Bmh1-dependent recruitment of phosphorylated Hst2 to mitotic chromatin is required for the H4K16 deacetylation component of rDNA and chromosome compaction phenotypes.
Type: chromatin recruitment assay
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Download this section (compressed HTML)Cytoplasmic NAD(+)-dependent protein deacetylase; deacetylation targets are primarily cytoplasmic proteins; member of the silencing information regulator 2 (Sir2) family of NAD(+)-dependent protein deacetylases; modulates nucleolar (rDNA) and telomeric silencing; possesses NAD(+)-dependent histone deacetylase activity in vitro; contains a nuclear export signal (NES); function regulated by its nuclear export
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