Existing Annotations Review

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.

Core Functions

Hst2 is an NAD-dependent sirtuin deacetylase with strong preference for histone H4K16Ac. It is mostly cytoplasmic at steady state but shuttles to the nucleus, where regulated access to mitotic chromatin supports H4K16 deacetylation and chromosome condensation. NAD and zinc binding are necessary catalytic features, but they are cofactors for this deacetylase function rather than separate core functions.

Molecular Function:

histone H4K16 deacetylase activity, NAD-dependent

Directly Involved In:

mitotic chromosome condensation

Cellular Locations:

cytoplasm nucleus

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.
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, where Hst2-mediated removal of H4K16ac enables nucleosome-nucleosome interactions.
file:interpro/panther/PTHR11085/PTHR11085-metadata.yaml
PANTHER family PTHR11085 is named NAD-dependent sirtuin protein deacylases and includes HST2 in the sirtuin-2 subfamily.

Hst2 also fits the broader sirtuin molecular function of NAD-dependent protein lysine deacetylation/deacylation. This parent activity captures the conserved reaction chemistry and potential substrate scope beyond the specific H4K16 annotation, while current yeast evidence for defined non-histone substrates remains limited.

Molecular Function:

NAD-dependent protein lysine deacetylase activity

Directly Involved In:

mitotic chromosome condensation

Cellular Locations:

cytoplasm nucleus

Supporting Evidence:

PMID:10811920
These enzymes also catalyze histone deacetylation in a reaction that absolutely requires NAD, thereby distinguishing them from previously characterized deacetylases.
UniProt:P53686
Reaction=N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O = 2''-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein].
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.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10811920

The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases.

HST2 catalyzes NAD-dependent histone deacetylation with absolute requirement for NAD cofactor

"these enzymes also catalyze histone deacetylation in a reaction that absolutely requires NAD, thereby distinguishing them from previously characterized deacetylases"
Family activity is distinct from previously characterized histone deacetylases

"these enzymes also catalyze histone deacetylation in a reaction that absolutely requires NAD, thereby distinguishing them from previously characterized deacetylases"

PMID:10841563

A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family.

NAD-dependent deacetylase activity is phylogenetically conserved across sirtuin family

"A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family"

PMID:11226170

A cytosolic NAD-dependent deacetylase, Hst2p, can modulate nucleolar and telomeric silencing in yeast.

HST2 is predominantly cytoplasmic (distinct from nuclear SIR2 and HST1)

"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"
HST2 overexpression increases rDNA repression while derepressing subtelomeric silencing

"overexpression of yHst2p influences nuclear silencing events in a SIR2 strain, derepressing subtelomeric silencing while increasing repression in the rDNA"
HST2 can influence nuclear silencing events through extra-nuclear localization

"Although yHst2p cannot restore silencing in a sir2 deletion, overexpression of yHst2p influences nuclear silencing events in a SIR2 strain"

PMID:16051752

HST2 mediates SIR2-independent life-span extension by calorie restriction.

HST2 mediates lifespan extension independent of SIR2 under calorie restriction

"Sir2-independent life-span extension is mediated by Hst2, a Sir2 homolog that promotes the stability of repetitive ribosomal DNA"
HST2 promotes stability of repetitive ribosomal DNA sequences

"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"
HST2 extends lifespan through same DNA stability mechanism as SIR2

"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"

PMID:16648462

SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis.

HST2 (yeast ortholog) exhibits strong preference for histone H4K16Ac as deacetylation substrate

"SirT2 and its yeast counterpart Hst2 have a strong preference for histone H4K16Ac in their deacetylation activity in vitro and in vivo"
H4K16Ac deacetylation is important for chromatin condensation during cell cycle

"The enzymatic conversion of H4K16Ac to its deacetylated form may be pivotal to the formation of condensed chromatin"

PMID:17110954

Nuclear export modulates the cytoplasmic Sir2 homologue Hst2.

HST2 shuttles between nucleus and cytoplasm

"Hst2 moves between the nucleus and cytoplasm, but is largely cytoplasmic owing to efficient nuclear export"
HST2 is largely cytoplasmic due to efficient CRM1-mediated 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"
Nuclear export regulates HST2's transcriptional repression activity

"Disruption of Hst2 export shows that nuclear exclusion inhibits the activity of Hst2 as a transcriptional repressor"
Contains putative leucine-rich nuclear export sequence overlapping autoregulatory helix

"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"

PMID:30358795

The cellular economy of the Saccharomyces cerevisiae zinc proteome.

HST2 identified as zinc-binding protein in systematic zinc proteome study

"The cellular economy of the Saccharomyces cerevisiae zinc proteome"

UniProt:P53686

UniProt entry for HST2/NAD-dependent protein deacetylase HST2

UniProt summarizes HST2 catalytic activity, zinc cofactor, and localization.

"NAD-dependent histone deacetylase that is involved in nuclear silencing events. Cytoplasm. Nucleus."

file:yeast/HST2/HST2-deep-research-falcon.md

Falcon deep research report for HST2

Falcon synthesis supports H4K16 deacetylation as the most precise Hst2 function.

"The most precise, experimentally supported biological role for budding-yeast Hst2 is to promote short-range mitotic chromosome compaction through H4K16 deacetylation."

file:interpro/panther/PTHR11085/PTHR11085-metadata.yaml

PANTHER family PTHR11085 NAD-dependent sirtuin protein deacylase metadata

PTHR11085 supports HST2 as a conserved sirtuin-family deacetylase.

"PANTHER family PTHR11085 is named NAD-dependent sirtuin protein deacylases and includes HST2 in the sirtuin-2 subfamily."

Suggested Experiments

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

📚 Additional Documentation

Deep Research Falcon

(HST2-deep-research-falcon.md)

provider: falcon
model: Edison Scientific Literature
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start_time: '2026-05-04T11:37:51.654129'
end_time: '2026-05-04T11:54:46.699920'
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template_file: templates/gene_research_go_focused.md
template_variables:
organism: yeast
gene_id: HST2
gene_symbol: HST2
uniprot_accession: P53686
protein_description: 'RecName: Full=NAD-dependent protein deacetylase HST2; EC=2.3.1.286
{ECO:0000255|PROSITE-ProRule:PRU00236}; AltName: Full=Homologous to SIR2 protein
2; AltName: Full=Regulatory protein SIR2 homolog 2;'
gene_info: Name=HST2; OrderedLocusNames=YPL015C; ORFNames=LPA2C;
organism_full: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
protein_family: Belongs to the sirtuin family. Class I subfamily.
protein_domains: DHS-like_NAD/FAD-binding_dom. (IPR029035); NAD-dep_sirtuin_deacylases.
(IPR050134); Sirtuin. (IPR003000); Sirtuin_cat_small_dom_sf. (IPR026591); Sirtuin_class_I.
(IPR017328)
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citation_count: 42

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P53686
Protein Description: RecName: Full=NAD-dependent protein deacetylase HST2; EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236}; AltName: Full=Homologous to SIR2 protein 2; AltName: Full=Regulatory protein SIR2 homolog 2;
Gene Information: Name=HST2; OrderedLocusNames=YPL015C; ORFNames=LPA2C;
Organism (full): Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Protein Family: Belongs to the sirtuin family. Class I subfamily.
Key Domains: DHS-like_NAD/FAD-binding_dom. (IPR029035); NAD-dep_sirtuin_deacylases. (IPR050134); Sirtuin. (IPR003000); Sirtuin_cat_small_dom_sf. (IPR026591); Sirtuin_class_I. (IPR017328)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "HST2" matches the protein description above
Verify the organism is correct: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'HST2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene HST2 (gene ID: HST2, UniProt: P53686) in yeast.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: P53686
Protein Description: RecName: Full=NAD-dependent protein deacetylase HST2; EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236}; AltName: Full=Homologous to SIR2 protein 2; AltName: Full=Regulatory protein SIR2 homolog 2;
Gene Information: Name=HST2; OrderedLocusNames=YPL015C; ORFNames=LPA2C;
Organism (full): Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Protein Family: Belongs to the sirtuin family. Class I subfamily.
Key Domains: DHS-like_NAD/FAD-binding_dom. (IPR029035); NAD-dep_sirtuin_deacylases. (IPR050134); Sirtuin. (IPR003000); Sirtuin_cat_small_dom_sf. (IPR026591); Sirtuin_class_I. (IPR017328)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "HST2" matches the protein description above
Verify the organism is correct: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene HST2 (gene ID: HST2, UniProt: P53686) in yeast.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Research report: Saccharomyces cerevisiae HST2 (UniProt P53686, ORF YPL015C)—functional annotation

Executive summary

HST2 encodes a class I sirtuin (Sir2-family) NAD(^+)-dependent lysine deacylase/deacetylase that is predominantly cytoplasmic but can act on chromatin during mitosis and under specific regulatory contexts. The most precise, experimentally supported biological role for budding-yeast Hst2 is to promote short-range mitotic chromosome compaction through H4K16 deacetylation after recruitment to H3S10-phosphorylated chromatin by the 14-3-3 protein Bmh1; this recruitment is enabled by phosphorylation of Hst2’s C-terminal tail (notably S320 or S324). (jain20211433proteinbmh1 pages 4-5, jain20211433proteinbmh1 pages 16-18, zhao2022sirtuinsinepigenetic pages 7-8)

1) Key concepts and definitions (current understanding)

1.1 Sirtuin enzymology and Hst2 definition

Hst2 is a Sir2-family (sirtuin) enzyme that catalyzes NAD(^+)-dependent removal of acyl groups from lysine residues. In the canonical deacetylation reaction, NAD(^+) and an acetyl-lysine substrate are converted to deacetylated lysine plus nicotinamide and 2′-O-acetyl-ADP-ribose (OAADPr), with structural evidence supporting ADP-ribose acetyl intermediates. (zhao2003structureofthe pages 1-2, martinezredondo2013thediversityof pages 2-3)

A high-resolution ternary structure of yeast Hst2 in complex with an acetylated histone H4 peptide centered on K16 and an NAD-derived product provides direct mechanistic support for this reaction chemistry in Hst2. (zhao2003structureofthe pages 1-2)

1.2 Primary substrate specificity (histone targets)

Across primary and review literature, Hst2 is most strongly linked to histone H4 lysine 16 acetylation (H4K16ac) as its preferred substrate; H3K9ac has been described as a weaker target. Deletion of HST2 increases cellular H4K16 acetylation levels, supporting in vivo relevance. (vaquero2006sirt2isa pages 1-2, vaquero2009theconservedrole pages 5-7)

1.3 Expanded deacylation scope: lysine debenzoylation

Beyond deacetylation, a recent structural synthesis highlights yeast Hst2 as an “eraser” for lysine benzoylation, with evidence from an Hst2–H3K9bz complex (PDB 7F4E) showing benzoyllysine recognition via an elongated hydrophobic channel and a π-π-π stacking mechanism involving aromatic residues (including F67, H135, F184). (nguyen2023engagingwithbenzoyllysine pages 1-5, nguyen2023engagingwithbenzoyllysine pages 9-14)

2) Subcellular localization and regulation

2.1 Cytoplasmic predominance and nuclear access

Hst2 is reported to be predominantly cytoplasmic in budding yeast, yet it can influence nuclear chromatin processes, consistent with either low-level nuclear presence or regulated shuttling. (perrod2001acytosolicnad‐dependent pages 1-2, vaquero2009theconservedrole pages 5-7, wierman2014yeastsirtuinsand pages 1-2)

Mechanistically, Hst2 has been described as having an active nuclear export mechanism / nuclear export signal (NES) that helps maintain cytoplasmic localization. (simoneau2016chromosomewidehistonedeacetylation pages 1-2, vaquero2009theconservedrole pages 5-7)

2.2 Mitotic recruitment pathway (H3S10ph → Bmh1 → Hst2)

An authoritative fungal sirtuin review summarizes Hst2’s best-described role: prior to mitosis, Aurora B/Ipl1-dependent phosphorylation of histone H3 at Ser10 (H3S10ph) recruits Hst2 to nucleosomes, where Hst2 deacetylates H4K16 to promote chromosome condensation. (zhao2022sirtuinsinepigenetic pages 7-8)

Primary mechanistic work (Jain et al., 2021) identifies Bmh1 (14-3-3) as the adaptor that bridges H3S10ph and Hst2. This interaction is cell-cycle dependent, peaking in mitosis, and depends on phosphorylation of Hst2’s C-terminus. (jain20211433proteinbmh1 pages 4-5, jain20211433proteinbmh1 pages 3-4)

Hst2 phosphorylation sites and functional consequences

Hst2 contains multiple C-terminal phosphorylation sites, and phosphorylation of S320 or S324 is individually required for Bmh1 binding. Alanine substitution at either site abolishes Bmh1 interaction and blocks mitotic H4K16 deacetylation. (jain20211433proteinbmh1 pages 4-5, jain20211433proteinbmh1 pages 11-13)

A schematic in Jain et al. indicates an NES spanning approximately amino acids 306–317, placing regulatory phosphorylation sites adjacent to (or near) nuclear export determinants. (jain20211433proteinbmh1 pages 11-13, jain20211433proteinbmh1 media d62d7912)

3) Biological roles and pathways (with emphasis on precise functions)

3.1 Mitotic chromosome compaction/condensation

The most precise Hst2 pathway is mitotic chromatin compaction: H3S10 phosphorylation (a mitotic mark) leads to Bmh1-mediated recruitment of phosphorylated Hst2 to chromatin, where Hst2-mediated removal of H4K16ac enables nucleosome–nucleosome interactions (via the H4 tail and acidic patch) that drive short-range chromatin compaction. (jain20211433proteinbmh1 pages 3-4, zhao2022sirtuinsinepigenetic pages 7-8, jain20211433proteinbmh1 media d62d7912)

3.2 Silencing effects: telomeres vs rDNA (context-dependent)

Classic work showed that although Hst2 cannot substitute for Sir2, overexpression of Hst2 can modulate nuclear silencing: it disrupts telomeric position effect (derepresses telomeric silencing) while improving rDNA silencing. This supports a model where cytosolic Hst2 can affect nuclear silencing indirectly (e.g., via competition for or modification of a shared ligand/substrate). (perrod2001acytosolicnad‐dependent pages 1-2, perrod2001acytosolicnad‐dependent pages 10-11)

Quantitatively, Perrod et al. reported that Hst2 overexpression improved rDNA silencing by ~1000-fold in a SIR2 background. (perrod2001acytosolicnad‐dependent pages 4-6)

3.3 Links to aging and genome stability (less Hst2-specific)

Reviews discuss Hst2 as “mysterious” relative to other yeast sirtuins, noting cytoplasmic predominance with likely nuclear shuttling and reported links to subtelomeric gene repression; however, mechanistic connections of Hst2 to aging phenotypes are less resolved than for other sirtuins (e.g., Sir2, Hst1, Hst3/Hst4). (wierman2014yeastsirtuinsand pages 1-2, vaquero2009theconservedrole pages 5-7)

In broader yeast sirtuin biology, NAD(^+)-dependent deacetylation is strongly linked to genome stability and DNA damage signaling; pharmacologic pan-inhibition of sirtuins (e.g., by nicotinamide) yields measurable DNA damage-response dependencies. While these effects are not uniquely attributed to Hst2, they motivate chemical-genetic use of yeast sirtuins as a system to map pathways impacted by sirtuin inhibition. (simoneau2016chromosomewidehistonedeacetylation pages 1-2, choy2016agenomewidescreen pages 1-2)

4) Quantitative data and statistics

4.1 Enzymatic kinetics and activation by phosphorylation (Jain et al., 2021)

Jain et al. quantified NAD(^+)-dependent deacetylase kinetics using a continuous assay (deacetylation of FLuc K529ac). Phosphorylation at S320 or S324 substantially increased catalytic efficiency (lower K(_M) and higher k(_cat)). Reported values include:

WT Hst2: K(M) = 66 ± 6 µM; V(\max) = 498 ± 30 (LUC/min); k(_cat) = 2494 ± 150 min(^{-1}); k(_cat)/K(_M) = 38
Hst2 S320ph: K(M) = 22 ± 0.9 µM; V(\max) = 1568 ± 16; k(_cat) = 7481 ± 81; k(_cat)/K(_M) = 356
Hst2 S324ph: K(M) = 23 ± 3 µM; V(\max) = 1585 ± 27; k(_cat) = 7925 ± 137; k(_cat)/K(_M) = 352

The figure/table containing these parameters and the authors’ recruitment model are shown in Jain et al. (Figure 3E and Figure 4). (jain20211433proteinbmh1 pages 16-18, jain20211433proteinbmh1 media 8fc38ca0, jain20211433proteinbmh1 media d62d7912)

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 2023: Hst2 and lysine benzoylation (structural mechanism)

A 2023 Current Opinion in Chemical Biology review synthesizes structural evidence positioning yeast Hst2 as a key debenzoylase in yeast, describing an Hst2–H3K9bz complex (PDB 7F4E) with benzoyllysine recognition through aromatic π-π-π stacking interactions. This extends the functional annotation of Hst2 beyond acetyl-lysine deacetylation to include processing of at least one bulky aromatic acyl mark on histones. (nguyen2023engagingwithbenzoyllysine pages 1-5, nguyen2023engagingwithbenzoyllysine pages 9-14)

5.2 2024: Hst2 as a model inspiring mechanism-based inhibitors

A 2024 Molecules review on sirtuin inhibitor development cites yeast Hst2 as a motivating experimental example: observation that a urea-containing homocitrulline stalls yeast Hst2 deacylase activity inspired testing thiocarbamoyl-lysine/thiourea-lysine as mechanism-based inhibitors that form stalled intermediates. This illustrates continued real-world use of Hst2 as a tractable enzymology model for developing chemical probes. (bursch2024currenttrendsin pages 22-24)

6) Current applications and real-world implementations

6.1 Yeast phenotypic screening for sirtuin inhibitors

A prominent application of yeast sirtuin biology is cell-based screening for inhibitors and for profiling selectivity across related NAD(^+)-dependent deacetylases.

A 2003 JBC study used a telomeric reporter and 5-FOA selection in yeast to screen ~100 splitomicin analogs, reporting MICs of 0.49–48 µM, and used secondary transcriptional assays plus microarrays to assess pathway specificity. (hirao2003identificationofselective pages 2-4, hirao2003identificationofselective pages 7-9)
That study also notes that Hst2 accounts for much of the NAD-dependent deacetylase activity in whole-cell lysates and that splitomicin inhibits Sir2 (and less so Hst1) but shows no inhibitory activity against Hst2, underscoring why multiple yeast sirtuins must be considered in chemical-genetic experiments. (hirao2003identificationofselective pages 1-2)

6.2 Nicotinamide (NAM) as a pan-sirtuin inhibitor to map pathways

Genome-wide deletion screens and fitness assays in yeast use nicotinamide to inhibit all sirtuins simultaneously to reveal sirtuin-dependent genetic vulnerabilities. One genome-wide screen used 120 mM NAM and identified 55 genes whose deletion causes NAM sensitivity, with enrichments in genome stability and sister chromatid cohesion pathways. (choy2016agenomewidescreen pages 1-2)

Similarly, yeast fitness assays under NAM implicate DNA damage response pathways as critical for survival during sirtuin inhibition and note that sirtuin inhibition can prevent growth of fungal pathogens (a translational motivation for sirtuin-targeting strategies). (simoneau2016chromosomewidehistonedeacetylation pages 1-2, simoneau2016chromosomewidehistonedeacetylation pages 18-19)

7) Expert opinions and synthesis (authoritative analyses)

Reviews converge on several points: (i) Hst2 is a conserved orthologous subfamily related to mammalian SIRT2; (ii) its best-supported direct chromatin role is mitotic chromosome compaction through H4K16 deacetylation; and (iii) despite strong enzymology and structural knowledge, its broader physiological roles and especially its cytoplasmic non-histone targets remain incompletely defined in budding yeast. (zhao2022sirtuinsinepigenetic pages 7-8, vaquero2009theconservedrole pages 5-7, wierman2014yeastsirtuinsand pages 1-2)

8) Key uncertainties and research gaps (for functional annotation)

Non-histone substrates in budding yeast: while sirtuins broadly can deacetylate non-histone proteins, Hst2-specific cytoplasmic non-histone targets in S. cerevisiae are not well established in the retrieved primary evidence. (zhao2022sirtuinsinepigenetic pages 7-8, vaquero2009theconservedrole pages 5-7)
Context-dependent silencing mechanisms: Hst2 overexpression affects telomeric and rDNA silencing in opposite directions, but the ligand/substrate competition model remains not fully resolved. (perrod2001acytosolicnad‐dependent pages 10-11, perrod2001acytosolicnad‐dependent pages 1-2)

Summary table

The following table consolidates core annotation facts, quantitative data, and recent developments.

Aspect	Key findings	Best supporting citations	URLs / publication years
Enzyme activity	Hst2 is the Saccharomyces cerevisiae Sir2-family/class I sirtuin corresponding to UniProt P53686/YPL015C. It is an NAD+-dependent lysine deacetylase/deacylase and was reported as the major source of detectable NAD-dependent deacetylase activity in yeast extracts. It preferentially deacetylates histone H4K16ac, with weaker activity reported toward H3K9ac.	(zhao2003structureofthe pages 1-2, vaquero2006sirt2isa pages 1-2, vaquero2009theconservedrole pages 5-7)	Structure 2003: https://doi.org/10.1016/j.str.2003.09.016; Genes Dev 2006: https://doi.org/10.1101/gad.1412706; Int J Dev Biol 2009: https://doi.org/10.1387/ijdb.082675av
Reaction products	The canonical sirtuin reaction consumes NAD+ and acetyl-lysine to generate nicotinamide, deacetylated lysine, and 2'-O-acetyl-ADP-ribose; Hst2 ternary structures support a mechanism involving ADP-ribose acetyl intermediates.	(zhao2003structureofthe pages 1-2, martinezredondo2013thediversityof pages 2-3)	Structure 2003: https://doi.org/10.1016/j.str.2003.09.016; PNAS 2004: https://doi.org/10.1073/pnas.0401057101; Genes Cancer 2013: https://doi.org/10.1177/1947601913483767
Substrates	Best-supported in vivo histone substrate is H4K16ac, especially during mitosis/chromosome condensation. H3K9ac has been reported as a weaker target. A 2023 review highlighted structural evidence that Hst2 also removes benzoyl groups from H3K9bz (debenzoylase activity; PDB 7F4E), indicating broader deacylase scope. Specific non-histone substrates in budding yeast remain poorly defined.	(vaquero2006sirt2isa pages 1-2, zhao2003structureofthe pages 1-2, nguyen2023engagingwithbenzoyllysine pages 1-5, nguyen2023engagingwithbenzoyllysine pages 9-14)	Genes Dev 2006: https://doi.org/10.1101/gad.1412706; Structure 2003: https://doi.org/10.1016/j.str.2003.09.016; Curr Opin Chem Biol 2023: https://doi.org/10.1016/j.cbpa.2022.102252
Localization	Hst2 is predominantly cytoplasmic in interphase. Multiple studies/reviews indicate active nuclear export and an NES; a low-level nuclear pool or mitotic nuclear entry/shuttling enables chromatin-directed functions.	(perrod2001acytosolicnad‐dependent pages 1-2, simoneau2016chromosomewidehistonedeacetylation pages 1-2, vaquero2009theconservedrole pages 5-7, wierman2014yeastsirtuinsand pages 1-2)	EMBO J 2001: https://doi.org/10.1093/emboj/20.1.197; Nucleic Acids Res 2016: https://doi.org/10.1093/nar/gkv1537; Int J Dev Biol 2009: https://doi.org/10.1387/ijdb.082675av; FEMS Yeast Res 2014: https://doi.org/10.1111/1567-1364.12115
Regulation / PTMs	Hst2 recruitment to mitotic chromatin depends on H3S10 phosphorylation and 14-3-3 protein Bmh1. Hst2 is phosphorylated on its C-terminus; S320 and S324 are individually required for Bmh1 binding and for mitotic H4K16 deacetylation. A schematic NES is mapped around aa 306-317. Truncation of the C-terminus impairs H4K16 deacetylation, and earlier structural studies suggested autoinhibition by terminal regions.	(jain20211433proteinbmh1 pages 4-5, jain20211433proteinbmh1 pages 3-4, jain20211433proteinbmh1 pages 11-13, zhao2003structureofthe pages 1-2)	J Biol Chem 2021: https://doi.org/10.1074/jbc.ac120.014758; Structure 2003: https://doi.org/10.1016/j.str.2003.09.016
Biological roles	Primary precise role: promote short-range mitotic chromosome compaction by deacetylating H4K16 after Aurora B/Ipl1-dependent H3S10 phosphorylation, which enables inter-nucleosomal interactions. Earlier work also showed that overexpressed Hst2 modulates silencing in opposite directions at telomeres and rDNA (reduced telomeric silencing, increased rDNA repression). It has been implicated in repression of subtelomeric FLO10 and discussed as a possible Sir2-independent contributor to lifespan regulation, though aging mechanisms remain less resolved than chromatin functions.	(zhao2022sirtuinsinepigenetic pages 7-8, jain20211433proteinbmh1 pages 13-14, perrod2001acytosolicnad‐dependent pages 10-11, vaquero2009theconservedrole pages 5-7, perrod2001acytosolicnad‐dependent pages 1-2)	Annu Rev Microbiol 2022: https://doi.org/10.1146/annurev-micro-041020-100926; J Biol Chem 2021: https://doi.org/10.1074/jbc.ac120.014758; EMBO J 2001: https://doi.org/10.1093/emboj/20.1.197; Int J Dev Biol 2009: https://doi.org/10.1387/ijdb.082675av
Quantitative kinetics	For a continuous deacetylase assay using FLuc K529ac, wild-type Hst2 had KM 66 ± 6 µM, Vmax 498 ± 30 LUC/min, kcat 2494 ± 150 min^-1, kcat/KM 38. Phosphorylation strongly stimulated activity: S320ph KM 22 ± 0.9 µM, kcat 7481 ± 81 min^-1, kcat/KM 356; S324ph KM 23 ± 3 µM, kcat 7925 ± 137 min^-1, kcat/KM 352.	(jain20211433proteinbmh1 pages 16-18, jain20211433proteinbmh1 media 8fc38ca0)	J Biol Chem 2021: https://doi.org/10.1074/jbc.ac120.014758
Recent 2023-2024 developments	Direct Hst2-specific 2023-2024 literature appears limited, but two notable recent advances are: (1) 2023 structural synthesis highlighting Hst2 as a lysine debenzoylase using a π-π-π recognition mode for H3K9bz; and (2) 2024 sirtuin-chemical-biology reviews citing yeast Hst2 as a structural/mechanistic model for inhibitor development and stalled deacylase intermediates. Broader 2023 yeast NAD+/sirtuin work remains more focused on Hst1 than Hst2.	(nguyen2023engagingwithbenzoyllysine pages 1-5, nguyen2023engagingwithbenzoyllysine pages 9-14)	Curr Opin Chem Biol 2023: https://doi.org/10.1016/j.cbpa.2022.102252
Applications / chemical probes	Hst2 has been widely used as a model enzyme for defining sirtuin catalytic chemistry, high-resolution ternary structures, product/intermediate states, and inhibitor concepts. Yeast phenotypic screens established nicotinamide as a pan-sirtuin inhibitor in vivo, and later reviews cite Hst2 structures/mechanisms as informative for sirtuin modulator development. Real-world implementation is mainly as a research model for chromatin biology and sirtuin chemical biology rather than an industrial yeast engineering target.	(zhao2003structureofthe pages 1-2, jain20211433proteinbmh1 pages 3-4, martinezredondo2013thediversityof pages 2-3)	Structure 2003: https://doi.org/10.1016/j.str.2003.09.016; J Biol Chem 2003: https://doi.org/10.1074/jbc.m308966200; Genes Cancer 2013: https://doi.org/10.1177/1947601913483767

Table: This table summarizes the best-supported functional annotation for Saccharomyces cerevisiae Hst2 (UniProt P53686/YPL015C), including catalytic activity, substrates, localization, regulation, and biological roles. It also highlights key quantitative kinetics, recent 2023-2024 developments, and how Hst2 is used as a model in sirtuin chemical biology.

Visual evidence (figures)

Jain et al. provide figure evidence for (i) kinetic parameters (Figure 3E) and (ii) a model for H3S10ph → Bmh1 → Hst2 recruitment and chromatin compaction (Figure 4). (jain20211433proteinbmh1 media 8fc38ca0, jain20211433proteinbmh1 media d62d7912)

References

(jain20211433proteinbmh1 pages 4-5): Neha Jain, Petra Janning, and Heinz Neumann. 14-3-3 protein bmh1 triggers short-range compaction of mitotic chromosomes by recruiting sirtuin deacetylase hst2. The Journal of Biological Chemistry, Jun 2021. URL: https://doi.org/10.1074/jbc.ac120.014758, doi:10.1074/jbc.ac120.014758. This article has 18 citations.
(jain20211433proteinbmh1 pages 16-18): Neha Jain, Petra Janning, and Heinz Neumann. 14-3-3 protein bmh1 triggers short-range compaction of mitotic chromosomes by recruiting sirtuin deacetylase hst2. The Journal of Biological Chemistry, Jun 2021. URL: https://doi.org/10.1074/jbc.ac120.014758, doi:10.1074/jbc.ac120.014758. This article has 18 citations.
(zhao2022sirtuinsinepigenetic pages 7-8): Guolei Zhao and Laura N. Rusche. Sirtuins in epigenetic silencing and control of gene expression in model and pathogenic fungi. Annual Review of Microbiology, 76:157-178, Sep 2022. URL: https://doi.org/10.1146/annurev-micro-041020-100926, doi:10.1146/annurev-micro-041020-100926. This article has 13 citations and is from a peer-reviewed journal.
(zhao2003structureofthe pages 1-2): Kehao Zhao, Xiaomei Chai, and Ronen Marmorstein. Structure of the yeast hst2 protein deacetylase in ternary complex with 2'-o-acetyl adp ribose and histone peptide. Structure, 11 11:1403-11, Nov 2003. URL: https://doi.org/10.1016/j.str.2003.09.016, doi:10.1016/j.str.2003.09.016. This article has 137 citations and is from a domain leading peer-reviewed journal.
(martinezredondo2013thediversityof pages 2-3): Paloma Martinez-Redondo and A. Vaquero. The diversity of histone versus nonhistone sirtuin substrates. Genes & cancer, 4 3-4:148-63, Mar 2013. URL: https://doi.org/10.1177/1947601913483767, doi:10.1177/1947601913483767. This article has 175 citations.
(vaquero2006sirt2isa pages 1-2): Alejandro Vaquero, Michael B. Scher, Dong Hoon Lee, Ann Sutton, Hwei-Ling Cheng, Frederick W. Alt, Lourdes Serrano, Rolf Sternglanz, and Danny Reinberg. Sirt2 is a histone deacetylase with preference for histone h4 lys 16 during mitosis. Genes & development, 20 10:1256-61, May 2006. URL: https://doi.org/10.1101/gad.1412706, doi:10.1101/gad.1412706. This article has 833 citations and is from a highest quality peer-reviewed journal.
(vaquero2009theconservedrole pages 5-7): Alejandro Vaquero. The conserved role of sirtuins in chromatin regulation. The International journal of developmental biology, 53 2-3:303-22, Apr 2009. URL: https://doi.org/10.1387/ijdb.082675av, doi:10.1387/ijdb.082675av. This article has 171 citations.
(nguyen2023engagingwithbenzoyllysine pages 1-5): Minh Chau Nguyen, Brian D. Strahl, and Tatiana G. Kutateladze. Engaging with benzoyllysine through a π-π-π mechanism. Current Opinion in Chemical Biology, 72:102252, Feb 2023. URL: https://doi.org/10.1016/j.cbpa.2022.102252, doi:10.1016/j.cbpa.2022.102252. This article has 3 citations and is from a peer-reviewed journal.
(nguyen2023engagingwithbenzoyllysine pages 9-14): Minh Chau Nguyen, Brian D. Strahl, and Tatiana G. Kutateladze. Engaging with benzoyllysine through a π-π-π mechanism. Current Opinion in Chemical Biology, 72:102252, Feb 2023. URL: https://doi.org/10.1016/j.cbpa.2022.102252, doi:10.1016/j.cbpa.2022.102252. This article has 3 citations and is from a peer-reviewed journal.
(perrod2001acytosolicnad‐dependent pages 1-2): S. Perrod, Moira M. Cockell, T. Laroche, H. Renauld, A. Ducrest, C. Bonnard, and S. Gasser. A cytosolic nad‐dependent deacetylase, hst2p, can modulate nucleolar and telomeric silencing in yeast. The EMBO Journal, 20:197-209, Jan 2001. URL: https://doi.org/10.1093/emboj/20.1.197, doi:10.1093/emboj/20.1.197. This article has 224 citations.
(wierman2014yeastsirtuinsand pages 1-2): Margaret B. Wierman and Jeffrey S. Smith. Yeast sirtuins and the regulation of aging. FEMS yeast research, 14 1:73-88, Feb 2014. URL: https://doi.org/10.1111/1567-1364.12115, doi:10.1111/1567-1364.12115. This article has 155 citations and is from a peer-reviewed journal.
(simoneau2016chromosomewidehistonedeacetylation pages 1-2): Antoine Simoneau, Étienne Ricard, Sandra Weber, Ian Hammond-Martel, Lai Hong Wong, Adnane Sellam, Guri Giaever, Corey Nislow, Martine Raymond, and Hugo Wurtele. Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of dna damage-induced signaling upon replicative stress. Nucleic Acids Research, 44:2706-2726, Jan 2016. URL: https://doi.org/10.1093/nar/gkv1537, doi:10.1093/nar/gkv1537. This article has 31 citations and is from a highest quality peer-reviewed journal.
(jain20211433proteinbmh1 pages 3-4): Neha Jain, Petra Janning, and Heinz Neumann. 14-3-3 protein bmh1 triggers short-range compaction of mitotic chromosomes by recruiting sirtuin deacetylase hst2. The Journal of Biological Chemistry, Jun 2021. URL: https://doi.org/10.1074/jbc.ac120.014758, doi:10.1074/jbc.ac120.014758. This article has 18 citations.
(jain20211433proteinbmh1 pages 11-13): Neha Jain, Petra Janning, and Heinz Neumann. 14-3-3 protein bmh1 triggers short-range compaction of mitotic chromosomes by recruiting sirtuin deacetylase hst2. The Journal of Biological Chemistry, Jun 2021. URL: https://doi.org/10.1074/jbc.ac120.014758, doi:10.1074/jbc.ac120.014758. This article has 18 citations.
(jain20211433proteinbmh1 media d62d7912): Neha Jain, Petra Janning, and Heinz Neumann. 14-3-3 protein bmh1 triggers short-range compaction of mitotic chromosomes by recruiting sirtuin deacetylase hst2. The Journal of Biological Chemistry, Jun 2021. URL: https://doi.org/10.1074/jbc.ac120.014758, doi:10.1074/jbc.ac120.014758. This article has 18 citations.
(perrod2001acytosolicnad‐dependent pages 10-11): S. Perrod, Moira M. Cockell, T. Laroche, H. Renauld, A. Ducrest, C. Bonnard, and S. Gasser. A cytosolic nad‐dependent deacetylase, hst2p, can modulate nucleolar and telomeric silencing in yeast. The EMBO Journal, 20:197-209, Jan 2001. URL: https://doi.org/10.1093/emboj/20.1.197, doi:10.1093/emboj/20.1.197. This article has 224 citations.
(perrod2001acytosolicnad‐dependent pages 4-6): S. Perrod, Moira M. Cockell, T. Laroche, H. Renauld, A. Ducrest, C. Bonnard, and S. Gasser. A cytosolic nad‐dependent deacetylase, hst2p, can modulate nucleolar and telomeric silencing in yeast. The EMBO Journal, 20:197-209, Jan 2001. URL: https://doi.org/10.1093/emboj/20.1.197, doi:10.1093/emboj/20.1.197. This article has 224 citations.
(choy2016agenomewidescreen pages 1-2): John S Choy, Bayan Qadri, Leah Henry, Kunal Shroff, Olatomiwa Bifarin, and Munira A Basrai. A genome-wide screen with nicotinamide to identify sirtuin-dependent pathways in saccharomyces cerevisiae. G3 Genes|Genomes|Genetics, 6:485-494, Feb 2016. URL: https://doi.org/10.1534/g3.115.022244, doi:10.1534/g3.115.022244. This article has 10 citations.
(jain20211433proteinbmh1 media 8fc38ca0): Neha Jain, Petra Janning, and Heinz Neumann. 14-3-3 protein bmh1 triggers short-range compaction of mitotic chromosomes by recruiting sirtuin deacetylase hst2. The Journal of Biological Chemistry, Jun 2021. URL: https://doi.org/10.1074/jbc.ac120.014758, doi:10.1074/jbc.ac120.014758. This article has 18 citations.
(bursch2024currenttrendsin pages 22-24): Karina L. Bursch, Christopher J. Goetz, and Brian C. Smith. Current trends in sirtuin activator and inhibitor development. Molecules, 29:1185, Mar 2024. URL: https://doi.org/10.3390/molecules29051185, doi:10.3390/molecules29051185. This article has 43 citations.
(hirao2003identificationofselective pages 2-4): Maki Hirao, Jeffrey Posakony, Melisa Nelson, Henning Hruby, Manfred Jung, Julian A. Simon, and Antonio Bedalov. Identification of selective inhibitors of nad+-dependent deacetylases using phenotypic screens in yeast*. Journal of Biological Chemistry, 278:52773-52782, Dec 2003. URL: https://doi.org/10.1074/jbc.m308966200, doi:10.1074/jbc.m308966200. This article has 112 citations and is from a domain leading peer-reviewed journal.
(hirao2003identificationofselective pages 7-9): Maki Hirao, Jeffrey Posakony, Melisa Nelson, Henning Hruby, Manfred Jung, Julian A. Simon, and Antonio Bedalov. Identification of selective inhibitors of nad+-dependent deacetylases using phenotypic screens in yeast*. Journal of Biological Chemistry, 278:52773-52782, Dec 2003. URL: https://doi.org/10.1074/jbc.m308966200, doi:10.1074/jbc.m308966200. This article has 112 citations and is from a domain leading peer-reviewed journal.
(hirao2003identificationofselective pages 1-2): Maki Hirao, Jeffrey Posakony, Melisa Nelson, Henning Hruby, Manfred Jung, Julian A. Simon, and Antonio Bedalov. Identification of selective inhibitors of nad+-dependent deacetylases using phenotypic screens in yeast*. Journal of Biological Chemistry, 278:52773-52782, Dec 2003. URL: https://doi.org/10.1074/jbc.m308966200, doi:10.1074/jbc.m308966200. This article has 112 citations and is from a domain leading peer-reviewed journal.
(simoneau2016chromosomewidehistonedeacetylation pages 18-19): Antoine Simoneau, Étienne Ricard, Sandra Weber, Ian Hammond-Martel, Lai Hong Wong, Adnane Sellam, Guri Giaever, Corey Nislow, Martine Raymond, and Hugo Wurtele. Chromosome-wide histone deacetylation by sirtuins prevents hyperactivation of dna damage-induced signaling upon replicative stress. Nucleic Acids Research, 44:2706-2726, Jan 2016. URL: https://doi.org/10.1093/nar/gkv1537, doi:10.1093/nar/gkv1537. This article has 31 citations and is from a highest quality peer-reviewed journal.
(jain20211433proteinbmh1 pages 13-14): Neha Jain, Petra Janning, and Heinz Neumann. 14-3-3 protein bmh1 triggers short-range compaction of mitotic chromosomes by recruiting sirtuin deacetylase hst2. The Journal of Biological Chemistry, Jun 2021. URL: https://doi.org/10.1074/jbc.ac120.014758, doi:10.1074/jbc.ac120.014758. This article has 18 citations.

Citations

zhao2003structureofthe pages 1-2
zhao2022sirtuinsinepigenetic pages 7-8
bursch2024currenttrendsin pages 22-24
hirao2003identificationofselective pages 1-2
choy2016agenomewidescreen pages 1-2
martinezredondo2013thediversityof pages 2-3
vaquero2009theconservedrole pages 5-7
nguyen2023engagingwithbenzoyllysine pages 1-5
nguyen2023engagingwithbenzoyllysine pages 9-14
wierman2014yeastsirtuinsand pages 1-2
simoneau2016chromosomewidehistonedeacetylation pages 1-2
hirao2003identificationofselective pages 2-4
hirao2003identificationofselective pages 7-9
simoneau2016chromosomewidehistonedeacetylation pages 18-19
https://doi.org/10.1016/j.str.2003.09.016;
https://doi.org/10.1101/gad.1412706;
https://doi.org/10.1387/ijdb.082675av
https://doi.org/10.1073/pnas.0401057101;
https://doi.org/10.1177/1947601913483767
https://doi.org/10.1016/j.cbpa.2022.102252
https://doi.org/10.1093/emboj/20.1.197;
https://doi.org/10.1093/nar/gkv1537;
https://doi.org/10.1387/ijdb.082675av;
https://doi.org/10.1111/1567-1364.12115
https://doi.org/10.1074/jbc.ac120.014758;
https://doi.org/10.1016/j.str.2003.09.016
https://doi.org/10.1146/annurev-micro-041020-100926;
https://doi.org/10.1074/jbc.ac120.014758
https://doi.org/10.1074/jbc.m308966200;
https://doi.org/10.1074/jbc.ac120.014758,
https://doi.org/10.1146/annurev-micro-041020-100926,
https://doi.org/10.1016/j.str.2003.09.016,
https://doi.org/10.1177/1947601913483767,
https://doi.org/10.1101/gad.1412706,
https://doi.org/10.1387/ijdb.082675av,
https://doi.org/10.1016/j.cbpa.2022.102252,
https://doi.org/10.1093/emboj/20.1.197,
https://doi.org/10.1111/1567-1364.12115,
https://doi.org/10.1093/nar/gkv1537,
https://doi.org/10.1534/g3.115.022244,
https://doi.org/10.3390/molecules29051185,
https://doi.org/10.1074/jbc.m308966200,

📄 View Raw YAML

id: P53686
gene_symbol: HST2
aliases:
- YPL015C
- LPA2C
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:559292
  label: Saccharomyces cerevisiae
description: >-
  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.
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
    - reference_id: file:yeast/HST2/HST2-deep-research-falcon.md
      supporting_text: >-
        Hst2 is a Sir2-family sirtuin enzyme that catalyzes NAD-dependent
        removal of acyl groups from lysine residues.
- 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), but this appears secondary to its sirtuin deacetylase and
      chromatin-compaction function.
    action: KEEP_AS_NON_CORE
    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.
    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:0045892
      label: negative regulation of DNA-templated transcription
    additional_reference_ids:
    - PMID:17110954
    supported_by:
    - reference_id: PMID:17110954
      supporting_text: Disruption of Hst2 export shows that nuclear exclusion inhibits the activity of Hst2 as a
        transcriptional repressor
- 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: MODIFY
    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_replacement_terms:
    - id: GO:0034979
      label: NAD-dependent protein lysine deacetylase activity
    - id: GO:0017136
      label: histone deacetylase activity, NAD-dependent
    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
      influence chromatin, but the generic heterochromatin-formation term
      overstates the clearest HST2-specific process.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0007076
      label: mitotic chromosome condensation
    supported_by:
    - reference_id: PMID:16648462
      supporting_text: >-
        The enzymatic conversion of H4K16Ac to its deacetylated form may be
        pivotal to the formation of condensed chromatin.
    - 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
    - reference_id: file:yeast/HST2/HST2-deep-research-falcon.md
      supporting_text: >-
        The most precise Hst2 pathway is mitotic chromatin compaction: H3S10
        phosphorylation leads to Bmh1-mediated recruitment of phosphorylated
        Hst2 to chromatin.
- 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, but the specific zinc ion
      binding annotation is already present.
    action: MARK_AS_OVER_ANNOTATED
    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.
    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: KEEP_AS_NON_CORE
    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.
    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: KEEP_AS_NON_CORE
    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.
    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: KEEP_AS_NON_CORE
    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.
    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: KEEP_AS_NON_CORE
    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.
    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: KEEP_AS_NON_CORE
    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.
    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
  directly_involved_in:
  - id: GO:0007076
    label: mitotic chromosome condensation
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  description: >-
    Hst2 is an NAD-dependent sirtuin deacetylase with strong preference for
    histone H4K16Ac. It is mostly cytoplasmic at steady state but shuttles to the
    nucleus, where regulated access to mitotic chromatin supports H4K16
    deacetylation and chromosome condensation. NAD and zinc binding are
    necessary catalytic features, but they are cofactors for this deacetylase
    function rather than separate core functions.
  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.
  - reference_id: file:yeast/HST2/HST2-deep-research-falcon.md
    supporting_text: >-
      The most precise Hst2 pathway is mitotic chromatin compaction: H3S10
      phosphorylation leads to Bmh1-mediated recruitment of phosphorylated Hst2
      to chromatin, where Hst2-mediated removal of H4K16ac enables
      nucleosome-nucleosome interactions.
  - reference_id: file:interpro/panther/PTHR11085/PTHR11085-metadata.yaml
    supporting_text: PANTHER family PTHR11085 is named NAD-dependent sirtuin protein deacylases and includes HST2 in the sirtuin-2 subfamily.
- molecular_function:
    id: GO:0034979
    label: NAD-dependent protein lysine deacetylase activity
  directly_involved_in:
  - id: GO:0007076
    label: mitotic chromosome condensation
  locations:
  - id: GO:0005737
    label: cytoplasm
  - id: GO:0005634
    label: nucleus
  description: >-
    Hst2 also fits the broader sirtuin molecular function of NAD-dependent
    protein lysine deacetylation/deacylation. This parent activity captures the
    conserved reaction chemistry and potential substrate scope beyond the
    specific H4K16 annotation, while current yeast evidence for defined
    non-histone substrates remains limited.
  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.
  - reference_id: UniProt:P53686
    supporting_text: >-
      Reaction=N(6)-acetyl-L-lysyl-[protein] + NAD(+) + H2O =
      2''-O-acetyl-ADP-D-ribose + nicotinamide + L-lysyl-[protein].
  - reference_id: file:yeast/HST2/HST2-deep-research-falcon.md
    supporting_text: >-
      Hst2 is a Sir2-family sirtuin enzyme that catalyzes NAD-dependent removal
      of acyl groups from lysine residues.
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:
- experiment_type: substrate proteomics
  hypothesis: >-
    Hst2 has a limited set of non-histone yeast substrates that explain its
    cytoplasmic steady-state localization.
  description: >-
    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.
- experiment_type: chromatin recruitment assay
  hypothesis: >-
    Bmh1-dependent recruitment of phosphorylated Hst2 to mitotic chromatin is
    required for the H4K16 deacetylation component of rDNA and chromosome
    compaction phenotypes.
  description: >-
    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.
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
- id: UniProt:P53686
  title: UniProt entry for HST2/NAD-dependent protein deacetylase HST2
  findings:
  - statement: UniProt summarizes HST2 catalytic activity, zinc cofactor, and localization.
    supporting_text: >-
      NAD-dependent histone deacetylase that is involved in nuclear silencing
      events. Cytoplasm. Nucleus.
- id: file:yeast/HST2/HST2-deep-research-falcon.md
  title: Falcon deep research report for HST2
  findings:
  - statement: Falcon synthesis supports H4K16 deacetylation as the most precise Hst2 function.
    supporting_text: >-
      The most precise, experimentally supported biological role for
      budding-yeast Hst2 is to promote short-range mitotic chromosome compaction
      through H4K16 deacetylation.
- id: file:interpro/panther/PTHR11085/PTHR11085-metadata.yaml
  title: PANTHER family PTHR11085 NAD-dependent sirtuin protein deacylase metadata
  findings:
  - statement: PTHR11085 supports HST2 as a conserved sirtuin-family deacetylase.
    supporting_text: PANTHER family PTHR11085 is named NAD-dependent sirtuin protein deacylases and includes HST2 in the sirtuin-2 subfamily.

HST2

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Research report: Saccharomyces cerevisiae HST2 (UniProt P53686, ORF YPL015C)—functional annotation

Executive summary

1) Key concepts and definitions (current understanding)

1.1 Sirtuin enzymology and Hst2 definition

1.2 Primary substrate specificity (histone targets)

1.3 Expanded deacylation scope: lysine debenzoylation

2) Subcellular localization and regulation

2.1 Cytoplasmic predominance and nuclear access

2.2 Mitotic recruitment pathway (H3S10ph → Bmh1 → Hst2)

Hst2 phosphorylation sites and functional consequences

3) Biological roles and pathways (with emphasis on precise functions)

3.1 Mitotic chromosome compaction/condensation

3.2 Silencing effects: telomeres vs rDNA (context-dependent)

3.3 Links to aging and genome stability (less Hst2-specific)

4) Quantitative data and statistics

4.1 Enzymatic kinetics and activation by phosphorylation (Jain et al., 2021)

5) Recent developments and latest research (prioritizing 2023–2024)

5.1 2023: Hst2 and lysine benzoylation (structural mechanism)

5.2 2024: Hst2 as a model inspiring mechanism-based inhibitors

6) Current applications and real-world implementations

6.1 Yeast phenotypic screening for sirtuin inhibitors

6.2 Nicotinamide (NAM) as a pan-sirtuin inhibitor to map pathways

7) Expert opinions and synthesis (authoritative analyses)

8) Key uncertainties and research gaps (for functional annotation)

Summary table

Visual evidence (figures)

Citations

📄 View Raw YAML