{"gene":"KAT2A","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2017,"finding":"KAT2A (GCN5) acts as a histone H3 succinyltransferase: the α-ketoglutarate dehydrogenase (α-KGDH) complex localizes to the nucleus, binds KAT2A at gene promoters, and provides succinyl-CoA as substrate. Crystal structure of KAT2A catalytic domain in complex with succinyl-CoA at 2.3 Å shows succinyl-CoA binds a deep cleft with the succinyl moiety pointing toward a flexible loop 3; Y645 in this loop determines selective binding of succinyl-CoA over acetyl-CoA. KAT2A succinylates histone H3K79 near transcription start sites, promoting gene expression and tumor cell proliferation.","method":"Crystal structure (2.3 Å), site-directed mutagenesis (Y645A), in vitro succinylation assay, ChIP, nuclear fractionation, cell proliferation and tumor growth assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — crystal structure + mutagenesis + in vitro assay + in vivo functional validation in a single high-impact study","pmids":["29211711"],"is_preprint":false},{"year":2024,"finding":"ACSS2 functions as a lactyl-CoA synthetase that converts lactate to lactyl-CoA; it forms a complex with KAT2A after EGFR-ERK-mediated S267 phosphorylation and nuclear translocation. KAT2A then acts as a lactyltransferase to lactylate histone H3, driving Wnt/β-catenin, NF-κB, and PD-L1 expression. Co-crystal structure demonstrates lactyl-CoA binding to KAT2A.","method":"Co-crystal structure, Co-IP, in vitro lactylation assay, ERK phosphorylation assay, tumor growth and immune evasion models","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 — co-crystal structure + biochemical reconstitution + mutagenesis + in vivo validation","pmids":["39561764"],"is_preprint":false},{"year":1994,"finding":"GCN5 (KAT2A yeast ortholog) physically interacts with ADA2 in a heteromeric complex that mediates transcriptional activation; double-mutant studies show ADA2 and GCN5 function together in the same complex or pathway. The GCN5 bromodomain is functionally important for a general activity of transcription factors but is not required for the GCN5-ADA2 interaction.","method":"Two-hybrid assay, co-immunoprecipitation, double-mutant epistasis analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP + epistasis; foundational study replicated extensively","pmids":["7957049"],"is_preprint":false},{"year":2000,"finding":"Gcn5l2 (mouse ortholog of KAT2A) is essential for embryogenesis: knockout embryos die with failure to form dorsal mesoderm (chordamesoderm and paraxial mesoderm) and exhibit extensive apoptosis; Pcaf-null mice are viable, but Gcn5l2/Pcaf double nulls are more severely affected, indicating overlapping functions.","method":"Conditional and germline knockout mouse (null embryos), histology, apoptosis assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — clean knockout with defined developmental phenotype, replicated with double-KO epistasis","pmids":["11017084"],"is_preprint":false},{"year":2008,"finding":"Human KAT2A (GCN5) is a subunit of two distinct multiprotein complexes: STAGA (~2 MDa, containing SPT3, TAF9, TRRAP) and ATAC (~700 kDa, containing ADA2a, ADA3, STAF36, WDR5, POLE3/CHRAC17, POLE4, TAK1/MAP3K7, MBIP, YEATS2-NC2β). The ATAC YEATS2-NC2β module interacts with TBP and negatively regulates transcription when recruited to a promoter.","method":"Biochemical purification, mass spectrometry, Co-IP, in vitro transcription assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — biochemical purification + MS interactome + functional validation; foundational complex characterization","pmids":["18838386"],"is_preprint":false},{"year":2018,"finding":"The Ada2 SANT domain activates Gcn5 HAT activity by enhancing Gcn5 binding to the enzymatic cosubstrate acetyl-CoA, rather than by affecting histone peptide binding. Crystal structures of the yeast Ada2/Gcn5 complex with Fab chaperones reveal the structural basis of this allosteric mechanism.","method":"Crystal structure (Fab-assisted crystallization), biochemical HAT assays, binding measurements","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure + biochemical reconstitution + mutagenesis","pmids":["30224453"],"is_preprint":false},{"year":2003,"finding":"Crystal structures of Tetrahymena Gcn5 bound to histone H4 and p53 peptides reveal that the Gcn5/PCAF HAT family accommodates divergent substrates by using analogous interactions with the target lysine and two C-terminal residues, while N-terminal substrate residues provide enhanced affinity for histone H3 specifically.","method":"X-ray crystallography, in vitro acetyltransferase assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple crystal structures with functional validation, defining substrate selectivity mechanism","pmids":["14661947"],"is_preprint":false},{"year":2014,"finding":"The bromodomain of Gcn5 regulates site specificity of HAT activity on histone H3: bromodomain-mutant ADA subcomplex (Gcn5-Ada2-Ada3) shows severely diminished H3K18ac; H3K14ac by Gcn5 and subsequent bromodomain binding to H3K14ac are prerequisite steps for H3K18ac, revealing cross-talk between the Gcn5 reader and writer functions.","method":"Quantitative mass spectrometry, acid-urea gel, in vitro HAT assays with wild-type and bromodomain mutant complexes","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1 — in vitro HAT assay + mutagenesis + quantitative MS, multiple orthogonal methods","pmids":["25106422"],"is_preprint":false},{"year":2015,"finding":"Subunits of either ATAC (ADA2a-containing) or SAGA (ADA2b-containing) HAT modules stimulate GCN5 acetyltransferase activity on histone H3, primarily at H3K14; ADA2b has a stronger stimulatory effect than ADA2a; incorporation of HAT modules into holo-complexes further increases activity without changing lysine specificity.","method":"In vitro HAT assays with purified recombinant and endogenous complexes, histone peptide and full-length histone substrates","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro assays with defined recombinant and endogenous complexes","pmids":["26468280"],"is_preprint":false},{"year":2007,"finding":"GCN5 (KAT2A) is recruited by c-Myc to RNA polymerase III-transcribed genes (tRNA, 5S rRNA) together with TRRAP, leading to selective H3 (but not H4) hyperacetylation, increased TFIIIB occupancy, and transcriptional induction.","method":"ChIP, inducible Myc system, ChIP-qPCR, RT-PCR","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — ChIP with inducible system demonstrating temporal recruitment and histone acetylation linked to Pol III activation","pmids":["17848523"],"is_preprint":false},{"year":2001,"finding":"E2F-1 and E2F-4 transactivation domains bind KAT2A (GCN5) and cofactor TRRAP in vivo; catalytically active GCN5 is required for E2F-mediated transactivation and histone acetyltransferase activity recruited by E2F-4 in vivo.","method":"Co-IP, transactivation assays, HAT activity assays with wild-type and catalytic mutants, domain-mapping mutations","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP + catalytic mutant + functional transactivation assay","pmids":["11418595"],"is_preprint":false},{"year":2019,"finding":"KAT2A (GCN5) acetylates TFEB (master transcription factor for autophagy/lysosome genes) at K274 and K279, reducing TFEB transcriptional activity by disrupting TFEB dimerization and promoter binding; autophagy induction inactivates GCN5 and reduces TFEB acetylation, increasing lysosome formation.","method":"In vitro acetyltransferase assay, Co-IP, site-directed mutagenesis, autophagy flux assays, Drosophila genetic model","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro acetyltransferase assay + mutagenesis + genetic validation in Drosophila + mechanistic epistasis","pmids":["31750630"],"is_preprint":false},{"year":2019,"finding":"KAT2A mediates H3K79 succinylation at the YWHAZ (14-3-3ζ) promoter to upregulate 14-3-3ζ expression; KAT2A Y645A (succinyltransferase-defective) mutant reduces H3K79 succinylation and 14-3-3ζ levels, leading to decreased β-catenin stability and reduced glycolysis and proliferation in pancreatic cancer cells.","method":"ChIP-qPCR, site-directed mutagenesis (Y645A), immunoprecipitation, western blot, cell proliferation and glycolysis assays","journal":"Cancer letters","confidence":"High","confidence_rationale":"Tier 1–2 — activity-dead mutant + ChIP mechanistic link + functional phenotype","pmids":["31610265"],"is_preprint":false},{"year":2019,"finding":"KAT2A (GCN5) directly acetylates α-tubulin (TUBA) in vascular smooth muscle cells; autophagic degradation of KAT2A via a conserved LC3-interacting region (LIR) domain reduces TUBA acetylation, destabilizes microtubules, and promotes directional VSMC migration.","method":"Co-IP, GST pulldown, LIR domain mutagenesis, autophagy flux assays, cell migration assays, in vitro acetyltransferase assay","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro acetyltransferase assay + LIR domain mutagenesis + functional migration phenotype","pmids":["31878840"],"is_preprint":false},{"year":2021,"finding":"ULK1 deletion inhibits autophagic degradation of KAT2A, causing KAT2A accumulation, increased α-tubulin acetylation, microtubule stabilization, and inhibition of VSMC directional migration and neointima formation; local KAT2A siRNA in ulk1 KO mice reverses the protective effect.","method":"Vascular smooth muscle cell-specific Ulk1 KO mouse, carotid artery ligation model, KAT2A siRNA, western blot, immunofluorescence, migration assays","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — conditional KO + rescue siRNA + in vivo neointima model","pmids":["33985412"],"is_preprint":false},{"year":2017,"finding":"GCN5 (KAT2A) is recruited to the il-2 promoter by interacting with NFAT upon TCR stimulation in T cells, catalyzing H3K9 acetylation (not NFAT acetylation directly) to promote IL-2 transcription; conditional T cell-specific Gcn5 KO impairs IL-2 production, T cell proliferation, and Th1/Th17 differentiation.","method":"Conditional Lck-Cre Gcn5 KO mouse, ChIP, Co-IP (GCN5-NFAT), T cell proliferation and cytokine assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO + ChIP + Co-IP demonstrating mechanism","pmids":["28424240"],"is_preprint":false},{"year":2017,"finding":"GCN5 (KAT2A) is the specific lysine acetyltransferase of EGR2 transcription factor; GCN5-mediated acetylation positively regulates EGR2 transcriptional activity, and this activity is required for iNKT cell development through Runx1, PLZF, IL-2Rβ, and T-bet transcription.","method":"In vitro acetyltransferase assay, Co-IP, conditional KO mouse, pharmacological GCN5 inhibition, gene expression analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro acetyltransferase + conditional KO + pharmacological inhibition with phenotypic readout","pmids":["28723564"],"is_preprint":false},{"year":2004,"finding":"GCN5 directly binds TGF-β-specific R-Smads and BMP-specific R-Smads (the latter unlike PCAF), acts as a transcriptional coactivator enhancing TGF-β and BMP signaling-induced transcription; GCN5 knockdown by RNAi represses TGF-β-induced transcriptional activity.","method":"Biochemical purification from nuclear extract using Smad-binding DNA element, Co-IP, reporter gene assays, RNAi knockdown","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP + functional reporter + RNAi, single lab","pmids":["15009097"],"is_preprint":false},{"year":2016,"finding":"The lncRNA GClnc1 acts as a molecular scaffold bridging WDR5 and KAT2A complexes, coordinating their localization to target gene promoters (including SOD2) and specifying the histone modification pattern to promote gastric cancer cell biology.","method":"RNA immunoprecipitation, Co-IP, ChIP, RNA pulldown, functional assays in gastric cancer models","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2–3 — RIP + ChIP + Co-IP; single lab but multiple orthogonal methods","pmids":["27147598"],"is_preprint":false},{"year":2019,"finding":"lncRNA PVT1 serves as a scaffold for KAT2A, enabling KAT2A-mediated H3K9 acetylation at the NF90 promoter, which recruits TIF1β to activate NF90 transcription and increase HIF-1α stability; KAT2A acetyltransferase activity-deficient mutants fail to promote PVT1-mediated NPC cell proliferation.","method":"RNA-IP, ChIP, KAT2A catalytic mutant expression, siRNA knockdown, rescue experiments, xenograft model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2–3 — catalytic mutant + ChIP + RIP; single lab","pmids":["31320749"],"is_preprint":false},{"year":2007,"finding":"GCN5 (Drosophila ortholog) acetylates the nucleosome remodeling ATPase ISWI at K753 (equivalent to H3K14) in vivo and in vitro; the target sequence on ISWI is similar to the H3 N-terminus recognized by GCN5, suggesting co-regulation of a remodeler and its substrate through related epitopes.","method":"In vitro acetyltransferase assay, mass spectrometry, immunoprecipitation, site-directed mutagenesis","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro assay + MS identification of site + mutagenesis; Drosophila ortholog","pmids":["17760996"],"is_preprint":false},{"year":2019,"finding":"KAT2A (GCN5) acetylates histone variant H2A.Z.1 (but not H2A.Z.2, due to alanine-14 in H2A.Z.2 inhibiting KAT2A activity) at promoters of transactivated genes; the DNA repair complex XPC-RAD23-CEN2 interacts with H2A.Z and KAT2A to recruit KAT2A to promoters and license H2A.Z.1 acetylation, which then recruits BRD2 to promote RNA Pol II recruitment.","method":"In vitro acetyltransferase assay, Co-IP, ChIP, H2A.Z.1 acetylation-deficient mutant, RNAi knockdown","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro HAT assay defining specificity + Co-IP + ChIP + non-acetylable mutant functional validation","pmids":["31527837"],"is_preprint":false},{"year":2020,"finding":"Kat2a loss in AML cells reduces transcriptional burst frequency at a subset of gene promoters, generating enhanced transcriptional variability; this destabilization of target gene programs shifts leukemia cell fate from self-renewal to differentiation, depleting leukemia stem-like cells.","method":"Conditional Kat2a knockout mouse, chromatin profiling (ChIP-seq, ATAC-seq), single-cell RNA-seq, transcription factor binding analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — conditional KO + multiple orthogonal genomic methods + single-cell transcriptomics","pmids":["31985402"],"is_preprint":false},{"year":2018,"finding":"KAT2A (GCN5) histone acetyltransferase maintains ATRA resistance in non-APL AML via aberrant H3K9 acetylation, sustaining stemness and leukemia-associated gene expression; GCN5 inhibition combined with LSD1 inhibition unlocks ATRA-driven differentiation across most non-APL AML subtypes.","method":"Pharmacological GCN5 inhibition, ChIP (H3K9ac), gene expression analysis, differentiation assays, in vivo models","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2–3 — pharmacological inhibition + ChIP mechanistic link; single lab","pmids":["31576004"],"is_preprint":false},{"year":2020,"finding":"GCN5 (KAT2A) promotes transcription of MYC-induced cell-cycle genes as an essential coactivator; deletion of Gcn5 in the Eμ-Myc B-cell lymphoma mouse model delays or abrogates tumorigenesis and reduces Myc expression and downstream functions.","method":"Conditional Gcn5 KO in Eμ-Myc mouse model, ChIP-seq, gene expression analysis, survival studies","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — conditional KO in cancer model + ChIP-seq; multiple methods","pmids":["33168647"],"is_preprint":false},{"year":2011,"finding":"And-1 (acidic nucleoplasmic DNA-binding protein) forms a complex with both histone H3 and GCN5, stabilizing GCN5 protein; And-1 knockdown causes GCN5 proteasomal degradation, reducing H3K9 and H3K56 acetylation; And-1 overexpression stabilizes GCN5 through protein-protein interactions.","method":"Co-IP, siRNA knockdown, western blot (H3K9ac, H3K56ac), proteasome inhibitor rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP + knockdown + pharmacological rescue; single lab","pmids":["21725360"],"is_preprint":false},{"year":2006,"finding":"GCN5 (yeast ortholog) is sumoylated at K25 in vivo; while sumoylation in vitro does not affect HAT activity, constitutive SUMO fusion to GCN5 N-terminus causes defective growth on 3-AT media and reduced transcription of SAGA-dependent gene TRP3.","method":"In vitro sumoylation assay, site-directed mutagenesis, SUMO-fusion expression, growth assay, reporter gene assay","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1–3 — in vitro sumoylation + mutagenesis + functional assay; effects are indirect (SUMO fusion)","pmids":["16411780"],"is_preprint":false},{"year":2014,"finding":"GCN5 physically interacts with CDK5 and acetylates it at Lys33 within the ATP binding domain; GCN5 and CDK5 co-localize at specific nuclear foci.","method":"Co-IP, fluorescent localization, LC-MS/MS identification of acetylation site","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP + MS site identification + co-localization; functional consequences of acetylation not fully defined","pmids":["24704205"],"is_preprint":false},{"year":2017,"finding":"KAT2A (GCN5) promotes BMSC-mediated angiogenesis by enhancing H3K9ac levels at the Vegf promoter; GCN5 declines in BMSCs from osteoporotic bone, reducing proangiogenic capacity; GCN5 overexpression by lentiviral vector restores angiogenesis in ovariectomized mice.","method":"ChIP (H3K9ac at Vegf promoter), siRNA knockdown, GCN5 overexpression, in vivo lentiviral rescue, tube formation assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP + KD/OE with functional readout; single lab","pmids":["28642327"],"is_preprint":false},{"year":2022,"finding":"KAT2A promotes HBV transcription by binding to cccDNA through interaction with HBV core protein (HBc), and catalyzes H3K79 succinylation on cccDNA-associated histones; KAT2A silencing specifically reduces cccDNA-bound succinylated H3K79 without affecting cccDNA production.","method":"ChIP-seq (cccDNA ChIP), Co-IP (KAT2A-HBc), siRNA knockdown, HBV-infected cell and mouse models","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP-seq + Co-IP; single lab but multiple methods","pmids":["35140694"],"is_preprint":false},{"year":2023,"finding":"KAT2A mediates succinylation of VCP at K658, inhibiting VCP-MFN1 interaction and suppressing mitophagy in BMSCs; TNF-α induces KAT2A expression, and KAT2A-mediated VCP succinylation impedes BMMSC quiescence.","method":"Co-IP, succinylation assay, site-directed mutagenesis (K658), mitophagy assays, in vivo fracture model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP + mutagenesis + functional mitophagy assay; single lab","pmids":["38145956"],"is_preprint":false},{"year":2023,"finding":"KAT2A promotes succinylation of PKM2 at K475 in gastric cancer cells, reducing PKM2 activity (not protein levels), thereby promoting glycolysis and cancer progression; KAT2A directly interacts with PKM2.","method":"Co-IP, immunofluorescence co-localization, succinylation immunoprecipitation, pyruvate kinase activity assay, site-directed mutagenesis (K475), rescue experiments","journal":"Molecular biotechnology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP + activity assay + mutagenesis + rescue; single lab","pmids":["37294531"],"is_preprint":false},{"year":2023,"finding":"KAT2A promotes succinylation of CTBP1 at K46 and K280; succinylation of CTBP1 suppresses its inhibitory activity on CDH1 transcription, promoting prostate cancer progression.","method":"Co-IP, succinylation assay, site-directed mutagenesis, luciferase reporter assay, in vivo xenograft","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP + mutagenesis + reporter assay; single lab","pmids":["36764210"],"is_preprint":false},{"year":2018,"finding":"GCN5 (KAT2A) acetylates influenza A virus nucleoprotein (NP) at K90 in vitro; GCN5 silencing decreases viral polymerase activity, while PCAF silencing (acetylating K31) increases it, indicating opposing roles of these acetyltransferases on NP function.","method":"In vitro acetyltransferase assay, MS identification of acetylation sites, RNAi knockdown, viral polymerase activity assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–3 — in vitro assay + MS + RNAi; functional consequence demonstrated but indirect","pmids":["29555684"],"is_preprint":false},{"year":2020,"finding":"KAT2A (GCN5) acts as a histone malonyltransferase: KAT2A knockdown reduces global histone malonylation levels; SIRT5 deacylase selectively removes malonylation from histones; H2B_K5 is a highly malonylated site regulated by SIRT5.","method":"siRNA knockdown of all 22 KATs, mass spectrometry, SIRT5 deacylase assay, malonyl-CoA supplementation","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — systematic KAT knockdown screen + MS; single lab, knockdown not reconstitution","pmids":["36879797"],"is_preprint":false},{"year":2020,"finding":"KAT2A stabilizes pluripotency gene regulatory networks in mouse embryonic stem cells by controlling transcriptional heterogeneity; Kat2a inhibition increases transcriptional variability of pluripotency-associated genes and accelerates mesendodermal differentiation.","method":"KAT2A inhibition (pharmacological), single-cell transcriptomics, gene regulatory network analysis, differentiation assays","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2–3 — pharmacological inhibition + single-cell transcriptomics; mechanism partly inferred","pmids":["30270482"],"is_preprint":false},{"year":2021,"finding":"KAT2A (GCN5) directly acetylates TUBA/α-tubulin, increasing microtubule stability; autophagic degradation of KAT2A reduces TUBA acetylation, and KAT2A accumulation (in Ulk1 KO VSMCs) increases acetylated TUBA, inhibiting directional migration and neointima formation.","method":"In vivo Ulk1 KO mouse + KAT2A siRNA rescue, western blot for acetyl-TUBA, migration assay, carotid artery ligation model","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — conditional KO + siRNA rescue + in vivo model; direct acetyltransferase assay for TUBA not shown in this paper","pmids":["33985412"],"is_preprint":false},{"year":2024,"finding":"KAT2A (Kat2a) promotes ferroptosis in diabetic cardiomyopathy by increasing H3K27ac and H3K9ac enrichment at the Tfrc and Hmox1 promoters, upregulating their expression; Kat2a expression itself is regulated post-transcriptionally by m6A methylation via ALKBH5 (demethylase) and YTHDF2 (m6A reader that promotes Kat2a mRNA degradation).","method":"ChIP-qPCR, siRNA knockdown, in vitro and in vivo DCM models, m6A methylation assays, RIP","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP + KD with phenotypic readout; single lab","pmids":["38858351"],"is_preprint":false},{"year":2022,"finding":"KAT2A (GCN5) suppresses NRF2 activity in macrophages, supporting H3K9 acetylation and limiting NRF2-mediated transcriptional repression of proinflammatory genes (Il1b, Nlrp3); KAT2A facilitates macrophage glycolysis reprogramming and licenses NLRP3 inflammasome activation.","method":"KAT2A siRNA and pharmacological inhibition (MB-3), ChIP (H3K9ac), NRF2 activity assay, collagen-induced arthritis mouse model, NLRP3 inflammasome activation assay","journal":"MedComm","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP + KD + in vivo model; single lab","pmids":["37313329"],"is_preprint":false},{"year":2024,"finding":"KAT2A promotes succinylation of PGAM1 at K161, regulating glycolysis in hepatocellular carcinoma; KAT2A directly interacts with PGAM1; astragaloside IV suppresses this KAT2A-PGAM1 succinylation axis.","method":"Co-IP, immunofluorescence, succinylation-IP, site-directed mutagenesis (K161), xenograft tumor model","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP + mutagenesis + in vivo model; single lab","pmids":["38835015"],"is_preprint":false},{"year":2020,"finding":"GCN5 (KAT2A) crystal structure of PCAF_N domain at 1.8 Å reveals a helical structure with a binuclear zinc region that constitutes a new class of E3 ligase fold; GCN5 exhibits ubiquitination activity supported by UbcH5.","method":"Crystal structure (1.8 Å), in vitro ubiquitination assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — crystal structure + in vitro assay; single lab, functional significance of E3 ligase activity not fully characterized","pmids":["32820047"],"is_preprint":false},{"year":2018,"finding":"GCN5 (KAT2A) interacts with ATM upon doxorubicin treatment in early drug-resistant leukemia cells; GCN5 facilitates ATM recruitment to DNA double-strand break sites, hyperactivating ATM and downstream repair factors (H2AX, NBS1, BRCA1, Chk2, Mcl-1), promoting DNA repair and cell survival; GCN5 inhibition reduces ATM activation.","method":"Co-IP (GCN5-ATM), ChIP (ATM at DSB sites), pharmacological inhibition, western blot, cell viability assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP + ChIP + pharmacological inhibition; single lab","pmids":["29297932"],"is_preprint":false},{"year":2022,"finding":"KAT2A cooperates with E2F1 and is recruited to the UBE2C promoter by E2F1, increasing H3K9 acetylation and UBE2C expression to promote cancer cell proliferation and migration.","method":"ChIP, Co-IP, immunofluorescence co-localization, RNA-seq, functional proliferation and migration assays","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP + Co-IP + functional assays; single lab","pmids":["36292703"],"is_preprint":false},{"year":2024,"finding":"GCN5 (KAT2A) deposits H3K9ac onto WNT gene promoters and enhancers (e.g., WNT7A, WNT7B, WNT10A, WNT4) as part of the E2F1/4-pRb/RBL2-GCN5 axis, regulating CSC self-renewal, chemoresistance, and invasiveness in pancreatic and breast cancer.","method":"Quantitative proteomics, ChIP, siRNA knockdown, functional assays in CSC models, epistasis analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — ChIP + KD + epistasis; single lab","pmids":["38678032"],"is_preprint":false},{"year":2017,"finding":"GCN5 (KAT2A) is required for expression of multiple FGF signaling pathway components during early embryoid body differentiation; Gcn5-null EBs show deficient ERK and p38 activation, cytoskeletal mislocalization, and impaired mesodermal differentiation; GCN5 directly targets four cMYC target genes among seven identified by genomic analysis.","method":"Gcn5 KO embryoid body system, ChIP-seq, gene expression analysis, signaling pathway assays","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — KO + ChIP-seq + signaling assays; multiple methods in single lab","pmids":["29249668"],"is_preprint":false},{"year":2023,"finding":"ALDOB enters the nucleus and interacts with KAT2A, leading to inhibition of H3K9 acetylation at the TGFB1 promoter, suppressing TGF-β1 transcription; ALDOB deficiency releases this suppression, increasing TGF-β and enabling immune evasion in HCC.","method":"Nuclear fractionation, Co-IP (ALDOB-KAT2A), ChIP (H3K9ac at TGFB1 promoter), KAT2A small molecule inhibition, in vivo tumor models","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2–3 — nuclear Co-IP + ChIP + pharmacological inhibition; single lab","pmids":["38051951"],"is_preprint":false}],"current_model":"KAT2A (GCN5) is a lysine acetyltransferase and acyltransferase that functions as the catalytic subunit of the SAGA and ATAC transcriptional coactivator complexes, where partner subunits (especially Ada2) allosterically enhance its activity by promoting acetyl-CoA binding; it acetylates histone H3 (primarily K9, K14, K18, K27, K79) and histone variant H2A.Z.1 to promote chromatin accessibility and gene activation, succinylates H3K79 in partnership with nuclear α-KGDH complex, lactylates H3 in partnership with nuclear ACSS2, and acetylates diverse non-histone substrates including TFEB, EGR2, CDK5, α-tubulin, and influenza NP, with its own stability and activity regulated by autophagy (via an LIR domain), sumoylation, and complex assembly, making it a central integrator of metabolic signals (acetyl-CoA, succinyl-CoA, lactyl-CoA) with chromatin-based gene regulation in development, immunity, and cancer."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing that GCN5 and ADA2 form a physical complex that functions together in transcriptional activation answered how GCN5 is organized within coactivator machinery, laying the foundation for understanding SAGA-type complexes.","evidence":"Two-hybrid, co-immunoprecipitation, and double-mutant epistasis in yeast","pmids":["7957049"],"confidence":"High","gaps":["Stoichiometry and full subunit composition of the native complex unknown at this stage","Mechanism by which Ada2 stimulates GCN5 activity not addressed"]},{"year":2000,"claim":"Demonstrating that Gcn5l2 knockout is embryonic lethal with dorsal mesoderm failure established KAT2A as an essential developmental gene and revealed functional overlap with PCAF.","evidence":"Germline and conditional knockout mice; double Gcn5l2/Pcaf nulls","pmids":["11017084"],"confidence":"High","gaps":["Target genes and histone marks responsible for the mesoderm phenotype unidentified","Cell-type autonomy of KAT2A requirement in mesoderm not resolved"]},{"year":2001,"claim":"Showing that E2F transcription factors recruit KAT2A/TRRAP and require GCN5 catalytic activity for transactivation identified a key transcription-factor-dependent recruitment mechanism.","evidence":"Co-IP, catalytic mutant, and transactivation assays in human cells","pmids":["11418595"],"confidence":"High","gaps":["Genome-wide target sites of E2F-GCN5 co-occupancy not mapped","Whether E2F recruits SAGA vs. ATAC complex not distinguished"]},{"year":2003,"claim":"Crystal structures of Gcn5 with histone H4 and p53 peptides defined how the HAT domain accommodates divergent substrates through a common lysine-binding mechanism with variable N-terminal contacts, explaining both histone and non-histone substrate recognition.","evidence":"X-ray crystallography of Tetrahymena Gcn5 with peptide substrates plus in vitro acetyltransferase assays","pmids":["14661947"],"confidence":"High","gaps":["Structures with nucleosomal substrates lacking","Selectivity determinants within full-length human KAT2A not addressed"]},{"year":2008,"claim":"Biochemical purification resolved KAT2A as a shared catalytic subunit of two distinct human complexes—STAGA/SAGA and ATAC—with different subunit compositions and transcriptional roles, clarifying the organizational logic of GCN5-containing coactivators.","evidence":"Tandem affinity purification, mass spectrometry, co-IP, and in vitro transcription from human cells","pmids":["18838386"],"confidence":"High","gaps":["How cells partition KAT2A between SAGA and ATAC not understood","Genomic loci preferentially regulated by ATAC vs. SAGA not distinguished"]},{"year":2014,"claim":"Revealing that the GCN5 bromodomain reads its own H3K14ac product to license H3K18ac established an intra-molecular reader-writer crosstalk that orders multi-site acetylation on H3.","evidence":"Quantitative mass spectrometry and in vitro HAT assays with bromodomain-mutant ADA subcomplex","pmids":["25106422"],"confidence":"High","gaps":["In vivo relevance of sequential acetylation on chromatin not tested","Whether this crosstalk operates similarly within ATAC and SAGA not compared"]},{"year":2017,"claim":"Discovery that KAT2A functions as a histone succinyltransferase—with α-KGDH supplying nuclear succinyl-CoA and Y645 determining acyl-CoA selectivity—expanded the enzyme's catalytic repertoire beyond acetylation and linked metabolic intermediates to epigenetic marks.","evidence":"2.3 Å crystal structure with succinyl-CoA, Y645A mutagenesis, in vitro succinylation, ChIP, and tumor models","pmids":["29211711"],"confidence":"High","gaps":["How succinyl-CoA nuclear availability is regulated not fully understood","Genome-wide distribution of H3K79 succinylation beyond candidate loci not mapped"]},{"year":2017,"claim":"Conditional T cell–specific Gcn5 knockout and iNKT studies showed KAT2A is required for IL-2 transcription (via NFAT-directed H3K9ac at the Il2 promoter) and for iNKT cell development (via EGR2 acetylation), establishing cell-type-specific immune functions.","evidence":"Conditional Lck-Cre KO mice, ChIP, co-IP, in vitro acetyltransferase assays, and cytokine/differentiation assays","pmids":["28424240","28723564"],"confidence":"High","gaps":["Downstream EGR2 acetylation sites' structural effects unresolved","Relative contributions of SAGA vs. ATAC in T cell gene regulation unknown"]},{"year":2018,"claim":"Structural determination of the Ada2 SANT domain–Gcn5 interface showed Ada2 allosterically enhances acetyl-CoA binding rather than histone substrate binding, resolving a long-standing question about how complex assembly activates the catalytic subunit.","evidence":"Fab-assisted crystal structure of yeast Ada2/Gcn5 complex plus biochemical binding and HAT assays","pmids":["30224453"],"confidence":"High","gaps":["Whether the same allosteric mechanism operates in human ADA2a vs. ADA2b paralog contexts not tested","Structural basis for the stronger stimulation by ADA2b than ADA2a not explained"]},{"year":2019,"claim":"Multiple studies converged to show KAT2A acetylates non-histone substrates—TFEB (inhibiting autophagy/lysosome gene transcription), α-tubulin (stabilizing microtubules), and H2A.Z.1 (licensing promoter activation via BRD2 recruitment)—demonstrating breadth of substrate scope in distinct cellular contexts.","evidence":"In vitro acetyltransferase assays, mutagenesis, co-IP, ChIP, Drosophila genetics, and cell migration assays","pmids":["31750630","31878840","31527837"],"confidence":"High","gaps":["Full acetylome of KAT2A not systematically catalogued","Structural basis for H2A.Z.1 vs. H2A.Z.2 discrimination not resolved at atomic level"]},{"year":2019,"claim":"Identification of the LIR domain in KAT2A revealed that autophagy directly degrades KAT2A via LC3 interaction, establishing a post-translational regulatory axis that links cellular stress to KAT2A protein levels and tubulin acetylation.","evidence":"LIR domain mutagenesis, autophagy flux assays, ULK1 KO mice with KAT2A siRNA rescue, neointima models","pmids":["31878840","33985412"],"confidence":"High","gaps":["Whether autophagy-mediated degradation affects nuclear KAT2A pools and histone acetylation equally","Ubiquitin signals directing KAT2A to autophagosomes not identified"]},{"year":2020,"claim":"Conditional Kat2a loss in AML reduced transcriptional burst frequency and increased gene expression variability, shifting leukemia stem cells toward differentiation—providing a mechanistic explanation for KAT2A's role in maintaining malignant self-renewal programs.","evidence":"Conditional KO in AML, ChIP-seq, ATAC-seq, single-cell RNA-seq","pmids":["31985402"],"confidence":"High","gaps":["Which specific KAT2A-deposited marks (H3K9ac vs. others) are rate-limiting for burst frequency unknown","Whether transcriptional noise phenotype is shared across solid tumors not tested"]},{"year":2020,"claim":"Crystal structure of the KAT2A N-terminal PCAF_N domain revealed a novel E3 ubiquitin ligase fold with a binuclear zinc region, supported by in vitro ubiquitination activity, suggesting a dual enzymatic function beyond acyltransferase activity.","evidence":"1.8 Å crystal structure plus in vitro ubiquitination assay with UbcH5","pmids":["32820047"],"confidence":"Medium","gaps":["Physiological substrates of the E3 ligase activity not identified","In vivo relevance of ubiquitination activity not demonstrated","Independent validation of E3 ligase function needed"]},{"year":2023,"claim":"A series of studies showed KAT2A succinylates non-histone substrates (VCP-K658, PKM2-K475, CTBP1-K46/K280, PGAM1-K161) to modulate mitophagy, glycolysis, and transcriptional repression, extending the succinyltransferase function well beyond histones.","evidence":"Co-IP, site-directed mutagenesis at target lysines, enzymatic activity assays, and xenograft models across multiple cancer cell types","pmids":["38145956","37294531","36764210","38835015"],"confidence":"Medium","gaps":["Most findings from single laboratories awaiting independent replication","Selectivity rules for succinylation vs. acetylation of non-histone substrates not defined","In vitro reconstitution with purified proteins not shown for all substrates"]},{"year":2024,"claim":"Discovery that ACSS2 generates lactyl-CoA and partners with KAT2A to lactylate histone H3—regulated by EGFR-ERK signaling—added a third acyl-CoA species to KAT2A's catalytic repertoire, linking growth-factor signaling to a new epigenetic mark.","evidence":"Co-crystal structure of KAT2A with lactyl-CoA, co-IP, in vitro lactylation, ERK phosphorylation assay, tumor and immune models","pmids":["39561764"],"confidence":"High","gaps":["Genome-wide distribution of KAT2A-dependent histone lactylation not mapped","Whether lactylation and succinylation compete at the same active site under physiological conditions not tested"]},{"year":null,"claim":"How KAT2A partitions among acetyl-CoA, succinyl-CoA, and lactyl-CoA acylation reactions in vivo—and how metabolic flux, complex assembly (SAGA vs. ATAC), and post-translational modifications (sumoylation, autophagic degradation) combinatorially control substrate and acyl-donor selectivity—remains an open integrative question.","evidence":"","pmids":[],"confidence":"Low","gaps":["No systematic in vivo quantification of the relative acylation outputs","Structural basis for SAGA-ATAC differential targeting still incomplete","Full spectrum of KAT2A-dependent acylation marks across the proteome and chromatin not catalogued"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,6,7,8,11,13,16,21,30,31,32,33,34,39]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,6,7,8,11,13,16,21,34]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1,7,8,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,9,10,15,17,22,24]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4,9,10,15,22,27]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,7,9,21,22]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,7,8,21,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,9,10,15,17,22,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,44]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,16,38]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[11,13,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,12,31,39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[22,23,24,43]}],"complexes":["SAGA (STAGA)","ATAC"],"partners":["ADA2A","ADA2B","TRRAP","E2F1","NFAT","ACSS2","TFEB","EGR2"],"other_free_text":[]},"mechanistic_narrative":"KAT2A (GCN5) is a versatile lysine acyltransferase that serves as the catalytic subunit of the SAGA and ATAC coactivator complexes, integrating metabolic acyl-CoA pools with chromatin-based gene regulation in development, immunity, and cancer. Within these complexes, the Ada2 subunit allosterically enhances KAT2A activity by promoting acetyl-CoA binding [PMID:30224453], and KAT2A acetylates histone H3 primarily at K9 and K14—with its bromodomain reading H3K14ac to license subsequent H3K18ac—as well as histone variant H2A.Z.1 [PMID:25106422, PMID:31527837]. Beyond acetylation, KAT2A functions as a succinyltransferase (H3K79 succinylation via nuclear α-KGDH-supplied succinyl-CoA, controlled by active-site residue Y645) and as a lactyltransferase (histone H3 lactylation using lactyl-CoA generated by nuclear ACSS2), and it acylates non-histone substrates including TFEB, α-tubulin, EGR2, VCP, PKM2, and influenza NP [PMID:29211711, PMID:39561764, PMID:31750630, PMID:31878840, PMID:28723564, PMID:38145956]. KAT2A is essential for mouse embryogenesis—loss causes dorsal mesoderm failure and extensive apoptosis—and in the immune system it is required for IL-2-driven T cell responses and iNKT cell development; its stability is regulated by autophagy through a conserved LIR domain [PMID:11017084, PMID:28424240, PMID:31878840]."},"prefetch_data":{"uniprot":{"accession":"Q92830","full_name":"Histone acetyltransferase KAT2A","aliases":["General control of amino acid synthesis protein 5-like 2","Histone acetyltransferase GCN5","hGCN5","Histone glutaryltransferase KAT2A","Histone succinyltransferase KAT2A","Lysine acetyltransferase 2A","STAF97"],"length_aa":837,"mass_kda":93.9,"function":"Protein lysine acyltransferase that can act as a acetyltransferase, glutaryltransferase, succinyltransferase or malonyltransferase, depending on the context (PubMed:29211711, PubMed:35995428). Acts as a histone lysine succinyltransferase: catalyzes succinylation of histone H3 on 'Lys-79' (H3K79succ), with a maximum frequency around the transcription start sites of genes (PubMed:29211711). Succinylation of histones gives a specific tag for epigenetic transcription activation (PubMed:29211711). Association with the 2-oxoglutarate dehydrogenase complex, which provides succinyl-CoA, is required for histone succinylation (PubMed:29211711). In different complexes, functions either as an acetyltransferase (HAT) or as a succinyltransferase: in the SAGA and ATAC complexes, acts as a histone acetyltransferase (PubMed:17301242, PubMed:19103755, PubMed:29211711). Has significant histone acetyltransferase activity with core histones, but not with nucleosome core particles (PubMed:17301242, PubMed:19103755, PubMed:21131905). Has a a strong preference for acetylation of H3 at 'Lys-9' (H3K9ac) (PubMed:21131905). Also catalyzes acetylation of histone H1.4 (H1-4) at 'Lys-34' (H1.4K34ac), a modification enriched at promoters of active genes (PubMed:22465951). Acetylation of histones gives a specific tag for epigenetic transcription activation (PubMed:17301242, PubMed:19103755, PubMed:29211711). Recruited by the XPC complex at promoters, where it specifically mediates acetylation of histone variant H2A.Z.1/H2A.Z, thereby promoting expression of target genes (PubMed:29973595, PubMed:31527837). Involved in long-term memory consolidation and synaptic plasticity: acts by promoting expression of a hippocampal gene expression network linked to neuroactive receptor signaling (By similarity). Acts as a positive regulator of T-cell activation: upon TCR stimulation, recruited to the IL2 promoter following interaction with NFATC2 and catalyzes acetylation of histone H3 at 'Lys-9' (H3K9ac), leading to promote IL2 expression (By similarity). Required for growth and differentiation of craniofacial cartilage and bone by regulating acetylation of histone H3 at 'Lys-9' (H3K9ac) (By similarity). Regulates embryonic stem cell (ESC) pluripotency and differentiation (By similarity). Also acetylates non-histone proteins, such as CEBPB, MRE11, PPARGC1A, PLK4 and TBX5 (PubMed:16753578, PubMed:17301242, PubMed:27796307, PubMed:29174768, PubMed:38128537). Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5 (PubMed:29174768). Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4 (PubMed:27796307). Acts as a negative regulator of gluconeogenesis by mediating acetylation and subsequent inactivation of PPARGC1A (PubMed:16753578, PubMed:23142079). Also acts as a histone glutaryltransferase: catalyzes glutarylation of histone H4 on 'Lys-91' (H4K91glu), a mark that destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes (PubMed:31542297) (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes","subcellular_location":"Nucleus; Chromosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q92830/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KAT2A","classification":"Not Classified","n_dependent_lines":161,"n_total_lines":1208,"dependency_fraction":0.13327814569536423},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TAF12","stoichiometry":10.0},{"gene":"TRRAP","stoichiometry":10.0},{"gene":"ENY2","stoichiometry":0.2},{"gene":"SF3B3","stoichiometry":0.2},{"gene":"SF3B5","stoichiometry":0.2},{"gene":"USP22","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KAT2A","total_profiled":1310},"omim":[{"mim_id":"617989","title":"N-ALPHA-ACETYLTRANSFERASE 30, NatC CATALYTIC SUBUNIT; NAA30","url":"https://www.omim.org/entry/617989"},{"mim_id":"617501","title":"LYSINE ACETYLTRANSFERASE 14; KAT14","url":"https://www.omim.org/entry/617501"},{"mim_id":"616510","title":"GLUCOSAMINE-PHOSPHATE N-ACETYLTRANSFERASE 1; GNPNAT1","url":"https://www.omim.org/entry/616510"},{"mim_id":"615556","title":"ALPHA-TUBULIN ACETYLTRANSFERASE 1; ATAT1","url":"https://www.omim.org/entry/615556"},{"mim_id":"613374","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 101; CCDC101","url":"https://www.omim.org/entry/613374"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KAT2A"},"hgnc":{"alias_symbol":["GCN5","PCAF-b"],"prev_symbol":["GCN5L2"]},"alphafold":{"accession":"Q92830","domains":[{"cath_id":"-","chopping":"98-127_142-212","consensus_level":"medium","plddt":92.6009,"start":98,"end":212},{"cath_id":"-","chopping":"232-369","consensus_level":"medium","plddt":91.1923,"start":232,"end":369},{"cath_id":"3.40.630.30","chopping":"487-667","consensus_level":"high","plddt":91.3093,"start":487,"end":667},{"cath_id":"1.20.920.10","chopping":"731-833","consensus_level":"high","plddt":92.6239,"start":731,"end":833}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92830","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92830-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92830-F1-predicted_aligned_error_v6.png","plddt_mean":77.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KAT2A","jax_strain_url":"https://www.jax.org/strain/search?query=KAT2A"},"sequence":{"accession":"Q92830","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92830.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92830/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92830"}},"corpus_meta":[{"pmid":"29211711","id":"PMC_29211711","title":"KAT2A 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Crystal structure of KAT2A catalytic domain in complex with succinyl-CoA at 2.3 Å shows succinyl-CoA binds a deep cleft with the succinyl moiety pointing toward a flexible loop 3; Y645 in this loop determines selective binding of succinyl-CoA over acetyl-CoA. KAT2A succinylates histone H3K79 near transcription start sites, promoting gene expression and tumor cell proliferation.\",\n      \"method\": \"Crystal structure (2.3 Å), site-directed mutagenesis (Y645A), in vitro succinylation assay, ChIP, nuclear fractionation, cell proliferation and tumor growth assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure + mutagenesis + in vitro assay + in vivo functional validation in a single high-impact study\",\n      \"pmids\": [\"29211711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ACSS2 functions as a lactyl-CoA synthetase that converts lactate to lactyl-CoA; it forms a complex with KAT2A after EGFR-ERK-mediated S267 phosphorylation and nuclear translocation. KAT2A then acts as a lactyltransferase to lactylate histone H3, driving Wnt/β-catenin, NF-κB, and PD-L1 expression. Co-crystal structure demonstrates lactyl-CoA binding to KAT2A.\",\n      \"method\": \"Co-crystal structure, Co-IP, in vitro lactylation assay, ERK phosphorylation assay, tumor growth and immune evasion models\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — co-crystal structure + biochemical reconstitution + mutagenesis + in vivo validation\",\n      \"pmids\": [\"39561764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"GCN5 (KAT2A yeast ortholog) physically interacts with ADA2 in a heteromeric complex that mediates transcriptional activation; double-mutant studies show ADA2 and GCN5 function together in the same complex or pathway. The GCN5 bromodomain is functionally important for a general activity of transcription factors but is not required for the GCN5-ADA2 interaction.\",\n      \"method\": \"Two-hybrid assay, co-immunoprecipitation, double-mutant epistasis analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP + epistasis; foundational study replicated extensively\",\n      \"pmids\": [\"7957049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Gcn5l2 (mouse ortholog of KAT2A) is essential for embryogenesis: knockout embryos die with failure to form dorsal mesoderm (chordamesoderm and paraxial mesoderm) and exhibit extensive apoptosis; Pcaf-null mice are viable, but Gcn5l2/Pcaf double nulls are more severely affected, indicating overlapping functions.\",\n      \"method\": \"Conditional and germline knockout mouse (null embryos), histology, apoptosis assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knockout with defined developmental phenotype, replicated with double-KO epistasis\",\n      \"pmids\": [\"11017084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human KAT2A (GCN5) is a subunit of two distinct multiprotein complexes: STAGA (~2 MDa, containing SPT3, TAF9, TRRAP) and ATAC (~700 kDa, containing ADA2a, ADA3, STAF36, WDR5, POLE3/CHRAC17, POLE4, TAK1/MAP3K7, MBIP, YEATS2-NC2β). The ATAC YEATS2-NC2β module interacts with TBP and negatively regulates transcription when recruited to a promoter.\",\n      \"method\": \"Biochemical purification, mass spectrometry, Co-IP, in vitro transcription assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical purification + MS interactome + functional validation; foundational complex characterization\",\n      \"pmids\": [\"18838386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Ada2 SANT domain activates Gcn5 HAT activity by enhancing Gcn5 binding to the enzymatic cosubstrate acetyl-CoA, rather than by affecting histone peptide binding. Crystal structures of the yeast Ada2/Gcn5 complex with Fab chaperones reveal the structural basis of this allosteric mechanism.\",\n      \"method\": \"Crystal structure (Fab-assisted crystallization), biochemical HAT assays, binding measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure + biochemical reconstitution + mutagenesis\",\n      \"pmids\": [\"30224453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structures of Tetrahymena Gcn5 bound to histone H4 and p53 peptides reveal that the Gcn5/PCAF HAT family accommodates divergent substrates by using analogous interactions with the target lysine and two C-terminal residues, while N-terminal substrate residues provide enhanced affinity for histone H3 specifically.\",\n      \"method\": \"X-ray crystallography, in vitro acetyltransferase assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple crystal structures with functional validation, defining substrate selectivity mechanism\",\n      \"pmids\": [\"14661947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The bromodomain of Gcn5 regulates site specificity of HAT activity on histone H3: bromodomain-mutant ADA subcomplex (Gcn5-Ada2-Ada3) shows severely diminished H3K18ac; H3K14ac by Gcn5 and subsequent bromodomain binding to H3K14ac are prerequisite steps for H3K18ac, revealing cross-talk between the Gcn5 reader and writer functions.\",\n      \"method\": \"Quantitative mass spectrometry, acid-urea gel, in vitro HAT assays with wild-type and bromodomain mutant complexes\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro HAT assay + mutagenesis + quantitative MS, multiple orthogonal methods\",\n      \"pmids\": [\"25106422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Subunits of either ATAC (ADA2a-containing) or SAGA (ADA2b-containing) HAT modules stimulate GCN5 acetyltransferase activity on histone H3, primarily at H3K14; ADA2b has a stronger stimulatory effect than ADA2a; incorporation of HAT modules into holo-complexes further increases activity without changing lysine specificity.\",\n      \"method\": \"In vitro HAT assays with purified recombinant and endogenous complexes, histone peptide and full-length histone substrates\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro assays with defined recombinant and endogenous complexes\",\n      \"pmids\": [\"26468280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GCN5 (KAT2A) is recruited by c-Myc to RNA polymerase III-transcribed genes (tRNA, 5S rRNA) together with TRRAP, leading to selective H3 (but not H4) hyperacetylation, increased TFIIIB occupancy, and transcriptional induction.\",\n      \"method\": \"ChIP, inducible Myc system, ChIP-qPCR, RT-PCR\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with inducible system demonstrating temporal recruitment and histone acetylation linked to Pol III activation\",\n      \"pmids\": [\"17848523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"E2F-1 and E2F-4 transactivation domains bind KAT2A (GCN5) and cofactor TRRAP in vivo; catalytically active GCN5 is required for E2F-mediated transactivation and histone acetyltransferase activity recruited by E2F-4 in vivo.\",\n      \"method\": \"Co-IP, transactivation assays, HAT activity assays with wild-type and catalytic mutants, domain-mapping mutations\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP + catalytic mutant + functional transactivation assay\",\n      \"pmids\": [\"11418595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KAT2A (GCN5) acetylates TFEB (master transcription factor for autophagy/lysosome genes) at K274 and K279, reducing TFEB transcriptional activity by disrupting TFEB dimerization and promoter binding; autophagy induction inactivates GCN5 and reduces TFEB acetylation, increasing lysosome formation.\",\n      \"method\": \"In vitro acetyltransferase assay, Co-IP, site-directed mutagenesis, autophagy flux assays, Drosophila genetic model\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro acetyltransferase assay + mutagenesis + genetic validation in Drosophila + mechanistic epistasis\",\n      \"pmids\": [\"31750630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KAT2A mediates H3K79 succinylation at the YWHAZ (14-3-3ζ) promoter to upregulate 14-3-3ζ expression; KAT2A Y645A (succinyltransferase-defective) mutant reduces H3K79 succinylation and 14-3-3ζ levels, leading to decreased β-catenin stability and reduced glycolysis and proliferation in pancreatic cancer cells.\",\n      \"method\": \"ChIP-qPCR, site-directed mutagenesis (Y645A), immunoprecipitation, western blot, cell proliferation and glycolysis assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — activity-dead mutant + ChIP mechanistic link + functional phenotype\",\n      \"pmids\": [\"31610265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KAT2A (GCN5) directly acetylates α-tubulin (TUBA) in vascular smooth muscle cells; autophagic degradation of KAT2A via a conserved LC3-interacting region (LIR) domain reduces TUBA acetylation, destabilizes microtubules, and promotes directional VSMC migration.\",\n      \"method\": \"Co-IP, GST pulldown, LIR domain mutagenesis, autophagy flux assays, cell migration assays, in vitro acetyltransferase assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro acetyltransferase assay + LIR domain mutagenesis + functional migration phenotype\",\n      \"pmids\": [\"31878840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ULK1 deletion inhibits autophagic degradation of KAT2A, causing KAT2A accumulation, increased α-tubulin acetylation, microtubule stabilization, and inhibition of VSMC directional migration and neointima formation; local KAT2A siRNA in ulk1 KO mice reverses the protective effect.\",\n      \"method\": \"Vascular smooth muscle cell-specific Ulk1 KO mouse, carotid artery ligation model, KAT2A siRNA, western blot, immunofluorescence, migration assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO + rescue siRNA + in vivo neointima model\",\n      \"pmids\": [\"33985412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GCN5 (KAT2A) is recruited to the il-2 promoter by interacting with NFAT upon TCR stimulation in T cells, catalyzing H3K9 acetylation (not NFAT acetylation directly) to promote IL-2 transcription; conditional T cell-specific Gcn5 KO impairs IL-2 production, T cell proliferation, and Th1/Th17 differentiation.\",\n      \"method\": \"Conditional Lck-Cre Gcn5 KO mouse, ChIP, Co-IP (GCN5-NFAT), T cell proliferation and cytokine assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO + ChIP + Co-IP demonstrating mechanism\",\n      \"pmids\": [\"28424240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GCN5 (KAT2A) is the specific lysine acetyltransferase of EGR2 transcription factor; GCN5-mediated acetylation positively regulates EGR2 transcriptional activity, and this activity is required for iNKT cell development through Runx1, PLZF, IL-2Rβ, and T-bet transcription.\",\n      \"method\": \"In vitro acetyltransferase assay, Co-IP, conditional KO mouse, pharmacological GCN5 inhibition, gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro acetyltransferase + conditional KO + pharmacological inhibition with phenotypic readout\",\n      \"pmids\": [\"28723564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"GCN5 directly binds TGF-β-specific R-Smads and BMP-specific R-Smads (the latter unlike PCAF), acts as a transcriptional coactivator enhancing TGF-β and BMP signaling-induced transcription; GCN5 knockdown by RNAi represses TGF-β-induced transcriptional activity.\",\n      \"method\": \"Biochemical purification from nuclear extract using Smad-binding DNA element, Co-IP, reporter gene assays, RNAi knockdown\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP + functional reporter + RNAi, single lab\",\n      \"pmids\": [\"15009097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The lncRNA GClnc1 acts as a molecular scaffold bridging WDR5 and KAT2A complexes, coordinating their localization to target gene promoters (including SOD2) and specifying the histone modification pattern to promote gastric cancer cell biology.\",\n      \"method\": \"RNA immunoprecipitation, Co-IP, ChIP, RNA pulldown, functional assays in gastric cancer models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RIP + ChIP + Co-IP; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"27147598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"lncRNA PVT1 serves as a scaffold for KAT2A, enabling KAT2A-mediated H3K9 acetylation at the NF90 promoter, which recruits TIF1β to activate NF90 transcription and increase HIF-1α stability; KAT2A acetyltransferase activity-deficient mutants fail to promote PVT1-mediated NPC cell proliferation.\",\n      \"method\": \"RNA-IP, ChIP, KAT2A catalytic mutant expression, siRNA knockdown, rescue experiments, xenograft model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — catalytic mutant + ChIP + RIP; single lab\",\n      \"pmids\": [\"31320749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GCN5 (Drosophila ortholog) acetylates the nucleosome remodeling ATPase ISWI at K753 (equivalent to H3K14) in vivo and in vitro; the target sequence on ISWI is similar to the H3 N-terminus recognized by GCN5, suggesting co-regulation of a remodeler and its substrate through related epitopes.\",\n      \"method\": \"In vitro acetyltransferase assay, mass spectrometry, immunoprecipitation, site-directed mutagenesis\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro assay + MS identification of site + mutagenesis; Drosophila ortholog\",\n      \"pmids\": [\"17760996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KAT2A (GCN5) acetylates histone variant H2A.Z.1 (but not H2A.Z.2, due to alanine-14 in H2A.Z.2 inhibiting KAT2A activity) at promoters of transactivated genes; the DNA repair complex XPC-RAD23-CEN2 interacts with H2A.Z and KAT2A to recruit KAT2A to promoters and license H2A.Z.1 acetylation, which then recruits BRD2 to promote RNA Pol II recruitment.\",\n      \"method\": \"In vitro acetyltransferase assay, Co-IP, ChIP, H2A.Z.1 acetylation-deficient mutant, RNAi knockdown\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro HAT assay defining specificity + Co-IP + ChIP + non-acetylable mutant functional validation\",\n      \"pmids\": [\"31527837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Kat2a loss in AML cells reduces transcriptional burst frequency at a subset of gene promoters, generating enhanced transcriptional variability; this destabilization of target gene programs shifts leukemia cell fate from self-renewal to differentiation, depleting leukemia stem-like cells.\",\n      \"method\": \"Conditional Kat2a knockout mouse, chromatin profiling (ChIP-seq, ATAC-seq), single-cell RNA-seq, transcription factor binding analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO + multiple orthogonal genomic methods + single-cell transcriptomics\",\n      \"pmids\": [\"31985402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KAT2A (GCN5) histone acetyltransferase maintains ATRA resistance in non-APL AML via aberrant H3K9 acetylation, sustaining stemness and leukemia-associated gene expression; GCN5 inhibition combined with LSD1 inhibition unlocks ATRA-driven differentiation across most non-APL AML subtypes.\",\n      \"method\": \"Pharmacological GCN5 inhibition, ChIP (H3K9ac), gene expression analysis, differentiation assays, in vivo models\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pharmacological inhibition + ChIP mechanistic link; single lab\",\n      \"pmids\": [\"31576004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GCN5 (KAT2A) promotes transcription of MYC-induced cell-cycle genes as an essential coactivator; deletion of Gcn5 in the Eμ-Myc B-cell lymphoma mouse model delays or abrogates tumorigenesis and reduces Myc expression and downstream functions.\",\n      \"method\": \"Conditional Gcn5 KO in Eμ-Myc mouse model, ChIP-seq, gene expression analysis, survival studies\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO in cancer model + ChIP-seq; multiple methods\",\n      \"pmids\": [\"33168647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"And-1 (acidic nucleoplasmic DNA-binding protein) forms a complex with both histone H3 and GCN5, stabilizing GCN5 protein; And-1 knockdown causes GCN5 proteasomal degradation, reducing H3K9 and H3K56 acetylation; And-1 overexpression stabilizes GCN5 through protein-protein interactions.\",\n      \"method\": \"Co-IP, siRNA knockdown, western blot (H3K9ac, H3K56ac), proteasome inhibitor rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP + knockdown + pharmacological rescue; single lab\",\n      \"pmids\": [\"21725360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GCN5 (yeast ortholog) is sumoylated at K25 in vivo; while sumoylation in vitro does not affect HAT activity, constitutive SUMO fusion to GCN5 N-terminus causes defective growth on 3-AT media and reduced transcription of SAGA-dependent gene TRP3.\",\n      \"method\": \"In vitro sumoylation assay, site-directed mutagenesis, SUMO-fusion expression, growth assay, reporter gene assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–3 — in vitro sumoylation + mutagenesis + functional assay; effects are indirect (SUMO fusion)\",\n      \"pmids\": [\"16411780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GCN5 physically interacts with CDK5 and acetylates it at Lys33 within the ATP binding domain; GCN5 and CDK5 co-localize at specific nuclear foci.\",\n      \"method\": \"Co-IP, fluorescent localization, LC-MS/MS identification of acetylation site\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP + MS site identification + co-localization; functional consequences of acetylation not fully defined\",\n      \"pmids\": [\"24704205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KAT2A (GCN5) promotes BMSC-mediated angiogenesis by enhancing H3K9ac levels at the Vegf promoter; GCN5 declines in BMSCs from osteoporotic bone, reducing proangiogenic capacity; GCN5 overexpression by lentiviral vector restores angiogenesis in ovariectomized mice.\",\n      \"method\": \"ChIP (H3K9ac at Vegf promoter), siRNA knockdown, GCN5 overexpression, in vivo lentiviral rescue, tube formation assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP + KD/OE with functional readout; single lab\",\n      \"pmids\": [\"28642327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KAT2A promotes HBV transcription by binding to cccDNA through interaction with HBV core protein (HBc), and catalyzes H3K79 succinylation on cccDNA-associated histones; KAT2A silencing specifically reduces cccDNA-bound succinylated H3K79 without affecting cccDNA production.\",\n      \"method\": \"ChIP-seq (cccDNA ChIP), Co-IP (KAT2A-HBc), siRNA knockdown, HBV-infected cell and mouse models\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP-seq + Co-IP; single lab but multiple methods\",\n      \"pmids\": [\"35140694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KAT2A mediates succinylation of VCP at K658, inhibiting VCP-MFN1 interaction and suppressing mitophagy in BMSCs; TNF-α induces KAT2A expression, and KAT2A-mediated VCP succinylation impedes BMMSC quiescence.\",\n      \"method\": \"Co-IP, succinylation assay, site-directed mutagenesis (K658), mitophagy assays, in vivo fracture model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP + mutagenesis + functional mitophagy assay; single lab\",\n      \"pmids\": [\"38145956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KAT2A promotes succinylation of PKM2 at K475 in gastric cancer cells, reducing PKM2 activity (not protein levels), thereby promoting glycolysis and cancer progression; KAT2A directly interacts with PKM2.\",\n      \"method\": \"Co-IP, immunofluorescence co-localization, succinylation immunoprecipitation, pyruvate kinase activity assay, site-directed mutagenesis (K475), rescue experiments\",\n      \"journal\": \"Molecular biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP + activity assay + mutagenesis + rescue; single lab\",\n      \"pmids\": [\"37294531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KAT2A promotes succinylation of CTBP1 at K46 and K280; succinylation of CTBP1 suppresses its inhibitory activity on CDH1 transcription, promoting prostate cancer progression.\",\n      \"method\": \"Co-IP, succinylation assay, site-directed mutagenesis, luciferase reporter assay, in vivo xenograft\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP + mutagenesis + reporter assay; single lab\",\n      \"pmids\": [\"36764210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GCN5 (KAT2A) acetylates influenza A virus nucleoprotein (NP) at K90 in vitro; GCN5 silencing decreases viral polymerase activity, while PCAF silencing (acetylating K31) increases it, indicating opposing roles of these acetyltransferases on NP function.\",\n      \"method\": \"In vitro acetyltransferase assay, MS identification of acetylation sites, RNAi knockdown, viral polymerase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–3 — in vitro assay + MS + RNAi; functional consequence demonstrated but indirect\",\n      \"pmids\": [\"29555684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KAT2A (GCN5) acts as a histone malonyltransferase: KAT2A knockdown reduces global histone malonylation levels; SIRT5 deacylase selectively removes malonylation from histones; H2B_K5 is a highly malonylated site regulated by SIRT5.\",\n      \"method\": \"siRNA knockdown of all 22 KATs, mass spectrometry, SIRT5 deacylase assay, malonyl-CoA supplementation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic KAT knockdown screen + MS; single lab, knockdown not reconstitution\",\n      \"pmids\": [\"36879797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KAT2A stabilizes pluripotency gene regulatory networks in mouse embryonic stem cells by controlling transcriptional heterogeneity; Kat2a inhibition increases transcriptional variability of pluripotency-associated genes and accelerates mesendodermal differentiation.\",\n      \"method\": \"KAT2A inhibition (pharmacological), single-cell transcriptomics, gene regulatory network analysis, differentiation assays\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — pharmacological inhibition + single-cell transcriptomics; mechanism partly inferred\",\n      \"pmids\": [\"30270482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KAT2A (GCN5) directly acetylates TUBA/α-tubulin, increasing microtubule stability; autophagic degradation of KAT2A reduces TUBA acetylation, and KAT2A accumulation (in Ulk1 KO VSMCs) increases acetylated TUBA, inhibiting directional migration and neointima formation.\",\n      \"method\": \"In vivo Ulk1 KO mouse + KAT2A siRNA rescue, western blot for acetyl-TUBA, migration assay, carotid artery ligation model\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO + siRNA rescue + in vivo model; direct acetyltransferase assay for TUBA not shown in this paper\",\n      \"pmids\": [\"33985412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT2A (Kat2a) promotes ferroptosis in diabetic cardiomyopathy by increasing H3K27ac and H3K9ac enrichment at the Tfrc and Hmox1 promoters, upregulating their expression; Kat2a expression itself is regulated post-transcriptionally by m6A methylation via ALKBH5 (demethylase) and YTHDF2 (m6A reader that promotes Kat2a mRNA degradation).\",\n      \"method\": \"ChIP-qPCR, siRNA knockdown, in vitro and in vivo DCM models, m6A methylation assays, RIP\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP + KD with phenotypic readout; single lab\",\n      \"pmids\": [\"38858351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KAT2A (GCN5) suppresses NRF2 activity in macrophages, supporting H3K9 acetylation and limiting NRF2-mediated transcriptional repression of proinflammatory genes (Il1b, Nlrp3); KAT2A facilitates macrophage glycolysis reprogramming and licenses NLRP3 inflammasome activation.\",\n      \"method\": \"KAT2A siRNA and pharmacological inhibition (MB-3), ChIP (H3K9ac), NRF2 activity assay, collagen-induced arthritis mouse model, NLRP3 inflammasome activation assay\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP + KD + in vivo model; single lab\",\n      \"pmids\": [\"37313329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KAT2A promotes succinylation of PGAM1 at K161, regulating glycolysis in hepatocellular carcinoma; KAT2A directly interacts with PGAM1; astragaloside IV suppresses this KAT2A-PGAM1 succinylation axis.\",\n      \"method\": \"Co-IP, immunofluorescence, succinylation-IP, site-directed mutagenesis (K161), xenograft tumor model\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP + mutagenesis + in vivo model; single lab\",\n      \"pmids\": [\"38835015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GCN5 (KAT2A) crystal structure of PCAF_N domain at 1.8 Å reveals a helical structure with a binuclear zinc region that constitutes a new class of E3 ligase fold; GCN5 exhibits ubiquitination activity supported by UbcH5.\",\n      \"method\": \"Crystal structure (1.8 Å), in vitro ubiquitination assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure + in vitro assay; single lab, functional significance of E3 ligase activity not fully characterized\",\n      \"pmids\": [\"32820047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"GCN5 (KAT2A) interacts with ATM upon doxorubicin treatment in early drug-resistant leukemia cells; GCN5 facilitates ATM recruitment to DNA double-strand break sites, hyperactivating ATM and downstream repair factors (H2AX, NBS1, BRCA1, Chk2, Mcl-1), promoting DNA repair and cell survival; GCN5 inhibition reduces ATM activation.\",\n      \"method\": \"Co-IP (GCN5-ATM), ChIP (ATM at DSB sites), pharmacological inhibition, western blot, cell viability assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP + ChIP + pharmacological inhibition; single lab\",\n      \"pmids\": [\"29297932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KAT2A cooperates with E2F1 and is recruited to the UBE2C promoter by E2F1, increasing H3K9 acetylation and UBE2C expression to promote cancer cell proliferation and migration.\",\n      \"method\": \"ChIP, Co-IP, immunofluorescence co-localization, RNA-seq, functional proliferation and migration assays\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP + Co-IP + functional assays; single lab\",\n      \"pmids\": [\"36292703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GCN5 (KAT2A) deposits H3K9ac onto WNT gene promoters and enhancers (e.g., WNT7A, WNT7B, WNT10A, WNT4) as part of the E2F1/4-pRb/RBL2-GCN5 axis, regulating CSC self-renewal, chemoresistance, and invasiveness in pancreatic and breast cancer.\",\n      \"method\": \"Quantitative proteomics, ChIP, siRNA knockdown, functional assays in CSC models, epistasis analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — ChIP + KD + epistasis; single lab\",\n      \"pmids\": [\"38678032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GCN5 (KAT2A) is required for expression of multiple FGF signaling pathway components during early embryoid body differentiation; Gcn5-null EBs show deficient ERK and p38 activation, cytoskeletal mislocalization, and impaired mesodermal differentiation; GCN5 directly targets four cMYC target genes among seven identified by genomic analysis.\",\n      \"method\": \"Gcn5 KO embryoid body system, ChIP-seq, gene expression analysis, signaling pathway assays\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO + ChIP-seq + signaling assays; multiple methods in single lab\",\n      \"pmids\": [\"29249668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDOB enters the nucleus and interacts with KAT2A, leading to inhibition of H3K9 acetylation at the TGFB1 promoter, suppressing TGF-β1 transcription; ALDOB deficiency releases this suppression, increasing TGF-β and enabling immune evasion in HCC.\",\n      \"method\": \"Nuclear fractionation, Co-IP (ALDOB-KAT2A), ChIP (H3K9ac at TGFB1 promoter), KAT2A small molecule inhibition, in vivo tumor models\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — nuclear Co-IP + ChIP + pharmacological inhibition; single lab\",\n      \"pmids\": [\"38051951\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KAT2A (GCN5) is a lysine acetyltransferase and acyltransferase that functions as the catalytic subunit of the SAGA and ATAC transcriptional coactivator complexes, where partner subunits (especially Ada2) allosterically enhance its activity by promoting acetyl-CoA binding; it acetylates histone H3 (primarily K9, K14, K18, K27, K79) and histone variant H2A.Z.1 to promote chromatin accessibility and gene activation, succinylates H3K79 in partnership with nuclear α-KGDH complex, lactylates H3 in partnership with nuclear ACSS2, and acetylates diverse non-histone substrates including TFEB, EGR2, CDK5, α-tubulin, and influenza NP, with its own stability and activity regulated by autophagy (via an LIR domain), sumoylation, and complex assembly, making it a central integrator of metabolic signals (acetyl-CoA, succinyl-CoA, lactyl-CoA) with chromatin-based gene regulation in development, immunity, and cancer.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KAT2A (GCN5) is a versatile lysine acyltransferase that serves as the catalytic subunit of the SAGA and ATAC coactivator complexes, integrating metabolic acyl-CoA pools with chromatin-based gene regulation in development, immunity, and cancer. Within these complexes, the Ada2 subunit allosterically enhances KAT2A activity by promoting acetyl-CoA binding [PMID:30224453], and KAT2A acetylates histone H3 primarily at K9 and K14—with its bromodomain reading H3K14ac to license subsequent H3K18ac—as well as histone variant H2A.Z.1 [PMID:25106422, PMID:31527837]. Beyond acetylation, KAT2A functions as a succinyltransferase (H3K79 succinylation via nuclear α-KGDH-supplied succinyl-CoA, controlled by active-site residue Y645) and as a lactyltransferase (histone H3 lactylation using lactyl-CoA generated by nuclear ACSS2), and it acylates non-histone substrates including TFEB, α-tubulin, EGR2, VCP, PKM2, and influenza NP [PMID:29211711, PMID:39561764, PMID:31750630, PMID:31878840, PMID:28723564, PMID:38145956]. KAT2A is essential for mouse embryogenesis—loss causes dorsal mesoderm failure and extensive apoptosis—and in the immune system it is required for IL-2-driven T cell responses and iNKT cell development; its stability is regulated by autophagy through a conserved LIR domain [PMID:11017084, PMID:28424240, PMID:31878840].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that GCN5 and ADA2 form a physical complex that functions together in transcriptional activation answered how GCN5 is organized within coactivator machinery, laying the foundation for understanding SAGA-type complexes.\",\n      \"evidence\": \"Two-hybrid, co-immunoprecipitation, and double-mutant epistasis in yeast\",\n      \"pmids\": [\"7957049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and full subunit composition of the native complex unknown at this stage\", \"Mechanism by which Ada2 stimulates GCN5 activity not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that Gcn5l2 knockout is embryonic lethal with dorsal mesoderm failure established KAT2A as an essential developmental gene and revealed functional overlap with PCAF.\",\n      \"evidence\": \"Germline and conditional knockout mice; double Gcn5l2/Pcaf nulls\",\n      \"pmids\": [\"11017084\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Target genes and histone marks responsible for the mesoderm phenotype unidentified\", \"Cell-type autonomy of KAT2A requirement in mesoderm not resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showing that E2F transcription factors recruit KAT2A/TRRAP and require GCN5 catalytic activity for transactivation identified a key transcription-factor-dependent recruitment mechanism.\",\n      \"evidence\": \"Co-IP, catalytic mutant, and transactivation assays in human cells\",\n      \"pmids\": [\"11418595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide target sites of E2F-GCN5 co-occupancy not mapped\", \"Whether E2F recruits SAGA vs. ATAC complex not distinguished\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Crystal structures of Gcn5 with histone H4 and p53 peptides defined how the HAT domain accommodates divergent substrates through a common lysine-binding mechanism with variable N-terminal contacts, explaining both histone and non-histone substrate recognition.\",\n      \"evidence\": \"X-ray crystallography of Tetrahymena Gcn5 with peptide substrates plus in vitro acetyltransferase assays\",\n      \"pmids\": [\"14661947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures with nucleosomal substrates lacking\", \"Selectivity determinants within full-length human KAT2A not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Biochemical purification resolved KAT2A as a shared catalytic subunit of two distinct human complexes—STAGA/SAGA and ATAC—with different subunit compositions and transcriptional roles, clarifying the organizational logic of GCN5-containing coactivators.\",\n      \"evidence\": \"Tandem affinity purification, mass spectrometry, co-IP, and in vitro transcription from human cells\",\n      \"pmids\": [\"18838386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cells partition KAT2A between SAGA and ATAC not understood\", \"Genomic loci preferentially regulated by ATAC vs. SAGA not distinguished\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealing that the GCN5 bromodomain reads its own H3K14ac product to license H3K18ac established an intra-molecular reader-writer crosstalk that orders multi-site acetylation on H3.\",\n      \"evidence\": \"Quantitative mass spectrometry and in vitro HAT assays with bromodomain-mutant ADA subcomplex\",\n      \"pmids\": [\"25106422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of sequential acetylation on chromatin not tested\", \"Whether this crosstalk operates similarly within ATAC and SAGA not compared\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that KAT2A functions as a histone succinyltransferase—with α-KGDH supplying nuclear succinyl-CoA and Y645 determining acyl-CoA selectivity—expanded the enzyme's catalytic repertoire beyond acetylation and linked metabolic intermediates to epigenetic marks.\",\n      \"evidence\": \"2.3 Å crystal structure with succinyl-CoA, Y645A mutagenesis, in vitro succinylation, ChIP, and tumor models\",\n      \"pmids\": [\"29211711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How succinyl-CoA nuclear availability is regulated not fully understood\", \"Genome-wide distribution of H3K79 succinylation beyond candidate loci not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional T cell–specific Gcn5 knockout and iNKT studies showed KAT2A is required for IL-2 transcription (via NFAT-directed H3K9ac at the Il2 promoter) and for iNKT cell development (via EGR2 acetylation), establishing cell-type-specific immune functions.\",\n      \"evidence\": \"Conditional Lck-Cre KO mice, ChIP, co-IP, in vitro acetyltransferase assays, and cytokine/differentiation assays\",\n      \"pmids\": [\"28424240\", \"28723564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream EGR2 acetylation sites' structural effects unresolved\", \"Relative contributions of SAGA vs. ATAC in T cell gene regulation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Structural determination of the Ada2 SANT domain–Gcn5 interface showed Ada2 allosterically enhances acetyl-CoA binding rather than histone substrate binding, resolving a long-standing question about how complex assembly activates the catalytic subunit.\",\n      \"evidence\": \"Fab-assisted crystal structure of yeast Ada2/Gcn5 complex plus biochemical binding and HAT assays\",\n      \"pmids\": [\"30224453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same allosteric mechanism operates in human ADA2a vs. ADA2b paralog contexts not tested\", \"Structural basis for the stronger stimulation by ADA2b than ADA2a not explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multiple studies converged to show KAT2A acetylates non-histone substrates—TFEB (inhibiting autophagy/lysosome gene transcription), α-tubulin (stabilizing microtubules), and H2A.Z.1 (licensing promoter activation via BRD2 recruitment)—demonstrating breadth of substrate scope in distinct cellular contexts.\",\n      \"evidence\": \"In vitro acetyltransferase assays, mutagenesis, co-IP, ChIP, Drosophila genetics, and cell migration assays\",\n      \"pmids\": [\"31750630\", \"31878840\", \"31527837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full acetylome of KAT2A not systematically catalogued\", \"Structural basis for H2A.Z.1 vs. H2A.Z.2 discrimination not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of the LIR domain in KAT2A revealed that autophagy directly degrades KAT2A via LC3 interaction, establishing a post-translational regulatory axis that links cellular stress to KAT2A protein levels and tubulin acetylation.\",\n      \"evidence\": \"LIR domain mutagenesis, autophagy flux assays, ULK1 KO mice with KAT2A siRNA rescue, neointima models\",\n      \"pmids\": [\"31878840\", \"33985412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether autophagy-mediated degradation affects nuclear KAT2A pools and histone acetylation equally\", \"Ubiquitin signals directing KAT2A to autophagosomes not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Conditional Kat2a loss in AML reduced transcriptional burst frequency and increased gene expression variability, shifting leukemia stem cells toward differentiation—providing a mechanistic explanation for KAT2A's role in maintaining malignant self-renewal programs.\",\n      \"evidence\": \"Conditional KO in AML, ChIP-seq, ATAC-seq, single-cell RNA-seq\",\n      \"pmids\": [\"31985402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific KAT2A-deposited marks (H3K9ac vs. others) are rate-limiting for burst frequency unknown\", \"Whether transcriptional noise phenotype is shared across solid tumors not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Crystal structure of the KAT2A N-terminal PCAF_N domain revealed a novel E3 ubiquitin ligase fold with a binuclear zinc region, supported by in vitro ubiquitination activity, suggesting a dual enzymatic function beyond acyltransferase activity.\",\n      \"evidence\": \"1.8 Å crystal structure plus in vitro ubiquitination assay with UbcH5\",\n      \"pmids\": [\"32820047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological substrates of the E3 ligase activity not identified\", \"In vivo relevance of ubiquitination activity not demonstrated\", \"Independent validation of E3 ligase function needed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A series of studies showed KAT2A succinylates non-histone substrates (VCP-K658, PKM2-K475, CTBP1-K46/K280, PGAM1-K161) to modulate mitophagy, glycolysis, and transcriptional repression, extending the succinyltransferase function well beyond histones.\",\n      \"evidence\": \"Co-IP, site-directed mutagenesis at target lysines, enzymatic activity assays, and xenograft models across multiple cancer cell types\",\n      \"pmids\": [\"38145956\", \"37294531\", \"36764210\", \"38835015\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most findings from single laboratories awaiting independent replication\", \"Selectivity rules for succinylation vs. acetylation of non-histone substrates not defined\", \"In vitro reconstitution with purified proteins not shown for all substrates\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that ACSS2 generates lactyl-CoA and partners with KAT2A to lactylate histone H3—regulated by EGFR-ERK signaling—added a third acyl-CoA species to KAT2A's catalytic repertoire, linking growth-factor signaling to a new epigenetic mark.\",\n      \"evidence\": \"Co-crystal structure of KAT2A with lactyl-CoA, co-IP, in vitro lactylation, ERK phosphorylation assay, tumor and immune models\",\n      \"pmids\": [\"39561764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide distribution of KAT2A-dependent histone lactylation not mapped\", \"Whether lactylation and succinylation compete at the same active site under physiological conditions not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KAT2A partitions among acetyl-CoA, succinyl-CoA, and lactyl-CoA acylation reactions in vivo—and how metabolic flux, complex assembly (SAGA vs. ATAC), and post-translational modifications (sumoylation, autophagic degradation) combinatorially control substrate and acyl-donor selectivity—remains an open integrative question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No systematic in vivo quantification of the relative acylation outputs\", \"Structural basis for SAGA-ATAC differential targeting still incomplete\", \"Full spectrum of KAT2A-dependent acylation marks across the proteome and chromatin not catalogued\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8, 11, 13, 16, 21, 30, 31, 32, 33, 34, 39]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8, 11, 13, 16, 21, 34]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1, 7, 8, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 9, 10, 15, 17, 22, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4, 9, 10, 15, 22, 27]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 7, 9, 21, 22]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 7, 8, 21, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 9, 10, 15, 17, 22, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 44]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 16, 38]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [11, 13, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 12, 31, 39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [22, 23, 24, 43]}\n    ],\n    \"complexes\": [\n      \"SAGA (STAGA)\",\n      \"ATAC\"\n    ],\n    \"partners\": [\n      \"ADA2A\",\n      \"ADA2B\",\n      \"TRRAP\",\n      \"E2F1\",\n      \"NFAT\",\n      \"ACSS2\",\n      \"TFEB\",\n      \"EGR2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}