GCN5

Summary: GCN5 is a core component of the histone acetyltransferase complex, as a key subunit of the SAGA and ADA complexes. IBA evidence indicates phylogenetic conservation of this association.

Reason: GCN5 is a well-documented component of two major HAT complexes: SAGA (Spt-Ada-Gcn5 acetyltransferase) and ADA. Within SAGA, GCN5 constitutes the central catalytic component of the HAT module (Grant et al., 1997). This is a core function clearly supported by multiple direct biochemical studies (PMID:9224714, PMID:9674426). IBA is appropriate because phylogenetic conservation of HAT complex architecture is well-established.

Summary: GCN5 functions as a general transcriptional coactivator through histone acetylation in SAGA complex, enabling activation of RNA pol II transcription genome-wide.

Reason: SAGA (containing GCN5) is a general cofactor required for global RNA polymerase II transcription. GCN5-mediated histone acetylation is a direct mechanism for transcriptional activation via chromatin remodeling (Baptista et al., 2017; Lee et al., 2000). The IBA evidence reflects conserved function across eukaryotes.

Summary: GCN5 has well-characterized histone H3 acetyltransferase activity, particularly targeting H3K9, H3K14, H3K18, H3K23, and H3K27 residues within SAGA and ADA complexes.

Reason: GCN5 is specifically documented to acetylate histone H3 at multiple lysine residues. In SAGA complex, GCN5 acetylates H3K9ac, H3K14ac, H3K18ac, H3K23ac. In ADA complex, preferential targets include H3K14ac and H3K18ac (Grant et al., 1999, 2001). Phylogenetic IBA is appropriate.

Summary: GCN5-mediated histone acetylation alters chromatin structure and accessibility, constituting a form of chromatin remodeling that is conserved across eukaryotes.

Reason: Histone acetylation by GCN5 directly leads to chromatin remodeling by loosening nucleosome-DNA interactions and facilitating access to transcriptional machinery (Grant et al., 1997). This function is core and conserved, supporting IBA classification.

Summary: GCN5 has intrinsic histone acetyltransferase catalytic activity as a member of the GNAT (GCN5-related N-acetyltransferases) family. IEA from InterPro domain mapping (IPR037800 GCN5) reflects the presence of the N-acetyltransferase catalytic domain.

Reason: The presence of the IPR037800 GCN5 domain ensures histone acetyltransferase activity. The broader GO:0004402 HAT activity term is appropriately inferred from domain annotation. Well-supported by crystal structures (PDB:1YGH, 1E6I, 6CW2, 6CW3) demonstrating catalytic mechanism.

Summary: GCN5 is predominantly localized to the nucleus, as indicated by UniProtKB subcellular location annotation from multiple experimental sources.

Reason: GCN5 functions as a nuclear transcriptional coregulator. IEA from UniProtKB subcellular location vocabulary (SL-0191) is well-supported by IDA evidence (PMID:22932476). Nuclear localization is consistent with SAGA complex function in transcription.

Summary: GCN5 can be detected in the cytoplasm, though this is not the primary compartment for its function.

Reason: While UniProtKB subcellular location indicates cytoplasmic presence (SL-0086), GCN5 is primarily nuclear and functions in nuclear transcriptional regulation. The cytoplasmic localization may represent transient localization or minor pool. Not contradicted but not core function.

Summary: GCN5 organizes chromatin through histone acetylation, which alters chromatin structure and gene accessibility. Inferred from UniProtKB keyword "Chromatin regulator" (KW-0156).

Reason: Histone acetylation by GCN5 is a primary mechanism of chromatin organization. The IEA annotation is supported by experimental evidence such as PMID:9674426 showing GCN5 involvement in SAGA-dependent nucleosome acetylation and transcriptional stimulation. This is a core function.

Summary: GCN5-mediated histone acetylation remodels chromatin structure. IEA from ARBA machine learning model (ARBA00027994).

Reason: This is a duplicate/redundant entry with the IBA GO:0006338 annotation already listed. Both refer to the same biological function of chromatin remodeling. The IEA evidence provides computational reinforcement of the same function. Keeping both is acceptable as they derive from different evidence lines.

Summary: GCN5 regulates transcription through chromatin modification. Inferred from "Transcription" keyword (KW-0804).

Reason: While GCN5 is involved in transcription regulation via chromatin acetylation, the term "DNA-templated transcription" (GO:0006351) refers to the core transcription machinery itself. GCN5 is a regulator/coactivator, not part of the basal transcription machinery. This annotation is too broad and non-specific. The more accurate annotation is transcriptional regulation (GO:0006357) or positive regulation of transcription (GO:0045944).

Summary: GCN5 regulates gene expression through histone acetylation and chromatin remodeling. IEA from ARBA (ARBA00028334).

Reason: This is an accurate but very broad parent term. GCN5 function is better captured by chromatin organization/remodeling and regulation of RNA polymerase II transcription annotations tied to histone acetylation.

Summary: GCN5 positively regulates biosynthetic processes by activating genes encoding biosynthetic enzymes. IEA from ARBA (ARBA00027412).

Reason: This is an indirect and overly broad downstream consequence of GCN5-dependent transcriptional regulation. More specific chromatin and RNA polymerase II transcription regulation terms should carry the functional interpretation.

Summary: GCN5 is a transferase that transfers acetyl groups (acetyltransferase activity). Inferred from "Transferase" keyword (KW-0808).

Reason: This is an appropriate parent term for histone acetyltransferase activity. The protein indeed catalyzes transfer of acetyl groups from CoA to histone lysines. This is a core molecular function reflected in the UniProtKB keywords.

Summary: GCN5 catalyzes acyl (acetyl) group transfer. Inferred from "Acyltransferase" keyword (KW-0012).

Reason: GCN5 is specifically an acetyltransferase, a subtype of acyltransferases. This parent term is appropriate. The UniProtKB keywords correctly reflect this function.

Summary: GCN5 transfers acetyl (non-amino-acyl) groups to histone lysines. Inferred from InterPro domain IPR000182 (GNAT domain).

Reason: This term precisely describes GCN5 catalytic function: transfer of acetyl groups (not amino-acyl groups) to target proteins. The GNAT domain (InterPro:IPR000182) is the defining feature. This annotation is accurate and specific.

Summary: GCN5 catalyzes acetylation of lysine residues on protein substrates, particularly histones. Inferred from EC number 2.3.1.48 via RHEA mapping (RHEA:45948).

Reason: This is the most specific and informative annotation for GCN5 catalytic activity. The EC number 2.3.1.48 uniquely identifies lysine acetyltransferases. This term correctly captures GCN5 activity toward histone lysine residues and is central to GCN5 function.

Summary: GCN5 can transfer crotonyl groups (derived from crotonyl-CoA) to histone lysines in addition to acetylation. This activity was discovered in recent studies showing GCN5 can use alternative acyl-CoA substrates.

Reason: GCN5 (and Esa1) have been demonstrated to function as histone crotonyltransferases using (2E)-butenoyl-CoA as substrate (PMID:31699900). This is a real catalytic function, though likely less prominent than acetylation. The IEA from RHEA mapping (RHEA:53908) for crotonylation reactions is appropriate.

Summary: GCN5 is a component of the ADA histone acetyltransferase complex. IEA from ARBA rule (ARBA00085714).

Reason: GCN5 is a core component of the ADA complex, distinct from SAGA (Eberharter et al., 1999). The ADA complex contains GCN5, ADA2, ADA3/NGG1, AHC1, AHC2, and SGF29. IEA is appropriate, though the IDA evidence is stronger (see IDA annotation below).

Summary: GCN5 protein binding with ADA2 documented by yeast two-hybrid and co-immunoprecipitation. All 21 IPI annotations (GO:0005515) represent documented protein-protein interactions from affinity purification and proteomics studies.

Reason: While protein binding interactions are real and documented, GO:0005515 "protein binding" is an uninformative annotation. Per GO best practices and these guidelines, protein binding should only be annotated when it describes a specific, functionally relevant interaction that is not better captured by a more specific molecular function term. GCN5 interactions are already captured by complex membership terms (GO:0000124 SAGA, GO:0140671 ADA, GO:0046695 SLIK). Individual protein-protein interactions (with ADA2, HFI1, etc.) are structural necessities for complex assembly, not functional outputs. A gene reviewer should avoid "protein binding" terms that provide no additional functional insight.

Summary: Nuclear localization of GCN5 supported by expert analysis (NAS) with reference to SAGA complex characterization papers.

Reason: NAS annotation with appropriate reference literature supports nuclear localization. This is consistent with GCN5 function in transcriptional coactivation. This duplicate nucleus annotation (also listed as IEA) is acceptable from different evidence sources.

Summary: GCN5 regulation of RNA pol II transcription established by curation (NAS) from comprehensive SAGA/SLIK literature. GCN5 is fundamental to transcriptional regulation via histone acetylation.

Reason: This is the most accurate and specific process term for GCN5 function. GCN5 directly regulates RNA pol II transcription through histone acetylation within the SAGA complex. NAS evidence from expert curation of chromatin-related literature is appropriate. This is a core functional annotation.

Summary: GCN5 bromodomain binds acetylated histone H4K12. Biochemical profiling study measured binding selectivity of yeast bromodomains.

Reason: GCN5 contains a bromodomain (residues 327-431) that specifically recognizes and binds acetylated histone lysines. PMID:20126658 experimentally determined the binding specificity of GCN5 bromodomain for H4K12ac among other acetylated residues. This is a validated reader function. IDA is appropriate.

Summary: GCN5 bromodomain binds acetylated histone H3K56. Experimentally determined binding selectivity in biochemical profiling study.

Reason: The GCN5 bromodomain demonstrates binding specificity for H3K56ac as part of its histone-binding repertoire (PMID:20126658). This reader function complements GCN5 writer activity (acetylation) to create a comprehensive epigenetic regulation mechanism. IDA is appropriate.

Summary: GCN5 bromodomain functions as a histone reader, recognizing acetylated histone residues. This is the parent term encompassing all specific histone reader activities (H3K56ac, H4K12ac, H4K16ac).

Reason: The three specific histone reader annotations (H3K56ac, H4K12ac, H4K16ac) logically roll up to the parent term GO:0140566 histone reader activity. The IDA evidence from PMID:20126658 supports this. The bromodomain structure (Owen et al., 2000) confirms acetyl-lysine binding capability. This is well-founded.

Summary: GCN5 catalytic acetylation activity directly demonstrated through in vitro and in vivo acetyltransferase assays. Referenced paper examined acetylation of Cdk9, showing GCN5-catalyzed lysine acetylation.

Reason: Remove this evidence row because PMID:18250157 studies human GCN5/PCAF acetylation of human CDK9, not Saccharomyces cerevisiae GCN5. The yeast lysine acetyltransferase function is supported by other yeast-specific evidence, but this cross-species IDA line is not appropriate for Q03330.

Summary: GCN5 bromodomain binds acetylated histone H4K16. Part of comprehensive bromodomain-histone binding study.

Reason: Biochemical profiling study (PMID:20126658) explicitly measured GCN5 bromodomain binding to various acetylated histone marks, including H4K16ac. This specific reader activity is experimentally validated. IDA is appropriate.

Summary: GCN5 functions as a transcriptional coregulator through multiple mechanisms: histone acetylation, histone crotonylation, and bromodomain-based histone reading within transcriptional complexes.

Reason: GCN5 is a canonical example of a transcription coregulator. The paper PMID:31699900 demonstrates GCN5 function as a coregulator through crotonylation-dependent transcription regulation, in addition to classical acetylation. GCN5 modulates transcription without directly binding DNA, consistent with coregulator function. IDA is appropriate.

Summary: GCN5 catalyzes crotonylation of histones using (2E)-butenoyl-CoA as substrate, expanding its catalytic repertoire beyond acetylation. Direct evidence from biochemical analysis.

Reason: PMID:31699900 directly demonstrates GCN5 crotonylation activity through biochemical assays and mass spectrometry. GCN5 and Esa1 catalyze histone crotonylation at specific lysine residues, regulating genes involved in metabolic regulation. This represents a newly appreciated but genuine GCN5 catalytic function. IDA is appropriate.

Summary: GCN5 localization to cytosolic compartment detected experimentally. Minor or transient localization relative to nuclear pool.

Reason: While experimental detection of GCN5 in cytosol is documented (PMID:22932476), the cytosolic localization is not functionally significant for GCN5 core roles in transcriptional regulation. Most GCN5 is nuclear. The IDA evidence is valid but this represents a peripheral aspect of GCN5 localization, better described as "nucleus" (primary) and "cytoplasm" (minor). Keeping as non-core recognizes real localization without inflating cytosolic function.

Summary: GCN5 organizes chromatin through histone acetylation, altering nucleosome positioning and accessibility. Directly observed in SAGA complex characterization studies.

Reason: GCN5, as part of SAGA, directly organizes chromatin by acetylating histones and facilitating nucleosome remodeling (PMID:9674426). The IDA evidence demonstrates this through biochemical reconstitution and cellular studies. Chromatin organization is a fundamental GCN5 function. This annotation captures the structural reorganization aspect of GCN5 function.

Summary: Chromatin remodeling function of GCN5 demonstrated through mutational analysis. GCN5 hyperacetylation at promoters enables transcription factor binding and transcriptional activation.

Reason: IMP (Inferred from Mutant Phenotype) evidence from PMID:11867538 showing that GCN5-mediated hyperacetylation at the ADH2 promoter allows Adr1 transcription factor binding in normally repressed conditions. This demonstrates GCN5 role in remodeling chromatin to allow regulatory proteins access. IMP is appropriate evidence.

Summary: GCN5 is a core component of the SAGA (Spt-Ada-Gcn5 acetyltransferase) complex, establishing its role within this major transcriptional regulatory complex. Identified through biochemical purification and mass spectrometry.

Reason: GCN5 is the central catalytic component of the SAGA complex HAT module. PMID:9224714 characterized SAGA and identified GCN5 as a core subunit. SAGA is 1.8 MDa complex with 19 subunits organized into four functional modules: HAT (containing GCN5), DUB, TAF, and SPT. GCN5 membership in SAGA is a defining feature. The Gcn5 HAT domain has been crystallized in complex with its activating SAGA partner subunit Ada2 (PDB 6CW2/6CW3; PMID:30224453), confirming Gcn5 as the catalytic HAT subunit of SAGA. IDA is appropriate.

Summary: GCN5 localizes to centromeric regions and plays a role in centromere/kinetochore function and chromosome segregation. Direct experimental evidence from immunofluorescence and chromatin immunoprecipitation studies.

Reason: PMID:18039853 demonstrates GCN5 localization to centromeres and a requirement for proper centromere kinetochore function in mitosis. GCN5 controls metaphase-to-anaphase transition and chromosome segregation. This is a specialized but documented GCN5 function. IDA is appropriate. This represents a non-canonical role for GCN5 beyond transcriptional regulation.

Summary: GCN5 histone acetyltransferase activity directly demonstrated. PMID:8601308 characterized a Tetrahymena HAT as a GCN5 homolog, linking histone acetylation to gene activation. The catalytic mechanism is further defined by crystal structures of the Gcn5 HAT domain in complex with Ada2 (PDB 6CW2/6CW3; PMID:30224453), which show that the Ada2 SANT domain activates Gcn5 HAT activity by enhancing acetyl-CoA cosubstrate binding.

Reason: GCN5 histone acetyltransferase activity is directly demonstrated through in vitro enzymatic assays. PMID:8601308 identified Tetrahymena histon acetyltransferase A as a GCN5 homolog, establishing the conservation of GCN5 HAT function. Multiple evidence lines support this core catalytic function. IDA is appropriate.

Summary: GCN5 histone H3 acetyltransferase activity directly measured through enzymatic assays and substrate analysis in context of chaperone regulation. Crystal structures of the Gcn5 HAT domain bound to its activating partner Ada2 (PDB 6CW2/6CW3; PMID:30224453) further establish that Gcn5 acetylates histone H3 N-terminal tails and that this HAT activity is potentiated by Ada2-enhanced acetyl-CoA binding.

Reason: PMID:18458063 directly examines GCN5 H3 acetyltransferase specificity in the context of chaperone control. GCN5 specifically acetylates histone H3 at multiple residues. This IDA evidence demonstrates the specific H3-directed activity. Combined with multiple other IDA, IMP, and IGI entries for the same term, this establishes H3K-specific acetylation as a core GCN5 function.

Summary: GCN5 H3 acetyltransferase activity inferred from mutant phenotype. Mutations in GCN5 acetyl-transferase domain or loss of GCN5 show defects in H3 acetylation.

Reason: IMP evidence from PMID:18458063 showing mutant GCN5 phenotype confirms H3 acetyltransferase activity. Multiple evidence types (IDA, IMP, IGI) for the same term reinforce core H3-directed catalytic function. All are valid and complementary.

Summary: GCN5 H3 acetyltransferase activity inferred from genetic interaction. Genetic interactions with other chromatin regulators (SGD:S000003651, S000003925, S000005190) demonstrate GCN5 role in H3 acetylation.

Reason: IGI (Inferred from Genetic Interaction) evidence from PMID:18458063 using genetic crosses identifies genetic partners in H3 acetylation pathway. Genetic interactions with Rtt109 and other chaperones support GCN5 functional role in H3 acetylation. IGI is appropriate evidence for core pathway function.

Summary: GCN5 function in transcription elongation regulation demonstrated through mutant analysis. In conjunction with NuA4 complex Esa1, GCN5 stimulates transcription elongation.

Reason: PMID:19822662 demonstrates that NuA4 lysine acetyltransferase Esa1, working with GCN5, is targeted to coding regions and stimulates transcription elongation. GCN5-mediated histone acetylation at gene bodies facilitates productive elongation. IMP evidence shows GCN5 mutants have elongation defects. This represents a specific GCN5 function beyond initiation.

Summary: GCN5 transcription elongation role supported by genetic interaction with ESA1 (SGD:S000005770). Genetic analysis indicates functional cooperation in elongation regulation.

Reason: IGI evidence from PMID:19822662 showing genetic interaction between GCN5 and ESA1 (encoding NuA4 catalytic subunit) confirms functional interaction in transcription elongation pathway. The genetic evidence complements the IMP data. Both IMP and IGI support this specialized GCN5 function.

Summary: GCN5 is a component of SLIK complex, an altered form of SAGA containing truncated Spt7 and lacking Spt8. SLIK functions in retrograde response pathway.

Reason: GCN5 is part of SLIK (SAGA-like) complex, characterized in PMID:12446794 as functioning in yeast retrograde response. SLIK is structurally and functionally equivalent to SAGA (Adamus et al., 2021) and retains GCN5-mediated HAT activity. This extends GCN5 function to retrograde response signaling. IDA is appropriate.

Summary: Duplicate annotation of SAGA complex membership with different reference (also see PMID:9224714).

Reason: Second IDA entry for SAGA complex membership, supported by different reference (PMID:9674426). Multiple independent experimental confirmations of GCN5-SAGA association strengthen the annotation.

Summary: Duplicate annotation of histone acetyltransferase activity with different reference (also see PMID:8601308).

Reason: Multiple IDA entries for general HAT activity reinforce this core catalytic function. PMID:10026213 specifically characterized lysine acetylation specificity in native SAGA and ADA complexes.

Summary: Protein binding interaction documented. All remaining IPI protein binding annotations are documented but not informative.

Reason: Part of 20 IPI protein binding entries. As noted in the PMID:10490601 entry, these represent structural protein-protein interactions necessary for complex assembly but do not convey functional information. Removed in favor of complex membership annotations (SAGA, ADA, SLIK).

Summary: Protein binding interaction documented via proteomics.

Reason: Uninformative generic protein binding annotation. Structural interactions are better captured by complex membership terms.

Summary: Protein binding with complex members.

Reason: Generic protein binding. Already captured by SALSA/SLIK complex annotations.

Summary: Protein binding in context of SLIK complex.

Reason: Generic protein binding. SLIK complex membership is the informative annotation.

Summary: Protein binding from proteomics analysis.

Reason: Generic protein binding from affinity purification/proteomics.

Summary: Protein binding with Sus1.

Reason: Generic protein binding. Structural component of SAGA complex.

Summary: Protein binding from chromatin complex proteomics.

Reason: Generic protein binding annotation from mass spectrometry.

Summary: Protein binding from proteome survey.

Reason: Generic protein binding from proteomics.

Summary: Protein binding from global complex mapping.

Reason: Generic protein binding. Complex membership is more informative.

Summary: Protein binding with TBP.

Reason: Generic protein binding. SAGA-TBP interaction is structural but complex membership annotation is more informative.

Summary: Protein binding in SAGA deubiquitinase module.

Reason: Generic protein binding from structural/biochemical studies.

Summary: Protein binding from chromatin-associated interactome.

Reason: Generic protein binding from proteomics/interaction mapping.

Summary: Protein binding with MAP kinase.

Reason: Generic protein binding annotation.

Summary: Second nucleus localization annotation from IDA.

Reason: Duplicate of earlier nucleus annotation but with different evidence source (IDA from subcellular localization study). Multiple independent demonstrations of nuclear localization strengthen this annotation.

Summary: Protein binding with TAF9.

Reason: Generic protein binding. TAF9 is SAGA core module component; complex membership more informative.

Summary: Second ADA complex membership annotation from different reference (also see PMID:10490601).

Reason: Independent confirmation of ADA complex membership. PMID:7862114 characterized ADA3 interactions with GCN5 and ADA2, establishing trimeric complex assembly. Multiple independent identifications strengthen this annotation.

Summary: Protein binding from SAGA deubiquitination module study.

Reason: Generic protein binding annotation.

Summary: Protein binding from NuA3 complex study.

Reason: Generic protein binding annotation. GCN5 is not part of NuA3 but may interact.

Summary: Protein binding from recent social/structural interactome study.

Reason: Generic protein binding from recent proteomics/interactome mapping.

Summary: Protein binding from SAGA/ADA network depletion study.

Reason: Generic protein binding annotation from SAGA complex characterization.

Summary: Protein binding with SAGA complex members.

Reason: Generic protein binding. Better captured by SAGA complex membership.

Summary: Third nucleus localization annotation from NAS with SAGA network study.

Reason: Additional NAS evidence for nuclear localization from SAGA/ADA network characterization. Multiple independent demonstrations of nuclear localization from different methodologies strengthen this annotation.

Summary: Second NAS entry for transcriptional regulation from SAGA/ADA network study.

Reason: NAS evidence from comprehensive SAGA/ADA network analysis. Multiple evidence types (NAS, IDA) for the same core function reinforce the annotation.

Summary: Third IDA entry for RNA pol II transcription regulation from SAGA architecture study.

Reason: Additional IDA evidence from SAGA complex architecture characterization. Multiple experimental approaches (NAS, IDA from different studies) confirm GCN5 role in transcriptional regulation.

Summary: Fourth IDA entry for transcriptional regulation from CDK9 deacetylation study.

Reason: Remove this evidence row because PMID:28426094 is a human SIRT7/GCN5/CDK9 study and does not directly demonstrate Saccharomyces cerevisiae GCN5 regulation of RNA polymerase II transcription. Yeast transcriptional regulation remains supported by yeast SAGA/ADA evidence elsewhere in the review.

Summary: Second IDA entry for protein-lysine-acetyltransferase activity from CDK9 study.

Reason: Remove this evidence row because PMID:28426094 studies human SIRT7/GCN5-directed acetylation of human CDK9, not yeast GCN5. It should not be used as IDA evidence for Saccharomyces cerevisiae Q03330.

Summary: Second IDA entry for ADA complex membership (also see PMID:7862114).

Reason: Primary IDA evidence establishing ADA complex as a distinct HAT complex with GCN5 as core component. PMID:10490601 characterized ADA as compositionally and functionally distinct from SAGA, containing ADA2, ADA3/NGG1, AHC1, AHC2, SGF29, and GCN5.