HST3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: HST3 localizes to the nucleus where it functions as a histone deacetylase. UniProt subcellular localization states both cytoplasm and nucleus. This IBA annotation is supported by phylogenetic inference from orthologs. IC evidence from PMID:12242223 also confirms nuclear localization, which is essential for its function in histone deacetylation and transcriptional regulation. Reason: HST3 is a nuclear protein required for histone H3K56 deacetylation during S/G2 phase transitions (PMID:17977840). IBA annotation is well-supported by orthologous relationships across sirtuins and confirmed experimentally. Supporting Evidence: PMID:12242223 Furthermore, Hst3 was physically present at 2mu ARS in a silencing context as well as at the endogenous 2mu plasmid
GO:0017136 histone deacetylase activity, NAD-dependent	IBA GO_REF:0000033	MODIFY	Summary: This parent term captures the correct NAD-dependent histone deacetylase chemistry, but HST3s core characterized activity is the more specific H3K56 deacetylase activity. Multiple experimental lines of evidence support the H3K56 substrate specificity. Reason: The annotation should use the current specific child term for HST3s demonstrated NAD-dependent histone H3K56 deacetylase activity. Proposed replacements: histone H3K56 deacetylase activity, NAD-dependent Supporting Evidence: PMID:17977840 Hst3 has NAD-dependent histone deacetylase activity in vitro and that it functions during S phase to deacetylate the core domain of histone H3 at lysine 56 (H3K56) file:yeast/HST3/HST3-deep-research-falcon.md Falcon literature synthesis supports HST3 as an NAD-dependent H3K56 deacetylase. PMID:23357952 These functions are necessary for the repair of replication-born DSBs by SCR
GO:0000183 rDNA heterochromatin formation	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: HST3 contributes to rDNA heterochromatin formation through its NAD-dependent histone deacetylase activity. However, this term appears somewhat over-specific compared to the broader silencing roles. UniProt documents roles in histone H3K56 deacetylation and telomeric silencing. The rDNA-specific annotation is less well-established than general transcriptional silencing. Reason: While HST3 participates in silencing processes that may include rDNA, this is not explicitly demonstrated as a core function. The primary characterized substrate is histone H3K56, which affects broader transcription and genome stability. The rDNA-specific function is an inferred application of the deacetylase activity rather than a primary function. Supporting Evidence: PMID:7498786 The SIR2 gene family, conserved from bacteria to humans, functions in silencing, cell cycle progression, and chromosome stability. PMID:31167142 Yeast Sirtuin Family Members Maintain Transcription Homeostasis to Ensure Genome Stability.
GO:0000781 chromosome, telomeric region	IEA GO_REF:0000108	KEEP AS NON CORE	Summary: This is a localization annotation indicating HST3 associates with telomeric regions of chromosomes. Evidence shows HST3 and HST4 contribute to telomeric silencing (PMID:7498786), but this is inferred primarily from functional effects rather than direct localization studies. The IEA inference from GO:0031509 (subtelomeric heterochromatin formation) is logically sound. Reason: HST3 function at telomeric regions is secondary to its core H3K56 deacetylase activity. The localization annotation is supported by functional genomics (silencing phenotypes) but this is not a primary function description. Better captured under heterochromatin formation processes.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Duplicate of annotation 1 (same GO term, different evidence code). UniProtKB subcellular location vocabulary explicitly states HST3 is localized to nucleus and cytoplasm. This IEA annotation from UniProt is consistent with the IBA annotation. Reason: Redundant but valid annotation. Multiple evidence types (IEA from subcellular location mapping and IBA from phylogenetics) support nuclear localization.
GO:0005737 cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: UniProtKB subcellular location states "Cytoplasm. Nucleus." HST3 is documented in both compartments, though primary function is nuclear. Cytoplasmic localization is less characterized but appears to be a minor component of HST3 localization. Reason: HST3 has documented cytoplasmic localization in UniProt, but its characterized functions (H3K56 deacetylation, transcription regulation, DNA repair) are nuclear. Cytoplasmic localization may represent transit or peripheral functions.
GO:0006351 DNA-templated transcription	IEA GO_REF:0000043	MODIFY	Summary: HST3 involvement in transcription is experimentally confirmed. PMID:31167142 demonstrates that Hst3 and Hst4 regulate transcription homeostasis by repressing nascent RNA transcription at many loci. This prevents excessive transcription-associated R-loops that cause DNA damage. The function is broader than suggested by general "DNA-templated transcription" term. Reason: HST3 is documented as repressing transcription through H3K56 deacetylation. IEA from UniProt keywords (Transcription) is supported by experimental evidence (PMID:31167142 shows HST3 and HST4 repress nascent transcription), but the more informative GO term is negative regulation of DNA-templated transcription. Proposed replacements: negative regulation of DNA-templated transcription Supporting Evidence: PMID:31167142 Hst3 and Hst4 are required to repress transcription of coding and non-coding RNAs
GO:0016740 transferase activity	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: Transferase activity is an extremely broad parent term, but it is not mechanistically wrong for class III/NAD-dependent deacetylases: the acetyl group is transferred to NAD during the sirtuin reaction. It is much less informative than the H3K56-specific deacetylase term. Reason: GO:0016740 is a valid broad superclass for NAD-dependent deacetylase chemistry, but HST3s core molecular function is better captured by GO:0140765 histone H3K56 deacetylase activity, NAD-dependent.
GO:0017136 histone deacetylase activity, NAD-dependent	IEA GO_REF:0000117	MODIFY	Summary: Duplicate parent-term annotation for NAD-dependent histone deacetylase activity. The biology is valid, but the stronger HST3-specific review should point to H3K56 deacetylase activity. Reason: Use the specific child term GO:0140765 for HST3s demonstrated H3K56 deacetylase activity. Proposed replacements: histone H3K56 deacetylase activity, NAD-dependent
GO:0031507 heterochromatin formation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: HST3 contributes to heterochromatin formation through histone deacetylation. PMID:7498786 shows hst3 hst4 double mutants are defective in telomeric silencing. However, PMID:31167142 suggests the primary mechanism is regulation of transcription homeostasis rather than structural heterochromatin formation. The term is somewhat over-general for the more specific H3K56 deacetylation function. Reason: While HST3 participates in silencing and heterochromatin-associated processes, its primary characterized function is H3K56 deacetylation and transcription regulation. Heterochromatin formation is an inferred downstream consequence rather than direct function.
GO:0034979 NAD-dependent protein lysine deacetylase activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: This is a correct but broad parent term for NAD-dependent protein lysine deacetylase chemistry. HST3s characterized substrate is histone H3 lysine 56, so the parent term should not be promoted as the core MF. Reason: The annotation is not wrong, but GO:0140765 is the informative core molecular-function term for HST3.
GO:0046872 metal ion binding	IEA GO_REF:0000043	ACCEPT	Summary: HST3 contains zinc-binding sites. UniProt specifically documents that HST3 binds 1 zinc ion per subunit, with 4 zinc-coordinating residues in the catalytic sirtuin domain (positions 195, 198, 220, 223). The annotation is inferred from UniProt keyword "Zinc" (GO_REF:0000043 is UniProt-KW mapping). PMID:30358795 on yeast zinc proteome may provide additional validation. Reason: HST3 contains a zinc cofactor essential for sirtuin catalytic activity. The annotation is well-supported by UniProt feature annotations identifying zinc-binding residues.
GO:0070403 NAD+ binding	IEA GO_REF:0000002	ACCEPT	Summary: HST3 is an NAD-dependent deacetylase and must bind NAD+ cofactor. UniProt documents multiple NAD+-binding residues (positions 60-79, 151-154, 282-284, 312-314, 333) in the characteristic sirtuin NAD+ binding domain. The inference from InterPro IPR003000 (sirtuin domain) is appropriate. This is a required cofactor binding activity. Reason: Essential cofactor binding for catalytic activity. HST3 catalytic mechanism absolutely requires NAD+ binding. The annotation is correctly inferred from the sirtuin domain structure.
GO:0008270 zinc ion binding	RCA PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc pr...	ACCEPT	Summary: Zinc ion binding is specifically documented by UniProt with four coordinating residues identified through structure. RCA (Reviewed Computational Analysis) using PMID:30358795 (yeast zinc proteome characterization) is appropriate evidence. This is equivalent to the metal ion binding annotation but more specific. Reason: Specific instance of the broader metal ion binding annotation. Zinc is specifically required for sirtuin catalytic activity. RCA evidence from zinc proteome characterization is valid. Supporting Evidence: PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc proteome.
GO:0005634 nucleus	IC PMID:12242223 A novel yeast silencer. the 2mu origin of Saccharomyces cere...	ACCEPT	Summary: Third annotation of nuclear localization. PMID:12242223 provides experimental evidence that HST3 is physically present at the 2mu ARS silencer element in a silencing context, inferred curated evidence (IC) of nuclear localization. Redundant with annotations 1 and 5. Reason: Valid experimental evidence of nuclear localization through physical presence at genomic elements. Redundant with other nuclear localization annotations but valid. Supporting Evidence: PMID:12242223 Furthermore, Hst3 was physically present at 2mu ARS in a silencing context as well as at the endogenous 2mu plasmid
GO:0031509 subtelomeric heterochromatin formation	IGI PMID:7498786 The SIR2 gene family, conserved from bacteria to humans, fun...	ACCEPT	Summary: PMID:7498786 shows that hst3 hst4 double mutants are defective in telomeric silencing, establishing that HST3 and HST4 contribute together to subtelomeric silencing. IGI (Inferred from Genetic Interaction) is appropriate evidence code, using HST4 as the interacting gene. This demonstrates HST3 function in telomeric silencing. Reason: Experimental evidence demonstrates HST3 requirement for subtelomeric silencing. The function is well-characterized even if redundant with HST4. This is a core genomic stability function. Supporting Evidence: PMID:7498786 hst3 hst4 double mutants are defective in telomeric silencing
GO:0017136 histone deacetylase activity, NAD-dependent	IDA PMID:17977840 Hst3 is regulated by Mec1-dependent proteolysis and controls...	MODIFY	Summary: IDA evidence from PMID:17977840 directly supports the specific H3K56 NAD-dependent deacetylase activity, not just the parent histone deacetylase term. Reason: The direct assay evidence should be represented with GO:0140765, the specific H3K56 child term. Proposed replacements: histone H3K56 deacetylase activity, NAD-dependent Supporting Evidence: PMID:17977840 Hst3 has NAD-dependent histone deacetylase activity in vitro and that it functions during S phase to deacetylate the core domain of histone H3 at lysine 56 (H3K56)
GO:0017136 histone deacetylase activity, NAD-dependent	IMP PMID:17977840 Hst3 is regulated by Mec1-dependent proteolysis and controls...	MODIFY	Summary: IMP evidence from PMID:17977840 supports the specific H3K56 deacetylase function: loss of Hst3 causes failure to regulate H3K56 acetylation and downstream checkpoint/cohesion phenotypes. Reason: The mutant phenotype evidence should be represented with GO:0140765 rather than only the parent NAD-dependent histone deacetylase term. Proposed replacements: histone H3K56 deacetylase activity, NAD-dependent Supporting Evidence: PMID:17977840 Loss of Hst3-mediated regulation of H3K56 acetylation results in a defect in the S phase DNA damage checkpoint
GO:0006351 DNA-templated transcription	IDA PMID:31167142 Yeast Sirtuin Family Members Maintain Transcription Homeosta...	MODIFY	Summary: IDA evidence from PMID:31167142 shows comprehensive transcriptomic analysis demonstrating HST3 directly regulates transcription. Using NET-seq (native elongating transcript sequencing), the authors show that loss of Hst3 and Hst4 leads to global increases in nascent transcription at ~1,000 genes. This is direct measurement of transcription dynamics, not merely inference. Highly specific to H3K56-mediated regulation. Reason: Robust experimental evidence supports transcriptional repression: NET-seq shows increased nascent transcription when HST3/HST4 are lost. The parent DNA-templated transcription term should be replaced by the more precise negative regulation term. Proposed replacements: negative regulation of DNA-templated transcription Supporting Evidence: PMID:31167142 Loss of Hst3 and Hst4 led to a global shift in the nascent RNA transcriptome, with an average fold increase of ~1.4
GO:0009299 mRNA transcription	IDA PMID:31167142 Yeast Sirtuin Family Members Maintain Transcription Homeosta...	MODIFY	Summary: PMID:31167142 demonstrates that HST3 negatively regulates RNA polymerase II mRNA transcription: metagene analysis shows higher nascent transcript levels throughout genic regions, especially near transcription start sites, when HST3/HST4 activity is lost. Reason: Direct NET-seq evidence shows mRNA-coding regions are specifically affected, but the direction is repressive rather than neutral participation in mRNA transcription. The annotation should therefore use a negative regulation child term consistent with the GO:0006351 reviews from the same paper. Proposed replacements: negative regulation of transcription by RNA polymerase II Supporting Evidence: PMID:31167142 Metagene plots of mean nascent transcript levels, representative genome browser views of NET-seq data, and a heatmap of the log2-fold change between the hst4Δ HST3-FRB mutant and WT confirmed higher levels of transcription throughout genic regions
GO:1990414 replication-born double-strand break repair via sister chromatid exchange	IMP PMID:23357952 Histone H3K56 acetylation, Rad52, and non-DNA repair factors...	ACCEPT	Summary: PMID:23357952 provides comprehensive evidence that HST3 is required for sister chromatid recombination (SCR) of replication-born double-strand breaks. The authors identify hst3 among 12 mutants consistently impaired in SCR using physical assay of recombination. Loss of HST3 (and HST4) severely impairs the ability to repair DSBs with the sister chromatid, with 50-fold decrease in intrachromosomal SCR. This is a major genome stability function dependent on H3K56 acetylation state. Reason: HST3 is a critical factor for proper DSB repair template choice (sister chromatid preference). Loss results in genome instability and increased recombination with homologs instead of sister chromatids. Core function in genome stability. Supporting Evidence: PMID:23357952 The hst3Δ mutation is strongly affected in intrachromosomal SCR repeat recombination (50-fold decrease)
GO:0046459 short-chain fatty acid metabolic process	IMP PMID:12618394 Short-chain fatty acid activation by acyl-coenzyme A synthet...	MARK AS OVER ANNOTATED	Summary: PMID:12618394 shows that growth on short-chain fatty acids (acetate, propionate) is severely impaired in quintuple sir2 hst1 hst2 hst3 hst4 mutant strain, with HST3 and HST4 identified as most important for growth on these substrates. However, this is not the primary function of HST3. The mechanism appears to involve SIR2 family proteins controlling acetyl-CoA synthetase (Acs) enzyme activity, suggesting an indirect metabolic role rather than direct involvement in lipid metabolism. Reason: While HST3 contributes to growth on short-chain fatty acids through its requirement for Acs activity regulation, this is not a primary enzymatic function. HST3 is a histone deacetylase whose role in fatty acid metabolism is indirect, mediated through NAD-dependent regulation of Acs protein acetylation. The annotation overstates HST3s direct involvement in metabolic process. Better annotated as a regulatory cofactor effect than a metabolic process function. Supporting Evidence: PMID:12618394 Short-chain fatty acid activation by acyl-coenzyme A synthetases requires SIR2 protein function in Salmonella enterica and Saccharomyces cerevisiae.

Gene Description

Existing Annotations Review

Core Functions

NAD-dependent deacetylation of histone H3 lysine 56, catalyzed during S/G2 phase transition. Essential NAD-dependent H3K56 deacetylase required for cell cycle checkpoint control and proper nucleosome reassembly after DNA replication.

References

Deep Research

Falcon

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