HST1 encodes a nuclear NAD-dependent sirtuin deacetylase that is recruited by Sum1 and the tethering factor Rfm1 to selected chromosomal loci. Local histone deacetylation, prominently at H4K5, represses middle-sporulation and metabolic gene programs during vegetative growth and also supports efficient initiation at a subset of replication origins. Unlike its paralog Sir2, native Hst1 is a gene-specific chromatin regulator rather than a regional silencing factor at telomeres or silent mating-type loci.
Definition: Catalysis of the removal of an acetyl group from lysine 5 of histone H4 using NAD+ as a reactant, producing deacetylated histone, nicotinamide, and 2'-O-acetyl-ADP-ribose.
Justification: Current GO has an H4K5-specific term for the hydrolytic mechanism and several residue-specific NAD-dependent histone deacetylase terms, but no NAD-dependent H4K5 child of GO:0017136. Hst1-specific experiments identify H4K5 as its main histone H4 target.
Parent term: histone deacetylase activity, NAD-dependent
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005634
nucleus
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Hst1 is a nuclear chromatin-associated sirtuin recruited to specific promoters and replication origins.
Reason: Nuclear localization and locus-specific chromatin association are supported by PMID:11711434 and PMID:29066473.
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|
GO:0006974
DNA damage response
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: A DNA-damage-response role has not been demonstrated for Hst1 itself.
Reason: This IBA appears to transfer a broad Sir2-family genome-stability role without positive Hst1-specific evidence; Hst1's demonstrated functions are locus-specific deacetylation and transcriptional repression.
|
|
GO:0003714
transcription corepressor activity
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Hst1 provides catalytic repression within the Sum1-Rfm1-Hst1 complex.
Reason: Rfm1 recruits Hst1 to Sum1-bound promoters to repress middle-sporulation genes (PMID:12612074).
Supporting Evidence:
PMID:12612074
Rfm1 interacts with both Sum1 and Hst1 and is required for the Sum1-Hst1 interaction.
|
|
GO:0031509
subtelomeric heterochromatin formation
|
IBA
GO_REF:0000033 |
REMOVE |
Summary: Native Hst1 is a gene-specific repressor, not a telomeric regional-silencing enzyme.
Reason: Hst1 and Sir2 have distinct cofactor-targeting specificities; PMID:17242192 assigns telomeric regional silencing to Sir2-Sir3-Sir4 and gene-specific repression to Hst1-Rfm1-Sum1. This IBA transfers the Sir2 role to Hst1.
Supporting Evidence:
PMID:17242192
Nevertheless, the two proteins promote two mechanistically distinct forms of gene repression.
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GO:0032041
histone H3K14 deacetylase activity, NAD-dependent
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: Hst1 deacetylates promoter histones, but H3K14 specificity has not been demonstrated for Hst1 itself.
Reason: Hst1-specific chromatin studies identify H4K5 as the predominant affected residue; this residue-specific IBA overextends broader sirtuin evidence. The proposed NAD-dependent H4K5 term records the supported specificity.
Supporting Evidence:
PMID:18990212
This was consistent with the notion that H4 K5 was the main target of the histone deacetylase Hst1, whereas other histone H4 lysine residues were minor or no targets of Hst1.
|
|
GO:0046969
histone H3K9 deacetylase activity, NAD-dependent
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: Hst1 is an NAD-dependent histone deacetylase, but H3K9 specificity is not established for Hst1.
Reason: The H3K9 assignment derives from family transfer, whereas Hst1-specific experiments primarily implicate H4K5. The proposed NAD-dependent H4K5 term records the supported specificity.
Supporting Evidence:
PMID:18990212
This was consistent with the notion that H4 K5 was the main target of the histone deacetylase Hst1, whereas other histone H4 lysine residues were minor or no targets of Hst1.
|
|
GO:0046970
histone H4K16 deacetylase activity, NAD-dependent
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: H4K16 can be affected at selected Hst1-regulated origins, but it is not a general Hst1 substrate.
Reason: PMID:18990212 explicitly found H4K16 was not a general Hst1 target; H4K5 was the main residue affected. The proposed NAD-dependent H4K5 term records the supported specificity.
Supporting Evidence:
PMID:18990212
Similarly, our analysis indicated that H4 K16 was not a general target of deacetylation by Hst1.
|
|
GO:0000781
chromosome, telomeric region
|
IEA
GO_REF:0000108 |
REMOVE |
Summary: Hst1 acts at selected nuclear loci but is not normally a telomere-associated silencing factor.
Reason: This GO_REF:0000108 IEA is derived mechanically from GO:0031509. PMID:17242192 instead assigns telomeric regional silencing to Sir2-Sir3-Sir4 and gene-specific repression to Hst1-Rfm1-Sum1.
Supporting Evidence:
PMID:17242192
Hst1 interacts with Rfm1 and Sum1 to repress the transcription of specific middle-sporulation genes.
|
|
GO:0000785
chromatin
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: Hst1 is recruited to chromatin at Sum1-regulated promoters and selected replication origins.
Reason: Chromatin association and locus-specific loss of Hst1 binding are directly demonstrated in PMID:29066473.
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: Hst1 localizes to the nucleus, where it acts on promoter chromatin.
Reason: Nuclear localization is experimentally supported and coherent with its chromatin-targeted repression.
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|
GO:0017136
histone deacetylase activity, NAD-dependent
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: NAD-dependent histone deacetylation is Hst1's core catalytic activity.
Reason: Direct genetic and biochemical studies establish Hst1-dependent histone deacetylation (PMID:11313477; PMID:12972620).
Supporting Evidence:
PMID:12972620
The NAD(+)-dependent deacetylase activity of Hst1p represses de novo NAD(+) biosynthesis genes in the absence of new protein synthesis, suggesting a direct effect.
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GO:0030466
silent mating-type cassette heterochromatin formation
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: Hst1 can support HMR silencing in engineered Sum1-1 or sensitized backgrounds, but this is not its normal physiological role.
Reason: The unqualified IEA obscures that Hst1-dependent mating-type silencing is conditional on altered targeting rather than native regional silencing.
Supporting Evidence:
PMID:11313477
Sum1-1 requires the Sir2 homolog, Hst1, for silencing and most probably requires the NAD(+)-dependent deacetylase activity of this protein.
|
|
GO:0031981
nuclear lumen
|
IEA
GO_REF:0000117 |
KEEP AS NON CORE |
Summary: Nuclear lumen is a correct broad localization but less informative than nucleus/chromatin.
Reason: The location is compatible with experimental nuclear localization but does not describe the locus-targeted activity.
|
|
GO:0034979
NAD-dependent protein lysine deacetylase activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Hst1 catalyzes NAD-dependent lysine deacetylation of protein substrates, physiologically including promoter histones.
Reason: This activity-level term accurately captures the sirtuin reaction without overcommitting to an unsupported histone residue.
Supporting Evidence:
PMID:12972620
The NAD(+)-dependent deacetylase activity of Hst1p represses de novo NAD(+) biosynthesis genes in the absence of new protein synthesis, suggesting a direct effect.
|
|
GO:0045892
negative regulation of DNA-templated transcription
|
IEA
GO_REF:0000108 |
ACCEPT |
Summary: Hst1 represses specific RNA polymerase II transcription programs through promoter histone deacetylation.
Reason: Middle-sporulation, NAD-biosynthesis, and thiamine-biosynthesis genes are directly repressed by Hst1. The NAD-biosynthesis program is represented more specifically by existing GO:1905013, negative regulation of 'de novo' NAD biosynthetic process from L-tryptophan.
Supporting Evidence:
PMID:10562556
SUM1 and HST1, genes previously associated with transcriptional silencing, are required for MSE-mediated repression.
|
|
GO:0045910
negative regulation of DNA recombination
|
IEA
GO_REF:0000117 |
MARK AS OVER ANNOTATED |
Summary: A broad negative-regulation-of-recombination role is not supported for Hst1.
Reason: The directly tested hst1 disruption had no rDNA recombination phenotype. The separate mitotic-recombination IMP remains UNDECIDED pending its inaccessible full-text evidence, but it does not justify this broad electronic assignment.
Supporting Evidence:
PMID:8810037
Disruption of HST1 has shown no phenotype with respect to mechanisms in which SIR2 has a role, namely, regional silencing of HML alpha, or in rDNA recombination.
|
|
GO:0070403
NAD+ binding
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: NAD+ binding is intrinsic to the Hst1 sirtuin catalytic cycle.
Reason: Hst1 consumes NAD+ during deacetylation, and PMID:12972620 directly reports its comparatively low NAD+ affinity.
Supporting Evidence:
PMID:12972620
In vitro experiments demonstrate that Hst1p has relatively low affinity toward NAD(+) in comparison to other NAD(+)-dependent enzymes.
|
|
GO:0005515
protein binding
|
IPI
PMID:12612074 Rfm1, a novel tethering factor required to recruit the Hst1 ... |
MARK AS OVER ANNOTATED |
Summary: The Rfm1-Hst1 interaction recruits Hst1 to Sum1-bound promoters, but generic protein binding is uninformative.
Reason: PMID:12612074 supports a specific tethering interaction that GO:0005515 fails to represent.
|
|
GO:0005515
protein binding
|
IPI
PMID:16429126 Proteome survey reveals modularity of the yeast cell machine... |
MARK AS OVER ANNOTATED |
Summary: A high-throughput interaction does not define Hst1's molecular function.
Reason: Generic protein binding should not replace the specific NAD-dependent deacetylase and corepressor activities.
|
|
GO:0005515
protein binding
|
IPI
PMID:37968396 The social and structural architecture of the yeast protein ... |
MARK AS OVER ANNOTATED |
Summary: Proteome-scale interaction evidence does not justify generic protein binding as an informative function.
Reason: Hst1's mechanistic partners and catalytic activity are already represented more specifically.
|
|
GO:0005634
nucleus
|
IDA
PMID:11711434 The S. cerevisiae SET3 complex includes two histone deacetyl... |
ACCEPT |
Summary: Hst1 is experimentally localized to the nucleus.
Reason: The Set3C study and independent localization data support nuclear localization.
|
|
GO:0006974
DNA damage response
|
NAS
PMID:11711434 The S. cerevisiae SET3 complex includes two histone deacetyl... |
MARK AS OVER ANNOTATED |
Summary: PMID:11711434 establishes Hst1-containing deacetylase complexes but not a direct Hst1 DNA-damage-response role.
Reason: This ComplexPortal-associated NAS extends chromatin-complex membership to a process not demonstrated for Hst1 in the cited paper.
|
|
GO:0009267
cellular response to starvation
|
NAS
PMID:11711434 The S. cerevisiae SET3 complex includes two histone deacetyl... |
KEEP AS NON CORE |
Summary: Nutrient state modulates Hst1-regulated sporulation and metabolic transcription programs.
Reason: Starvation response is biologically relevant to relief of sporulation repression but is downstream of Hst1's catalytic core function.
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|
GO:0034967
Set3 complex
|
IPI
PMID:11711434 The S. cerevisiae SET3 complex includes two histone deacetyl... |
KEEP AS NON CORE |
Summary: Hst1 is an experimentally identified Set3C subunit, although it is largely dispensable for Set3C repression.
Reason: PMID:11711434 places Hst1 in Set3C but identifies the Sum1-Rfm1-Hst1 complex as the stronger Hst1-dependent context.
Supporting Evidence:
PMID:11711434
The S. cerevisiae SET3 complex includes two histone deacetylases, Hos2 and Hst1, and is a meiotic-specific repressor of the sporulation gene program.
|
|
GO:0045835
negative regulation of meiotic nuclear division
|
IDA
PMID:11711434 The S. cerevisiae SET3 complex includes two histone deacetyl... |
MARK AS OVER ANNOTATED |
Summary: Hst1 represses middle-sporulation genes during vegetative growth, but direct negative regulation of meiotic nuclear division overstates that transcriptional role.
Reason: The cited Set3C study reports that Hst1 is not required for meiotic repression by Set3C; the supported Hst1 role is gene-specific repression through Sum1-Rfm1.
Supporting Evidence:
PMID:11711434
However, Hst1 is not required for meiotic repression by Set3C, thus implying that Set3C (-Hst1) and not Hst1-Sum1, is the meiotic-specific repressor.
|
|
GO:0000118
histone deacetylase complex
|
IPI
PMID:11711434 The S. cerevisiae SET3 complex includes two histone deacetyl... |
ACCEPT |
Summary: Hst1 is the catalytic subunit of promoter-targeted histone deacetylase complexes.
Reason: Physical association with Sum1-Rfm1 and Set3C supports membership in histone deacetylase complexes.
|
|
GO:0006357
regulation of transcription by RNA polymerase II
|
NAS
PMID:12612074 Rfm1, a novel tethering factor required to recruit the Hst1 ... |
ACCEPT |
Summary: Hst1 regulates selected RNA polymerase II genes through local chromatin deacetylation.
Reason: PMID:12612074 directly links Sum1-Rfm1 recruitment of Hst1 to repression of middle-sporulation genes.
Supporting Evidence:
PMID:10562556
SUM1 and HST1, genes previously associated with transcriptional silencing, are required for MSE-mediated repression.
|
|
GO:0030174
regulation of DNA-templated DNA replication initiation
|
NAS
PMID:18990212 Control of replication initiation by the Sum1/Rfm1/Hst1 hist... |
KEEP AS NON CORE |
Summary: Hst1 promotes efficient initiation at a subset of Sum1-bound replication origins through histone deacetylation.
Reason: PMID:18990212 provides direct Hst1-specific evidence, but origin control is secondary to promoter repression.
Supporting Evidence:
PMID:18990212
We identified seven ARS elements whose initiation capacity depended on Sum1 and Hst1.
|
|
GO:0043937
regulation of sporulation
|
NAS
PMID:12612074 Rfm1, a novel tethering factor required to recruit the Hst1 ... |
ACCEPT |
Summary: Hst1 represses middle-sporulation genes during vegetative growth and thereby regulates the sporulation program.
Reason: Sum1-Rfm1 recruits Hst1 to these promoters, and loss of the complex derepresses the program (PMID:12612074).
Supporting Evidence:
PMID:10562556
SUM1 and HST1, genes previously associated with transcriptional silencing, are required for MSE-mediated repression.
|
|
GO:0008270
zinc ion binding
|
RCA
PMID:30358795 The cellular economy of the Saccharomyces cerevisiae zinc pr... |
ACCEPT |
Summary: Hst1 contains the conserved structural zinc-binding subdomain of sirtuins.
Reason: Zinc binding is a conserved structural feature of the sirtuin catalytic domain and is consistent with the Hst1 sequence/domain annotation.
|
|
GO:0017136
histone deacetylase activity, NAD-dependent
|
IDA
PMID:11313477 A novel form of transcriptional silencing by Sum1-1 requires... |
ACCEPT |
Summary: Hst1-dependent NAD-dependent histone deacetylase activity is required for engineered Sum1-1 silencing.
Reason: PMID:11313477 directly tested the requirement for Hst1 in this conditional silencing system.
|
|
GO:0017136
histone deacetylase activity, NAD-dependent
|
IDA
PMID:11711434 The S. cerevisiae SET3 complex includes two histone deacetyl... |
ACCEPT |
Summary: Hst1 is one of the histone deacetylases identified in Set3C.
Reason: PMID:11711434 experimentally identifies Hst1 in the complex and supports NAD-dependent histone deacetylase activity.
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GO:0030466
silent mating-type cassette heterochromatin formation
|
IGI
PMID:27185881 Determinants of Sir2-Mediated, Silent Chromatin Cohesion. |
UNDECIDED |
Summary: The study concerns Sir2-mediated silent-chromatin cohesion; the cached abstract is insufficient to verify the Hst1 genetic interaction.
Reason: Preserve the curator's experimental IGI annotation pending access to the full supporting evidence; do not infer misattribution from an abstract centered on Sir2.
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GO:0030466
silent mating-type cassette heterochromatin formation
|
IMP
PMID:11313477 A novel form of transcriptional silencing by Sum1-1 requires... |
KEEP AS NON CORE |
Summary: Hst1 is required for HMR silencing when recruited by the gain-of-function Sum1-1 protein.
Reason: PMID:11313477 supports the annotation in this engineered context, but native Hst1 does not normally perform regional mating-type silencing.
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GO:0030466
silent mating-type cassette heterochromatin formation
|
IGI
PMID:11313477 A novel form of transcriptional silencing by Sum1-1 requires... |
KEEP AS NON CORE |
Summary: Genetic evidence supports Hst1-dependent Sum1-1 silencing at HMR.
Reason: Retain the experimentally curated interaction while making the non-native targeting context explicit.
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GO:0034967
Set3 complex
|
IDA
PMID:11711434 The S. cerevisiae SET3 complex includes two histone deacetyl... |
KEEP AS NON CORE |
Summary: Hst1 is an experimentally identified Set3C component.
Reason: Set3C membership is real, but Hst1 is not essential for the complex's meiotic repression and its main complex is Sum1-Rfm1-Hst1.
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GO:0045950
negative regulation of mitotic recombination
|
IMP
PMID:16051752 HST2 mediates SIR2-independent life-span extension by calori... |
UNDECIDED |
Summary: The cached abstract focuses on Hst2-mediated lifespan regulation and does not expose the experiment supporting Hst1-dependent recombination control.
Reason: The IMP annotation should not be overruled without the relevant full-text evidence; retain for curator follow-up.
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GO:0070623
regulation of thiamine biosynthetic process
|
IMP
PMID:20439498 Thiamine biosynthesis in Saccharomyces cerevisiae is regulat... |
KEEP AS NON CORE |
Summary: Hst1 links NAD+ availability to basal repression of thiamine biosynthesis genes.
Reason: PMID:20439498 directly supports this extra program, but it is one target set of the broader Hst1 promoter-repression mechanism.
Supporting Evidence:
PMID:20439498
We have determined that multiple thiamine ( THI ) genes in Saccharomyces cerevisiae are also regulated by the intracellular NAD + concentration via the NAD + -dependent histone deacetylase (HDAC) Hst1 and, to a lesser extent, Sir2.
|
Q: Which endogenous Hst1 target proteins, if any, are deacetylated outside chromatin, and do such substrates account for the secondary DNA-damage and recombination phenotypes assigned to the Sir2 family?
Q: How does the Sum1-Rfm1-Hst1 complex choose between middle-sporulation, NAD-biosynthesis, thiamine-biosynthesis, and replication-origin targets as nutrient state and intracellular NAD+ change?
Experiment: Combine acute Hst1 depletion with calibrated residue-specific histone acetylation profiling and Hst1/Sum1 ChIP-seq across vegetative, NAD-limited, and sporulation-inducing conditions, then test catalytic-dead Hst1 rescue at directly bound loci.
Hypothesis: H4K5 is the dominant physiological histone substrate of promoter-bound Hst1, whereas the H3K9, H3K14, and H4K16 residue-specific IBA assignments are not broadly applicable to native Hst1 targets.
Type: acute depletion, quantitative histone acetyl-proteomics, and ChIP-seq
HST1 (Homologous to Sir Two 1; systematic name YOL068C; UniProt P53685) encodes a nuclear, chromatin-associated NADβΊ-dependent protein/histone lysine deacetylase of the Sir2 (sirtuin) family, classified as EC 2.3.1.286 and belonging to the sirtuin Class I subfamily. The enzyme removes acetyl groups from acetyl-lysine residues on nucleosomal histone tails (histone H4, including H4K5 and H4K16; histone H3 at K9/K14) using an obligate, stoichiometric consumption of NADβΊ. For each lysine deacetylated, one molecule of NADβΊ is cleaved, generating three products: the deacetylated lysine, nicotinamide, and the novel metabolite 2β²-O-acetyl-ADP-ribose (OAADPr). This catalytic chemistry β coupling deacetylation to NADβΊ hydrolysis β is the defining and mechanistically conserved feature of the entire sirtuin family, and it distinguishes sirtuins (Class III HDACs) from the zinc-dependent Class I/II histone deacetylases.
The primary physiological function of Hst1 is gene-specific transcriptional repression, not the regional heterochromatic silencing performed by its close paralog Sir2. Hst1 is the catalytic engine of the Sum1βRfm1βHst1 complex, in which the DNA-binding protein Sum1 recognizes Middle Sporulation Elements (MSEs) in target promoters, the tethering factor Rfm1 bridges Sum1 to Hst1, and Hst1 then deacetylates promoter nucleosomes to condense local chromatin and silence transcription. Through this complex, Hst1 represses middle-sporulation/meiotic genes (including the master meiotic activator NDT80, as well as IME2 and SMA2/mORC1) during vegetative (mitotic) growth. This repression is gene-specific β it does not spread to neighboring genes β and it is relieved during meiosis when the activator Ndt80 outcompetes Sum1 for MSE occupancy. A second distinct regulatory role identifies Hst1 as an NADβΊ sensor: because it has relatively low affinity for NADβΊ, its deacetylase activity (and hence its repression of the de novo NADβΊ biosynthesis "BNA" genes) declines when cellular NADβΊ falls, forming a feedback loop that homeostatically regulates NADβΊ biosynthesis.
Hst1 operates in the nucleus, on chromatin, at specific gene promoters. Although Hst1 is 71% identical to Sir2 and shares a near-identical catalytic core (a large Rossmann-fold NADβΊ-binding domain plus a small zinc-binding subdomain), the two enzymes are functionally divergent: Hst1's endogenous role is gene-specific promoter repression via Sum1/Rfm1, whereas Sir2's is regional silencing via Sir3/Sir4. This divergence arises from distinct cofactor/targeting specificities rather than differences in catalytic chemistry β a conclusion supported by domain-swap experiments. Only when artificially targeted (e.g., in the SUM1-1 gain-of-function background via the origin recognition complex) can Hst1 substitute for Sir2 in HMR silencing. The gene symbol is not ambiguous in this context: all literature reviewed corresponds precisely to the S. cerevisiae sirtuin HST1.
Hst1 (YOL068C) is one of four Sir2 homologs (Hst1βHst4) in budding yeast and is a phylogenetically conserved NADβΊ-dependent protein deacetylase. The sirtuins are described as "a phylogenetically conserved family of NAD(+)-dependent protein deacetylases that consume one molecule of NAD(+) for every deacetylated lysine side chain" (PMID: 24164855). This one-to-one stoichiometry of NADβΊ consumption to lysine deacetylation is the biochemical signature of the family and the reason Hst1's activity is inherently coupled to the cell's metabolic state.
The reaction catalyzed produces three products. Sir2-family enzymes are "NAD(+)-dependent histone/protein deacetylases that tightly couple the hydrolysis of NAD(+) and the deacetylation of an acetylated substrate to form nicotinamide, the deacetylated product, and the novel metabolite O-acetyl-ADP-ribose (OAADPR)" (PMID: 15274642). Mechanistic studies establish a sequential ternary-complex mechanism: nicotinamide is cleaved from NADβΊ first, forming a covalent Ξ±-1β²-O-alkylamidate intermediate, after which the acetyl group is transferred to ADP-ribose. Direct evidence for this pathway comes from work "providing direct evidence for the formation of a covalent alpha-1'-O-alkylamidate" (PMID: 16388603), which also implicates a conserved catalytic histidine (His135 in the paralog Hst2) acting as a general base that activates the ribose 2β²-OH. Because nicotinamide is both a reaction product and a feedback inhibitor, the mechanism itself provides a natural regulatory handle (see Finding 8).
This is the assigned enzymatic identity of Hst1: EC 2.3.1.286, a NAD-dependent protein deacetylase of the sirtuin Class I subfamily.
The central physiological role of Hst1 is to serve as the catalytic subunit of a promoter-targeted repressor complex. Hst1 does not itself bind DNA; instead it is recruited to specific promoters by the sequence-specific DNA-binding protein Sum1, with the bridging/tethering factor Rfm1 connecting the two. The architecture was defined by the discovery that "Rfm1 interacts with both Sum1 and Hst1 and is required for the Sum1-Hst1 interaction" (PMID: 12612074). Rfm1 is required both for the physical Sum1βHst1 interaction and for repression of the Hst1-dependent subset of middle-sporulation genes.
The functional output is described as the cooperation of "the NAD(+)-dependent histone deacetylase Hst1 and the DNA-binding protein Sum1 for vegetative repression of many middle sporulation genes" (PMID: 12612074). Mechanistically, once recruited, Hst1 deacetylates promoter nucleosomes, condensing local chromatin and blocking transcription of genes needed for meiotic progression and spore formation during vegetative growth. A later study confirmed that "Hst1 interacts with Rfm1 and Sum1 to repress the transcription of specific middle-sporulation genes" (PMID: 17242192).
Critically, the difference between Hst1 (gene-specific repression) and Sir2 (regional silencing) is not a difference in enzymatic chemistry. Domain-swap and chimera experiments showed that "the differences in the silencing and repression functions of Sir2 and Hst1 may not be due to differences in enzymatic activities of the proteins but rather may be the result of distinct cofactor specificities" (PMID: 17242192). Gene-specific repression requires the Rfm1 + Sum1 cofactors, whereas Sir2's regional silencing requires Sir3 + Sir4; specificity is set by non-conserved N-terminal sequences and a small number of core residues, not by catalysis.
Beyond its role in meiotic-gene repression, Hst1 functions as a metabolic sensor that closes a feedback loop on NADβΊ biosynthesis. Transcript-array analyses demonstrated that "the NAD(+)-dependent deacetylase activity of Hst1p represses de novo NAD(+) biosynthesis genes in the absence of new protein synthesis, suggesting a direct effect" (PMID: 12972620). The salvage-pathway genes are unaffected, and Sum1 occupies the promoters of the inducible de novo (BNA) biosynthesis genes, tying this repression to the same Sum1-targeting logic as the meiotic genes.
This established "a critical role of the NAD(+)-dependent deacetylase Hst1p as a sensor of NAD(+) levels and regulator of NAD(+) biosynthesis" (PMID: 12972620). The logic is elegant: because Hst1 has relatively low affinity for NADβΊ compared with other sirtuins, its activity is sensitive to falling NADβΊ concentrations. When NADβΊ is plentiful, Hst1 is active and represses the biosynthesis genes; when NADβΊ drops, Hst1 activity declines, de-repressing the de novo pathway to restore NADβΊ. Consistent with this, "the removal of HST1-mediated repression of the NAD(+) de novo biosynthesis pathway leads to increased cellular NAD(+) levels" (PMID: 12972620). A subsequent study further linked Hst1 (together with the copper-sensing transcription factor Mac1 and nicotinic acid) to the regulation of NAD biosynthesis genes (PMID: 30760525).
Although Hst1 does not natively perform regional silencing, its catalytic capacity to silence chromatin can be revealed by artificial targeting. In the SUM1-1 gain-of-function background, Sir-independent silencing at the HMR locus requires Hst1: "Sum1-1 requires the Sir2 homolog, Hst1, for silencing and most probably requires the NAD(+)-dependent deacetylase activity of this protein" (PMID: 11313477). In this context, the mutant Sum1-1 protein binds the origin recognition complex (ORC) at HMR and recruits Hst1, which then "deacetylates histones or other chromatin-associated proteins to cause chromatin condensation and transcriptional silencing" (PMID: 11313477).
Evolutionary analyses reinforce that Hst1 is a functionally central and retained sirtuin. In the CTG-clade Candida yeasts, "HST1 has been consistently retained throughout the clade, whereas SIR2 is only present in a subset of species" (PMID: 27543294), and the retained HST1 paralog can regain ancestral silencing functions β underscoring that the near-identical catalytic core is readily repurposed by changing its targeting partners. Genome-wide nicotinamide sensitivity screens further found that genome-stability pathways, including sister-chromatid cohesion, are especially vulnerable to loss of sirtuin activity (PMID: 26646153).
The gene-specificity of Hst1/Sum1 repression is encoded in Middle Sporulation Elements (MSEs) in target promoters. "SUM1 and HST1, genes previously associated with transcriptional silencing, are required for MSE-mediated repression. Sum1 binds specifically in vitro to MSEs that function as strong repressor sites in vivo. Repression by Sum1 is gene specific and does not extend to neighboring genes" (PMID: 10562556). This non-spreading, promoter-local character sharply distinguishes Hst1-mediated repression from Sir2-mediated heterochromatin, which spreads across kilobases.
The switch from repression to activation during meiosis is governed by direct competition between the repressor Sum1 and the activator Ndt80 for the same DNA elements: "Sum1 and Ndt80 compete for binding to MSEs and that small changes in the sequence of an MSE can yield large differences in which protein is bound" (PMID: 12832469). As cells enter middle meiosis, Ndt80 accumulates and displaces the Sum1βRfm1βHst1 repressor, de-repressing the middle-sporulation gene program. Target genes include the master meiotic regulators NDT80, IME2, and the SMA2/mORC1 locus (PMID: 27362276).
HST1 was originally identified as a SIR2-related gene, defining the HST (Homologous to Sir Two) family. It is "very closely related to SIR2, showing 71% sequence identity over 84% of its length" (PMID: 8810037). Despite this near-identity in the catalytic core, the endogenous roles diverge: "Disruption of HST1 has shown no phenotype with respect to mechanisms in which SIR2 has a role, namely, regional silencing of HML alpha, or in rDNA recombination" (PMID: 8810037). This is a key negative result: it establishes that Hst1's native function is distinct from Sir2's heterochromatin/rDNA maintenance, and that Hst1's silencing capacity is latent, revealed only when the enzyme is redirected by alternative targeting cofactors.
The structural fold of Hst1 is inferred with high confidence from its close paralog Hst2, whose full-length crystal structure was solved. That structure revealed "a central catalytic core domain fold that is characteristic of the other Sir2 homologs, and C- and N-terminal extensions that interact with the NAD(+) and acetyl-lysine substrate-binding sites" (PMID: 14502267). The catalytic core is bipartite: a large Rossmann-fold domain that binds NADβΊ (corresponding to InterPro IPR029035, DHS-like NAD/FAD-binding) and a smaller zinc-binding subdomain (IPR026591). A related sirtuin structure confirms "the characteristic small zinc-binding domain, and the larger Rossmann-fold domain involved in NAD+-binding interactions" (PMID: 29543820). The acetyl-lysine substrate binds in a cleft/hydrophobic tunnel between the two domains, and the sequence-divergent N- and C-terminal extensions provide autoregulatory modulation of substrate and cofactor binding β the structural basis for the cofactor/targeting specificity that distinguishes Hst1 from Sir2.
Functionally, Hst1 acts in the nucleus, on chromatin. Loss or mislocalization of the Sum1βHst1 machinery causes "loss of the DNA-binding transcriptional regulator Sum1 and the associated histone deacetylase Hst1 from chromatin in a locus-specific manner. This is linked to increased H4K5ac at these loci" (PMID: 29066473). This directly demonstrates that Hst1 operates at specific chromatin loci and that its removal raises local histone acetylation β pinning down both its subcellular location (nuclear chromatin) and its substrate (nucleosomal histone tails).
Hst1 activity is regulated post-translationally by nicotinamide (NAM), the reaction product that acts as a physiological sirtuin inhibitor. The nicotinamidase Pnc1 clears NAM, relieving inhibition: "PNC1 overexpression suppresses the inhibitory effect of exogenously added NAM on silencing, life span, and Hst1-mediated transcriptional repression" (PMID: 14729974). Because PNC1 is stress-inducible, this links Hst1-dependent repression to environmental and metabolic stress signals.
Hst1 is also a shared subunit of a second repressive assembly, the Set3 complex (Set3C). "Set3 forms a single complex, Set3C, with Snt1, YIL112w, Sif2, Cpr1, and two putative histone deacetylases, Hos2 and NAD-dependent Hst1" (PMID: 11711434). Set3C thereby contains both NAD-dependent (Hst1) and NAD-independent (the Class I HDAC Hos2) deacetylase activities and represses early/middle sporulation genes such as IME2 and NDT80. Importantly, the same study confirms that "Hst1 is also present in a complex with Sum1, supporting previous characterizations of Hst1 and Sum1 as repressors of middle sporulation genes during vegetative growth" (PMID: 11711434). Because Hst1 is largely dispensable for Set3C's meiotic repression, the Sum1βRfm1βHst1 complex is regarded as the primary Hst1-dependent repressor.
Hst1's characterized physiological substrates are the acetyl-lysines of N-terminal histone tails at repressed promoters. The yeast Sir2 family deacetylates specific histone lysines: "yeast and mouse Sir2 proteins are nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases, which deacetylate lysines 9 and 14 of H3 and specifically lysine 16 of H4" (PMID: 10693811). Structural work captured the Hst1 paralog Hst2 "in complex with its acetyl-lysine 16 histone H4 substrate" (PMID: 17289592), defining H4K16ac as a canonical family substrate.
For Hst1 specifically, in vivo evidence comes from the observation that loss of Sum1/Hst1 targeting produces "increased H4K5ac at these loci and aberrant middle gene expression" (PMID: 29066473), identifying nucleosomal histone H4 tail lysines (notably H4K5) as in vivo substrates at Hst1-repressed promoters. In vitro, sirtuins including this family can also accept longer acyl-lysine substrates (propionyl-, butyryl-lysine) (PMID: 17951578), and can deacetylate non-histone proteins β but Hst1's physiologically documented substrates are promoter nucleosomal histones. Its relatively low NADβΊ affinity (PMID: 12972620) tunes its output to cellular NADβΊ levels.
Hst1 is best understood as a targeted, metabolically-gated chromatin repressor. It integrates three inputs β DNA sequence (via Sum1/MSE), cellular NADβΊ level, and nicotinamide/stress signals β to control the timing of the meiotic gene program and NADβΊ biosynthesis.
Acetyl-Lys(histone) + NADβΊ
β
βΌ [Hst1 catalytic core: Rossmann fold + Zn subdomain]
Step 1: nicotinamide cleavage β Ξ±-1β²-O-alkylamidate intermediate
β
Step 2: acetyl transfer to ADP-ribose (His as general base)
βΌ
Deacetylated-Lys(histone) + Nicotinamide + 2β²-O-acetyl-ADP-ribose (OAADPr)
MSE promoter element
βββββββββ ββββββββββββββββββββββββ (target gene, e.g. NDT80, IME2, SMA2, BNA genes)
β
[Sum1] ββ DNA-binding, sequence-specific
β
[Rfm1] ββ tethering/bridging factor
β
[Hst1] ββ NADβΊ-dependent deacetylase (catalytic subunit)
β
βΌ
Deacetylation of H4K5/H4K16 (H3K9/K14) on promoter nucleosomes
β
βΌ
Local chromatin condensation β GENE-SPECIFIC REPRESSION (non-spreading)
Vegetative growth: Sum1βRfm1βHst1 bound at MSE β genes OFF
β
Meiosis: Ndt80 accumulates
β (competes for MSE)
βΌ
Middle meiosis: Ndt80 bound at MSE β genes ON
| Property | Hst1 | Sir2 |
|---|---|---|
| Catalytic activity | NADβΊ-dependent deacetylase (EC 2.3.1.286) | NADβΊ-dependent deacetylase |
| Sequence identity | β | 71% identical to Hst1 over 84% of length |
| Targeting cofactors | Sum1 + Rfm1 (also Set3C) | Sir3 + Sir4 |
| Mode of repression | Gene-specific, promoter-local, non-spreading | Regional heterochromatin, spreads |
| Native targets | Middle-sporulation genes; de novo NADβΊ (BNA) genes | HM loci, telomeres, rDNA |
| NADβΊ affinity | Relatively low (metabolic sensor) | Higher |
| Basis of divergence | Cofactor/targeting specificity, not catalysis | Cofactor/targeting specificity |
High NADβΊ βββΊ Hst1 active βββΊ BNA (de novo) genes repressed βββΊ NADβΊ held in check
β² β
βββββββββββββ Low NADβΊ βββΊ Hst1 inactive βββΊ BNA de-repressed βββββ
(low NADβΊ affinity makes Hst1 the sensor)
Nicotinamide (NAM, a product) inhibits Hst1; Pnc1 clears NAM (stress-induced) β relieves inhibition
Taken together, these modules explain why Hst1 is specialized as a precise developmental and metabolic switch rather than a bulk chromatin silencer: its DNA targeting is delegated to Sum1/Rfm1, its catalysis is throttled by NADβΊ availability and nicotinamide, and its low NADβΊ affinity makes it a dedicated sensor of the very cofactor it consumes.
| PMID | Title (abbrev.) | Role in this report |
|---|---|---|
| 24164855 | Yeast sirtuins and the regulation of aging | Defines sirtuin family enzymatic activity; names Hst1 as a Sir2 homolog (F1) |
| 15274642 | Substrate specificity and kinetic mechanism of the Sir2 family | Reaction products: nicotinamide + deacetylated product + OAADPr (F1) |
| 16388603 | Sir2 protein deacetylases: chemical intermediates & conserved histidine | Direct evidence for Ξ±-1β²-O-alkylamidate intermediate; catalytic His (F1) |
| 12612074 | Rfm1, a novel tethering factorβ¦ | Establishes Sum1βRfm1βHst1 architecture; vegetative repression of MSGs (F2) |
| 17242192 | Swapping gene-specific and regional silencing specificities of Hst1 and Sir2 | Divergence is cofactor specificity, not catalysis (F2) |
| 12972620 | Hst1p controls biosynthesis and cellular NADβΊ levels | Hst1 as NADβΊ sensor repressing de novo BNA genes (F3) |
| 30760525 | Mac1, Hst1, and nicotinic acid regulate NAD biosynthesis | Additional regulatory link for NAD biosynthesis (F3) |
| 11313477 | A novel form of silencing by Sum1-1 requires Hst1 and ORC | Hst1 can silence HMR when targeted via Sum1-1/ORC (F4) |
| 27543294 | Gene loss & functional divergence of sirtuins in Candida | HST1 evolutionarily retained; can regain silencing (F4) |
| 26646153 | Genome-wide NAM screen for sirtuin-dependent pathways | Genome-stability pathways vulnerable to sirtuin loss (F4) |
| 10562556 | Sum1 and Hst1 repress middle sporulation genes during mitosis | Gene-specific, non-spreading MSE-based repression (F5) |
| 12832469 | Sum1 and Ndt80 compete for MSE binding | Meiotic de-repression via Ndt80 competition (F5) |
| 27362276 | Ndt80 activates mORC1 and SMA2 via bi-directional MSE | Target genes SMA2/mORC1; Sum1 represses in mitosis (F5) |
| 8810037 | HST1, a new member of the SIR2 family | 71% identity to SIR2; distinct native role (no HMLΞ±/rDNA phenotype) (F6) |
| 14502267 | Structure and autoregulation of yeast Hst2 | Structural fold applicable to Hst1 by homology; N/C autoregulation (F7) |
| 29543820 | Crystal structure of Leishmania Sir2-related protein 1 | Confirms Zn subdomain + Rossmann NADβΊ domain fold (F7) |
| 29066473 | Repression of middle sporulation genes | Hst1 acts on chromatin locus-specifically; H4K5ac rises on loss (F7, F9) |
| 14729974 | Nicotinamide clearance by Pnc1 regulates silencing | Pnc1/NAM regulation of Hst1-mediated repression (F8) |
| 11711434 | SET3 complex includes Hos2 and Hst1 | Hst1 membership in Set3C; also in Sum1 complex (F8) |
| 10693811 | Sir2 is an NAD-dependent histone deacetylase | Histone lysine substrate specificity (H3K9/K14, H4K16) (F9) |
| 17289592 | Structural basis for nicotinamide inhibition and base exchange | Hst2 bound to acetyl-H4K16 substrate (F9) |
| 17951578 | Acetyl-lysine analog peptides as probes | In vitro propionyl-/butyryl-lysine substrates (F9) |
How the evidence hangs together: The catalytic identity (F1, F9) is derived from broadly conserved sirtuin biochemistry with structural support from the near-identical paralog Hst2 (F7). The physiological function (F2, F3, F5, F8) rests on Hst1-specific genetic and transcript-profiling studies in S. cerevisiae. The most direct in vivo, Hst1-specific substrate evidence is the locus-specific rise in H4K5ac upon loss of Sum1/Hst1 chromatin association (F7/F9, PMID: 29066473). The negative result that Hst1 disruption causes no HMLΞ±/rDNA phenotype (F6) is essential for correctly bounding the claim: Hst1's native role is gene-specific promoter repression, not regional silencing.
Structural inference by homology. No experimentally solved structure of Hst1 (P53685) itself is cited here; its fold, active site, and autoregulatory extensions are inferred from the paralog Hst2 and other sirtuins (PMID: 14502267, PMID: 17289592). Given 71% identity to Sir2 and close relatedness to Hst2, this inference is strong, but Hst1-specific active-site kinetic constants (Km for NADβΊ, kcat) are only qualitatively described ("relatively low NADβΊ affinity").
Direct histone-substrate mapping for Hst1 is limited. The most-cited residue-specific in vivo readout is H4K5ac at target loci (PMID: 29066473); the H3K9/K14/H4K16 assignments come from the Sir2 family generally (PMID: 10693811) or from Hst2 structures (PMID: 17289592). A comprehensive, quantitative map of Hst1's preferred histone (and possible non-histone) acetyl-lysine substrates at native promoters is not fully established.
Non-histone substrates. While the family can deacetylate non-histone proteins and longer acyl-lysines in vitro (PMID: 17951578), Hst1's physiological non-histone substrates (if any) are not defined.
Quantitative division of labor between the two Hst1 complexes. Hst1 is in both the Sum1βRfm1βHst1 complex and Set3C (PMID: 11711434). The relative contribution of each complex to specific target genes, and the extent of functional overlap with the NAD-independent HDAC Hos2 within Set3C, remain incompletely quantified.
Localization detail. The nuclear/chromatin localization is well supported functionally (recruitment to promoters, locus-specific H4K5ac), but fine-grained genome-wide occupancy (ChIP-seq) data for Hst1 across all conditions is not exhaustively catalogued here.
Determine the Hst1 structure (ideally the Sum1βRfm1βHst1 complex on a nucleosome bearing acetyl-H4 tails) by crystallography or cryo-EM to directly visualize substrate engagement and the N-terminal targeting determinants that distinguish Hst1 from Sir2.
Quantitative enzymology of Hst1. Measure Km(NADβΊ), kcat, and nicotinamide Ki for purified Hst1 against defined acetyl-histone peptides/nucleosomes to rigorously establish the "low NADβΊ affinity" that underlies its sensor function, and compare head-to-head with Sir2, Hst2β4.
Genome-wide, condition-resolved Hst1 substrate mapping. Combine Hst1 ChIP-seq with quantitative histone-PTM proteomics (H4K5ac, H4K16ac, H3K9/K14ac) in wild-type vs. hst1Ξ across vegetative growth, NADβΊ-limited conditions, and meiotic entry, to build a residue-resolved substrate map at each target promoter.
Test the NADβΊ-sensor feedback loop directly. Titrate cellular NADβΊ (via BNA/salvage pathway perturbation and PNC1 modulation) and measure Hst1 occupancy, BNA-gene derepression, and NADβΊ levels to quantify the sensor's set-point and gain.
Dissect the Ndt80βSum1βHst1 switch kinetics with time-resolved ChIP through meiosis to determine whether Ndt80 actively evicts the Hst1 repressor or passively wins by mass action at MSEs of key targets (NDT80, IME2, SMA2/mORC1).
Separate Set3C vs. Sum1-complex contributions using complex-specific separation-of-function alleles (e.g., Rfm1-binding vs. Snt1/Set3-binding mutants of Hst1) to assign each target gene to its responsible complex.
HST1 (YOL068C; UniProt P53685) is unambiguously the NADβΊ-dependent protein/histone deacetylase HST1 of Saccharomyces cerevisiae β a Class I sirtuin, EC 2.3.1.286, and a Sir2 paralog. All literature reviewed corresponds precisely to this gene and organism; the gene symbol is not ambiguous in this context. Its primary function is gene-specific transcriptional repression of meiotic/middle-sporulation genes as the catalytic subunit of the Sum1βRfm1βHst1 complex at MSE promoters, executed by NADβΊ-dependent deacetylation of nucleosomal histone tails in the nucleus, and gated developmentally by Ndt80 competition and metabolically by its role as a low-affinity NADβΊ sensor that controls de novo NADβΊ biosynthesis.
HST1 synonym caused the formerUNDECIDED; the review does not overruleprotein binding annotations are marked over-annotated; specificid: P53685
gene_symbol: HST1
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:559292
label: Saccharomyces cerevisiae
description: >-
HST1 encodes a nuclear NAD-dependent sirtuin deacetylase that is recruited by
Sum1 and the tethering factor Rfm1 to selected chromosomal loci. Local histone
deacetylation, prominently at H4K5, represses middle-sporulation and metabolic
gene programs during vegetative growth and also supports efficient initiation
at a subset of replication origins. Unlike its paralog Sir2, native Hst1 is a
gene-specific chromatin regulator rather than a regional silencing factor at
telomeres or silent mating-type loci.
existing_annotations:
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: Hst1 is a nuclear chromatin-associated sirtuin recruited to specific promoters
and replication origins.
action: ACCEPT
reason: Nuclear localization and locus-specific chromatin association are supported
by PMID:11711434 and PMID:29066473.
- term:
id: GO:0006974
label: DNA damage response
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: A DNA-damage-response role has not been demonstrated for Hst1 itself.
action: MARK_AS_OVER_ANNOTATED
reason: This IBA appears to transfer a broad Sir2-family genome-stability role without
positive Hst1-specific evidence; Hst1's demonstrated functions are locus-specific
deacetylation and transcriptional repression.
- term:
id: GO:0003714
label: transcription corepressor activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: Hst1 provides catalytic repression within the Sum1-Rfm1-Hst1 complex.
action: ACCEPT
reason: Rfm1 recruits Hst1 to Sum1-bound promoters to repress middle-sporulation genes
(PMID:12612074).
supported_by:
- reference_id: PMID:12612074
supporting_text: Rfm1 interacts with both Sum1 and Hst1 and is required for the
Sum1-Hst1 interaction.
reference_section_type: ABSTRACT
- term:
id: GO:0031509
label: subtelomeric heterochromatin formation
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Native Hst1 is a gene-specific repressor, not a telomeric regional-silencing
enzyme.
action: REMOVE
reason: Hst1 and Sir2 have distinct cofactor-targeting specificities; PMID:17242192
assigns telomeric regional silencing to Sir2-Sir3-Sir4 and gene-specific repression
to Hst1-Rfm1-Sum1. This IBA transfers the Sir2 role to Hst1.
supported_by:
- reference_id: PMID:17242192
supporting_text: Nevertheless, the two proteins promote two mechanistically distinct
forms of gene repression.
reference_section_type: ABSTRACT
- term:
id: GO:0032041
label: histone H3K14 deacetylase activity, NAD-dependent
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: Hst1 deacetylates promoter histones, but H3K14 specificity has not been demonstrated
for Hst1 itself.
action: MARK_AS_OVER_ANNOTATED
reason: Hst1-specific chromatin studies identify H4K5 as the predominant affected
residue; this residue-specific IBA overextends broader sirtuin evidence. The proposed
NAD-dependent H4K5 term records the supported specificity.
supported_by:
- reference_id: PMID:18990212
supporting_text: This was consistent with the notion that H4 K5 was the main target
of the histone deacetylase Hst1, whereas other histone H4 lysine residues were
minor or no targets of Hst1.
reference_section_type: RESULTS
- term:
id: GO:0046969
label: histone H3K9 deacetylase activity, NAD-dependent
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: Hst1 is an NAD-dependent histone deacetylase, but H3K9 specificity is not
established for Hst1.
action: MARK_AS_OVER_ANNOTATED
reason: The H3K9 assignment derives from family transfer, whereas Hst1-specific experiments
primarily implicate H4K5. The proposed NAD-dependent H4K5 term records the supported
specificity.
supported_by:
- reference_id: PMID:18990212
supporting_text: This was consistent with the notion that H4 K5 was the main target
of the histone deacetylase Hst1, whereas other histone H4 lysine residues were
minor or no targets of Hst1.
reference_section_type: RESULTS
- term:
id: GO:0046970
label: histone H4K16 deacetylase activity, NAD-dependent
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: H4K16 can be affected at selected Hst1-regulated origins, but it is not a
general Hst1 substrate.
action: MARK_AS_OVER_ANNOTATED
reason: PMID:18990212 explicitly found H4K16 was not a general Hst1 target; H4K5 was
the main residue affected. The proposed NAD-dependent H4K5 term records the supported
specificity.
supported_by:
- reference_id: PMID:18990212
supporting_text: Similarly, our analysis indicated that H4 K16 was not a general
target of deacetylation by Hst1.
reference_section_type: RESULTS
- term:
id: GO:0000781
label: chromosome, telomeric region
evidence_type: IEA
original_reference_id: GO_REF:0000108
qualifier: located_in
review:
summary: Hst1 acts at selected nuclear loci but is not normally a telomere-associated
silencing factor.
action: REMOVE
reason: This GO_REF:0000108 IEA is derived mechanically from GO:0031509. PMID:17242192
instead assigns telomeric regional silencing to Sir2-Sir3-Sir4 and gene-specific
repression to Hst1-Rfm1-Sum1.
supported_by:
- reference_id: PMID:17242192
supporting_text: Hst1 interacts with Rfm1 and Sum1 to repress the transcription
of specific middle-sporulation genes.
reference_section_type: ABSTRACT
- term:
id: GO:0000785
label: chromatin
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: located_in
review:
summary: Hst1 is recruited to chromatin at Sum1-regulated promoters and selected replication
origins.
action: ACCEPT
reason: Chromatin association and locus-specific loss of Hst1 binding are directly
demonstrated in PMID:29066473.
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: Hst1 localizes to the nucleus, where it acts on promoter chromatin.
action: ACCEPT
reason: Nuclear localization is experimentally supported and coherent with its chromatin-targeted
repression.
- term:
id: GO:0017136
label: histone deacetylase activity, NAD-dependent
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: enables
review:
summary: NAD-dependent histone deacetylation is Hst1's core catalytic activity.
action: ACCEPT
reason: Direct genetic and biochemical studies establish Hst1-dependent histone deacetylation
(PMID:11313477; PMID:12972620).
supported_by:
- reference_id: PMID:12972620
supporting_text: The NAD(+)-dependent deacetylase activity of Hst1p represses de
novo NAD(+) biosynthesis genes in the absence of new protein synthesis, suggesting
a direct effect.
reference_section_type: ABSTRACT
- term:
id: GO:0030466
label: silent mating-type cassette heterochromatin formation
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: Hst1 can support HMR silencing in engineered Sum1-1 or sensitized backgrounds,
but this is not its normal physiological role.
action: MARK_AS_OVER_ANNOTATED
reason: The unqualified IEA obscures that Hst1-dependent mating-type silencing is
conditional on altered targeting rather than native regional silencing.
supported_by:
- reference_id: PMID:11313477
supporting_text: Sum1-1 requires the Sir2 homolog, Hst1, for silencing and most
probably requires the NAD(+)-dependent deacetylase activity of this protein.
reference_section_type: ABSTRACT
- term:
id: GO:0031981
label: nuclear lumen
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: located_in
review:
summary: Nuclear lumen is a correct broad localization but less informative than nucleus/chromatin.
action: KEEP_AS_NON_CORE
reason: The location is compatible with experimental nuclear localization but does
not describe the locus-targeted activity.
- term:
id: GO:0034979
label: NAD-dependent protein lysine deacetylase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
summary: Hst1 catalyzes NAD-dependent lysine deacetylation of protein substrates,
physiologically including promoter histones.
action: ACCEPT
reason: This activity-level term accurately captures the sirtuin reaction without
overcommitting to an unsupported histone residue.
supported_by:
- reference_id: PMID:12972620
supporting_text: The NAD(+)-dependent deacetylase activity of Hst1p represses de
novo NAD(+) biosynthesis genes in the absence of new protein synthesis, suggesting
a direct effect.
reference_section_type: ABSTRACT
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000108
qualifier: involved_in
review:
summary: Hst1 represses specific RNA polymerase II transcription programs through
promoter histone deacetylation.
action: ACCEPT
reason: Middle-sporulation, NAD-biosynthesis, and thiamine-biosynthesis genes are
directly repressed by Hst1. The NAD-biosynthesis program is represented more specifically
by existing GO:1905013, negative regulation of 'de novo' NAD biosynthetic process
from L-tryptophan.
supported_by:
- reference_id: PMID:10562556
supporting_text: SUM1 and HST1, genes previously associated with transcriptional
silencing, are required for MSE-mediated repression.
reference_section_type: ABSTRACT
- term:
id: GO:0045910
label: negative regulation of DNA recombination
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: A broad negative-regulation-of-recombination role is not supported for Hst1.
action: MARK_AS_OVER_ANNOTATED
reason: The directly tested hst1 disruption had no rDNA recombination phenotype.
The separate mitotic-recombination IMP remains UNDECIDED pending its inaccessible
full-text evidence, but it does not justify this broad electronic assignment.
supported_by:
- reference_id: PMID:8810037
supporting_text: Disruption of HST1 has shown no phenotype with respect to mechanisms
in which SIR2 has a role, namely, regional silencing of HML alpha, or in rDNA
recombination.
reference_section_type: ABSTRACT
- term:
id: GO:0070403
label: NAD+ binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: NAD+ binding is intrinsic to the Hst1 sirtuin catalytic cycle.
action: ACCEPT
reason: Hst1 consumes NAD+ during deacetylation, and PMID:12972620 directly reports
its comparatively low NAD+ affinity.
supported_by:
- reference_id: PMID:12972620
supporting_text: In vitro experiments demonstrate that Hst1p has relatively low
affinity toward NAD(+) in comparison to other NAD(+)-dependent enzymes.
reference_section_type: ABSTRACT
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12612074
qualifier: enables
review:
summary: The Rfm1-Hst1 interaction recruits Hst1 to Sum1-bound promoters, but generic
protein binding is uninformative.
action: MARK_AS_OVER_ANNOTATED
reason: PMID:12612074 supports a specific tethering interaction that GO:0005515 fails
to represent.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16429126
qualifier: enables
review:
summary: A high-throughput interaction does not define Hst1's molecular function.
action: MARK_AS_OVER_ANNOTATED
reason: Generic protein binding should not replace the specific NAD-dependent deacetylase
and corepressor activities.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:37968396
qualifier: enables
review:
summary: Proteome-scale interaction evidence does not justify generic protein binding
as an informative function.
action: MARK_AS_OVER_ANNOTATED
reason: Hst1's mechanistic partners and catalytic activity are already represented
more specifically.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:11711434
qualifier: located_in
review:
summary: Hst1 is experimentally localized to the nucleus.
action: ACCEPT
reason: The Set3C study and independent localization data support nuclear localization.
- term:
id: GO:0006974
label: DNA damage response
evidence_type: NAS
original_reference_id: PMID:11711434
qualifier: involved_in
review:
summary: PMID:11711434 establishes Hst1-containing deacetylase complexes but not a
direct Hst1 DNA-damage-response role.
action: MARK_AS_OVER_ANNOTATED
reason: This ComplexPortal-associated NAS extends chromatin-complex membership to a
process not demonstrated for Hst1 in the cited paper.
- term:
id: GO:0009267
label: cellular response to starvation
evidence_type: NAS
original_reference_id: PMID:11711434
qualifier: involved_in
review:
summary: Nutrient state modulates Hst1-regulated sporulation and metabolic transcription
programs.
action: KEEP_AS_NON_CORE
reason: Starvation response is biologically relevant to relief of sporulation repression
but is downstream of Hst1's catalytic core function.
- term:
id: GO:0034967
label: Set3 complex
evidence_type: IPI
original_reference_id: PMID:11711434
qualifier: part_of
review:
summary: Hst1 is an experimentally identified Set3C subunit, although it is largely
dispensable for Set3C repression.
action: KEEP_AS_NON_CORE
reason: PMID:11711434 places Hst1 in Set3C but identifies the Sum1-Rfm1-Hst1 complex
as the stronger Hst1-dependent context.
supported_by:
- reference_id: PMID:11711434
supporting_text: The S. cerevisiae SET3 complex includes two histone deacetylases,
Hos2 and Hst1, and is a meiotic-specific repressor of the sporulation gene program.
reference_section_type: TITLE
- term:
id: GO:0045835
label: negative regulation of meiotic nuclear division
evidence_type: IDA
original_reference_id: PMID:11711434
qualifier: involved_in
review:
summary: Hst1 represses middle-sporulation genes during vegetative growth, but direct
negative regulation of meiotic nuclear division overstates that transcriptional role.
action: MARK_AS_OVER_ANNOTATED
reason: The cited Set3C study reports that Hst1 is not required for meiotic repression
by Set3C; the supported Hst1 role is gene-specific repression through Sum1-Rfm1.
supported_by:
- reference_id: PMID:11711434
supporting_text: However, Hst1 is not required for meiotic repression by Set3C,
thus implying that Set3C (-Hst1) and not Hst1-Sum1, is the meiotic-specific repressor.
reference_section_type: ABSTRACT
- term:
id: GO:0000118
label: histone deacetylase complex
evidence_type: IPI
original_reference_id: PMID:11711434
qualifier: part_of
review:
summary: Hst1 is the catalytic subunit of promoter-targeted histone deacetylase complexes.
action: ACCEPT
reason: Physical association with Sum1-Rfm1 and Set3C supports membership in histone
deacetylase complexes.
- term:
id: GO:0006357
label: regulation of transcription by RNA polymerase II
evidence_type: NAS
original_reference_id: PMID:12612074
qualifier: involved_in
review:
summary: Hst1 regulates selected RNA polymerase II genes through local chromatin deacetylation.
action: ACCEPT
reason: PMID:12612074 directly links Sum1-Rfm1 recruitment of Hst1 to repression of
middle-sporulation genes.
supported_by:
- reference_id: PMID:10562556
supporting_text: SUM1 and HST1, genes previously associated with transcriptional
silencing, are required for MSE-mediated repression.
reference_section_type: ABSTRACT
- term:
id: GO:0030174
label: regulation of DNA-templated DNA replication initiation
evidence_type: NAS
original_reference_id: PMID:18990212
qualifier: involved_in
review:
summary: Hst1 promotes efficient initiation at a subset of Sum1-bound replication
origins through histone deacetylation.
action: KEEP_AS_NON_CORE
reason: PMID:18990212 provides direct Hst1-specific evidence, but origin control is
secondary to promoter repression.
supported_by:
- reference_id: PMID:18990212
supporting_text: We identified seven ARS elements whose initiation capacity depended
on Sum1 and Hst1.
reference_section_type: ABSTRACT
- term:
id: GO:0043937
label: regulation of sporulation
evidence_type: NAS
original_reference_id: PMID:12612074
qualifier: involved_in
review:
summary: Hst1 represses middle-sporulation genes during vegetative growth and thereby
regulates the sporulation program.
action: ACCEPT
reason: Sum1-Rfm1 recruits Hst1 to these promoters, and loss of the complex derepresses
the program (PMID:12612074).
supported_by:
- reference_id: PMID:10562556
supporting_text: SUM1 and HST1, genes previously associated with transcriptional
silencing, are required for MSE-mediated repression.
reference_section_type: ABSTRACT
- term:
id: GO:0008270
label: zinc ion binding
evidence_type: RCA
original_reference_id: PMID:30358795
qualifier: enables
review:
summary: Hst1 contains the conserved structural zinc-binding subdomain of sirtuins.
action: ACCEPT
reason: Zinc binding is a conserved structural feature of the sirtuin catalytic domain
and is consistent with the Hst1 sequence/domain annotation.
- term:
id: GO:0017136
label: histone deacetylase activity, NAD-dependent
evidence_type: IDA
original_reference_id: PMID:11313477
qualifier: enables
review:
summary: Hst1-dependent NAD-dependent histone deacetylase activity is required for
engineered Sum1-1 silencing.
action: ACCEPT
reason: PMID:11313477 directly tested the requirement for Hst1 in this conditional
silencing system.
- term:
id: GO:0017136
label: histone deacetylase activity, NAD-dependent
evidence_type: IDA
original_reference_id: PMID:11711434
qualifier: enables
review:
summary: Hst1 is one of the histone deacetylases identified in Set3C.
action: ACCEPT
reason: PMID:11711434 experimentally identifies Hst1 in the complex and supports NAD-dependent
histone deacetylase activity.
- term:
id: GO:0030466
label: silent mating-type cassette heterochromatin formation
evidence_type: IGI
original_reference_id: PMID:27185881
qualifier: involved_in
review:
summary: The study concerns Sir2-mediated silent-chromatin cohesion; the cached abstract
is insufficient to verify the Hst1 genetic interaction.
action: UNDECIDED
reason: Preserve the curator's experimental IGI annotation pending access to the full
supporting evidence; do not infer misattribution from an abstract centered on Sir2.
- term:
id: GO:0030466
label: silent mating-type cassette heterochromatin formation
evidence_type: IMP
original_reference_id: PMID:11313477
qualifier: involved_in
review:
summary: Hst1 is required for HMR silencing when recruited by the gain-of-function
Sum1-1 protein.
action: KEEP_AS_NON_CORE
reason: PMID:11313477 supports the annotation in this engineered context, but native
Hst1 does not normally perform regional mating-type silencing.
- term:
id: GO:0030466
label: silent mating-type cassette heterochromatin formation
evidence_type: IGI
original_reference_id: PMID:11313477
qualifier: involved_in
review:
summary: Genetic evidence supports Hst1-dependent Sum1-1 silencing at HMR.
action: KEEP_AS_NON_CORE
reason: Retain the experimentally curated interaction while making the non-native
targeting context explicit.
- term:
id: GO:0034967
label: Set3 complex
evidence_type: IDA
original_reference_id: PMID:11711434
qualifier: part_of
review:
summary: Hst1 is an experimentally identified Set3C component.
action: KEEP_AS_NON_CORE
reason: Set3C membership is real, but Hst1 is not essential for the complex's meiotic
repression and its main complex is Sum1-Rfm1-Hst1.
- term:
id: GO:0045950
label: negative regulation of mitotic recombination
evidence_type: IMP
original_reference_id: PMID:16051752
qualifier: involved_in
review:
summary: The cached abstract focuses on Hst2-mediated lifespan regulation and does
not expose the experiment supporting Hst1-dependent recombination control.
action: UNDECIDED
reason: The IMP annotation should not be overruled without the relevant full-text
evidence; retain for curator follow-up.
- term:
id: GO:0070623
label: regulation of thiamine biosynthetic process
evidence_type: IMP
original_reference_id: PMID:20439498
qualifier: involved_in
review:
summary: Hst1 links NAD+ availability to basal repression of thiamine biosynthesis
genes.
action: KEEP_AS_NON_CORE
reason: PMID:20439498 directly supports this extra program, but it is one target set
of the broader Hst1 promoter-repression mechanism.
supported_by:
- reference_id: PMID:20439498
supporting_text: We have determined that multiple thiamine ( THI ) genes in Saccharomyces
cerevisiae are also regulated by the intracellular NAD + concentration via the
NAD + -dependent histone deacetylase (HDAC) Hst1 and, to a lesser extent, Sir2.
reference_section_type: ABSTRACT
core_functions:
- description: >-
Hst1 is the NAD-dependent histone deacetylase of the Sum1-Rfm1-Hst1
transcriptional repressor. Sum1 specifies target loci and Rfm1 recruits Hst1,
whose local deacetylation of promoter chromatin, predominantly H4K5, represses
middle-sporulation and selected metabolic genes during vegetative growth.
molecular_function:
id: GO:0017136
label: histone deacetylase activity, NAD-dependent
directly_involved_in:
- id: GO:0045892
label: negative regulation of DNA-templated transcription
locations:
- id: GO:0000785
label: chromatin
- id: GO:0005634
label: nucleus
in_complex:
id: GO:0000118
label: histone deacetylase complex
supported_by:
- reference_id: PMID:12612074
supporting_text: Rfm1 interacts with both Sum1 and Hst1 and is required for the Sum1-Hst1 interaction.
reference_section_type: ABSTRACT
- reference_id: PMID:29066473
supporting_text: Set1 appeared to promote the association of the sequence-specific DNA binding protein Sum1 and the HDAC Hst1 with middle sporulation genes to maintain deacetylation, primarily at H4K5, and gene repression.
reference_section_type: ABSTRACT
proposed_new_terms:
- proposed_name: histone H4K5 deacetylase activity, NAD-dependent
proposed_definition: >-
Catalysis of the removal of an acetyl group from lysine 5 of histone H4 using
NAD+ as a reactant, producing deacetylated histone, nicotinamide, and
2'-O-acetyl-ADP-ribose.
justification: >-
Current GO has an H4K5-specific term for the hydrolytic mechanism and several
residue-specific NAD-dependent histone deacetylase terms, but no NAD-dependent
H4K5 child of GO:0017136. Hst1-specific experiments identify H4K5 as its main
histone H4 target.
proposed_parent:
id: GO:0017136
label: histone deacetylase activity, NAD-dependent
supported_by:
- reference_id: PMID:18990212
supporting_text: This was consistent with the notion that H4 K5 was the main target
of the histone deacetylase Hst1, whereas other histone H4 lysine residues were
minor or no targets of Hst1.
reference_section_type: RESULTS
suggested_questions:
- question: >-
Which endogenous Hst1 target proteins, if any, are deacetylated outside
chromatin, and do such substrates account for the secondary DNA-damage and
recombination phenotypes assigned to the Sir2 family?
- question: >-
How does the Sum1-Rfm1-Hst1 complex choose between middle-sporulation,
NAD-biosynthesis, thiamine-biosynthesis, and replication-origin targets as
nutrient state and intracellular NAD+ change?
suggested_experiments:
- hypothesis: >-
H4K5 is the dominant physiological histone substrate of promoter-bound Hst1,
whereas the H3K9, H3K14, and H4K16 residue-specific IBA assignments are not
broadly applicable to native Hst1 targets.
description: >-
Combine acute Hst1 depletion with calibrated residue-specific histone
acetylation profiling and Hst1/Sum1 ChIP-seq across vegetative, NAD-limited,
and sporulation-inducing conditions, then test catalytic-dead Hst1 rescue at
directly bound loci.
experiment_type: acute depletion, quantitative histone acetyl-proteomics, and ChIP-seq
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: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:0000108
title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
links
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: file:yeast/HST1/HST1-deep-research-openscientist.md
title: OpenScientist GO-focused literature synthesis for yeast HST1
findings: []
- id: PMID:8810037
title: HST1, a new member of the SIR2 family of genes.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified primary study; the abstract directly reports the negative
HST1 results for HML regional silencing and rDNA recombination used in this review.
- id: PMID:10562556
title: Sum1 and Hst1 repress middle sporulation-specific gene expression during mitosis in Saccharomyces cerevisiae.
findings: []
- id: PMID:12972620
title: NAD+-dependent deacetylase Hst1p controls biosynthesis and cellular NAD+ levels in Saccharomyces cerevisiae.
findings: []
- id: PMID:17242192
title: Swapping the gene-specific and regional silencing specificities of the Hst1 and Sir2 histone deacetylases.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified primary study; directly distinguishes Hst1-Rfm1-Sum1
gene-specific repression from Sir2-Sir3-Sir4 regional silencing.
- id: PMID:29066473
title: Repression of Middle Sporulation Genes in Saccharomyces cerevisiae by the Sum1-Rfm1-Hst1 Complex Is Maintained by Set1 and H3K4 Methylation.
findings: []
- id: PMID:11313477
title: A novel form of transcriptional silencing by Sum1-1 requires Hst1 and the
origin recognition complex.
findings: []
- id: PMID:11711434
title: The S. cerevisiae SET3 complex includes two histone deacetylases, Hos2 and
Hst1, and is a meiotic-specific repressor of the sporulation gene program.
findings: []
- id: PMID:12612074
title: Rfm1, a novel tethering factor required to recruit the Hst1 histone deacetylase
for repression of middle sporulation genes.
findings: []
- id: PMID:16051752
title: HST2 mediates SIR2-independent life-span extension by calorie restriction.
findings: []
- id: PMID:16429126
title: Proteome survey reveals modularity of the yeast cell machinery.
findings: []
- id: PMID:18990212
title: Control of replication initiation by the Sum1/Rfm1/Hst1 histone deacetylase.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Full text verified; directly supports Hst1-dependent replication-origin
control and the H4K5-predominant substrate-specificity conclusions.
- id: PMID:20439498
title: Thiamine biosynthesis in Saccharomyces cerevisiae is regulated by the NAD+-dependent
histone deacetylase Hst1.
findings: []
- id: PMID:27185881
title: Determinants of Sir2-Mediated, Silent Chromatin Cohesion.
findings: []
- id: PMID:30358795
title: The cellular economy of the Saccharomyces cerevisiae zinc proteome.
findings: []
- id: PMID:37968396
title: The social and structural architecture of the yeast protein interactome.
findings: []