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 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. 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 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. 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:11226170 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 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. 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, 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 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 | MODIFY | Summary: IEA annotation from ARBA machine learning model. HST2 does influence chromatin, but the generic heterochromatin-formation term overstates the clearest HST2-specific process. Reason: HST2 is best represented by its NAD-dependent H4K16 deacetylase function in mitotic chromatin compaction. Generic heterochromatin formation and rDNA heterochromatin should remain non-core contexts. Proposed replacements: mitotic chromosome condensation Supporting Evidence: PMID:16648462 The enzymatic conversion of H4K16Ac to its deacetylated form may be pivotal to the formation of condensed chromatin. 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 file:yeast/HST2/HST2-deep-research-falcon.md The most precise Hst2 pathway is mitotic chromatin compaction: H3S10 phosphorylation leads to Bmh1-mediated recruitment of phosphorylated Hst2 to chromatin. |
| GO:0034979 NAD-dependent protein lysine deacetylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation from InterPro and RHEA mapping. This is a more general parent term encompassing both histone and non-histone protein deacetylation. 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. Supporting Evidence: GO_REF:0000120 Combined Automated Annotation using Multiple IEA Methods with RHEA:43636 |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | 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 term is less informative than zinc ion binding, and GO:0008270 is already represented by an RCA annotation from PMID:30358795. Keep the zinc cofactor evidence but avoid proposing a duplicate replacement annotation from this generic IEA term. 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: PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc proteome |
| 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... | UNDECIDED | Summary: IMP annotation indicating HST2 negatively regulates mitotic recombination, inferred from mutant phenotype in calorie restriction study. 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. Supporting Evidence: PMID:16051752 Jul 28. HST2 mediates SIR2-independent life-span extension by calorie restriction. |
| GO:0045950 negative regulation of mitotic recombination | IGI PMID:16051752 HST2 mediates SIR2-independent life-span extension by calori... | UNDECIDED | Summary: IGI annotation indicating genetic interaction evidence for HST2's role in negative regulation of mitotic recombination. 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. Supporting Evidence: PMID:16051752 Jul 28. HST2 mediates SIR2-independent life-span extension by calorie restriction. |
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Download this section (compressed HTML)Q: Does HST2 regulate mitotic recombination directly, or is the apparent connection mediated through effects on rDNA stability?
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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