{"gene":"ING2","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2006,"finding":"The PHD domain of ING2 is a specific, high-affinity binding module for trimethylated and dimethylated histone H3 lysine 4 (H3K4me3/me2), and ING2 as a native subunit of the mSin3a-HDAC1 histone deacetylase complex uses this interaction to stabilize the repressive complex at promoters of proliferation genes in response to DNA damage.","method":"Biochemical binding assays, co-immunoprecipitation, chromatin immunoprecipitation, loss-of-function experiments with PHD domain mutants","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (binding assays, ChIP, mutagenesis, Co-IP), replicated in companion structural paper same issue","pmids":["16728974"],"is_preprint":false},{"year":2006,"finding":"Crystal structure (2.0 Å) of the mouse ING2 PHD finger in complex with H3K4me3 peptide revealed that trimethylated Lys4 is recognized by aromatic cage residues Y215 and W238, and mutagenesis of these binding-site residues disrupts H3K4me3 interaction in vitro and impairs ING2-induced apoptosis in vivo.","method":"X-ray crystallography, in vitro binding assays, site-directed mutagenesis, apoptosis assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution structure with mutagenesis and functional validation","pmids":["16728977"],"is_preprint":false},{"year":2003,"finding":"The PHD finger of ING2 binds phosphoinositides, particularly phosphatidylinositol 5-phosphate (PtdIns(5)P), in vitro and in vivo in the nucleus, and this interaction regulates ING2's ability to activate p53 and p53-dependent apoptotic pathways.","method":"Lipid-binding assays, in vivo PtdIns(5)P interaction, p53 activation assays, PHD finger mutagenesis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple methods (in vitro binding, in vivo interaction, functional assays), high-citation foundational paper","pmids":["12859901"],"is_preprint":false},{"year":2001,"finding":"ING2 (p33ING2) enhances p53 transcriptional activity and increases acetylation of p53 at Lys-382, negatively regulating cell growth through p53-dependent G1 cell cycle arrest and apoptosis in response to DNA damage.","method":"Overexpression, p53 transcriptional assay, Western blot for acetylated p53, cell cycle analysis, apoptosis assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, independently replicated","pmids":["11481424"],"is_preprint":false},{"year":2005,"finding":"ING2 complexes with p53 and the histone acetyltransferase p300, enhancing their interaction and acting as a cofactor for p300-mediated acetylation of p53, thereby promoting p53-dependent replicative senescence.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, senescence assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, siRNA and overexpression with defined senescence phenotype","pmids":["16024799"],"is_preprint":false},{"year":2010,"finding":"HDAC inhibitor SAHA causes dissociation of ING2 from the Sin3 deacetylase complex, and loss of ING2 disrupts in vivo binding of the Sin3 complex to the p21 promoter.","method":"Mass spectrometry of complex composition after SAHA treatment, chromatin immunoprecipitation","journal":"Chemistry & biology","confidence":"Medium","confidence_rationale":"Tier 2 — MS-based complex analysis plus ChIP, single lab","pmids":["20142042"],"is_preprint":false},{"year":2006,"finding":"ING2 is required for UV-induced nucleotide excision repair in melanoma cells; it promotes rapid histone H4 acetylation, chromatin relaxation, and recruitment of damage-recognition protein XPA to photolesions, functioning upstream of chromatin remodeling in NER.","method":"Host-cell reactivation assay, siRNA knockdown, histone acetylation assay, chromatin accessibility assay, XPA recruitment by ChIP/immunofluorescence","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — functional repair assay plus chromatin endpoints, single lab","pmids":["16488987"],"is_preprint":false},{"year":2006,"finding":"The leucine zipper-like (LZL) motif in the N-terminus of ING2 is required for association with p53 (but not p300), and its deletion abolishes ING2-dependent DNA repair, apoptosis, and chromatin remodeling after UV irradiation, placing ING2 as a scaffold mediating p53–p300 interaction.","method":"Deletion mutagenesis, co-immunoprecipitation, host-cell reactivation assay, apoptosis assay","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — domain mapping by mutagenesis with multiple functional readouts, single lab","pmids":["16782091"],"is_preprint":false},{"year":2008,"finding":"ING2 promotes TGF-β-induced transcription and cell cycle arrest; it interacts with the transcriptional modulator SnoN to form a complex with SnoN–ING2–Smad2, and SnoN is required for ING2-mediated enhancement of TGF-β/Smad-dependent transcription.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP showing complex plus reciprocal siRNA/overexpression functional assays, single lab","pmids":["18334480"],"is_preprint":false},{"year":2010,"finding":"ING2 is sumoylated by SUMO1 on lysine 195 both in vitro and in vivo, and this sumoylation enhances ING2 association with Sin3A and is required for ING2 binding to specific gene promoters (e.g., TMEM71) to mediate Sin3A/HDAC-dependent transcriptional repression.","method":"In vitro sumoylation assay, in vivo SUMO modification, co-immunoprecipitation, chromatin immunoprecipitation, mutagenesis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro and in vivo PTM mapping with mutagenesis and functional ChIP, single lab","pmids":["20676127"],"is_preprint":false},{"year":2010,"finding":"The HECT-type ubiquitin ligase Smurf1 directly interacts with ING2 via its HECT domain, polyubiquitinates ING2 requiring the C-terminal PHD domain of ING2, and targets ING2 for proteasomal degradation.","method":"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, domain mapping","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP, ubiquitination assay, domain mapping; single lab","pmids":["20621832"],"is_preprint":false},{"year":2009,"finding":"ING2 interacts with proliferating cell nuclear antigen (PCNA) and regulates PCNA loading onto chromatin, controlling DNA replication fork progression; ING2 depletion reduces global replication rate and causes endoreduplication and increased sister chromatid exchange.","method":"DNA fiber spreading assay, co-immunoprecipitation, chromatin fractionation, siRNA knockdown","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (fiber assay, Co-IP, fractionation), single lab","pmids":["19730436"],"is_preprint":false},{"year":2013,"finding":"Direct association of ING2 with nuclear phosphatidylinositol-5-phosphate (PtdIns(5)P) is required for ING2 promoter occupancy and ING2-associated gene repression at a subset of genomic targets in response to DNA damage; PtdIns(5)P depletion attenuates ING2-mediated gene regulation at these sites.","method":"Chromatin immunoprecipitation, PtdIns(5)P depletion, lipid-binding assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and lipid manipulation with functional gene regulation readout, single lab","pmids":["23823870"],"is_preprint":false},{"year":2008,"finding":"ING2 associates with histone methyltransferase (HMT) activity in vitro and in vivo, methylating histone H3 at a site distinct from K9 but dependent on the methylation state of K4; this HDAC-independent silencing function maps to the ING2 C-terminus.","method":"In vitro HMT assay, co-immunoprecipitation, deletion and mutation analysis, reporter silencing assay with TSA","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro enzymatic assay plus domain mapping, single lab","pmids":["18513492"],"is_preprint":false},{"year":2010,"finding":"ING2 knockout mice develop soft-tissue sarcomas and show male infertility due to meiotic arrest; in Ing2-null testes, HDAC1 accumulation is lost and chromatin acetylation is deregulated, establishing that ING2 functions through both p53-dependent and chromatin (HDAC1/H3K4me3)-mediated mechanisms in spermatogenesis.","method":"Targeted germline knockout, histopathology, immunofluorescence, p53 double-knockout rescue","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — clean KO with multiple defined phenotypes, partial rescue by p53 co-deletion establishing epistasis","pmids":["21124965"],"is_preprint":false},{"year":2010,"finding":"ING2 regulates the G1/S transition by maintaining p21 expression independently of p53; ING2 knockdown accelerates G1-to-S progression and decreases p21 levels, a function not shared by its homolog ING1.","method":"siRNA knockdown, flow cytometry cell cycle analysis, Western blot/qPCR for p21","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA with defined cell cycle phenotype and molecular readout, single lab","pmids":["20890119"],"is_preprint":false},{"year":2012,"finding":"ING2 is required for C2C12 myoblast differentiation into myotubes; the leucine zipper motif of ING2 promotes differentiation while the PHD domain inhibits it, and the Sin3A-HDAC1 complex that interacts with ING2 is essential for ING2-dependent myogenesis.","method":"RNAi knockdown, overexpression of domain mutants, myotube formation assay, Co-IP of Sin3A-HDAC1","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 — RNAi phenotype plus domain structure-function analysis with complex interaction, single lab","pmids":["22808232"],"is_preprint":false},{"year":2009,"finding":"ING2 regulates cell death in response to the alkylating agent MNNG through a MMR/c-Abl→ING2→p73α signaling axis; ING2 induction is dependent on MLH1 and c-Abl, and ING2 associates with p73α in the nucleus, promoting its stabilization and acetylation.","method":"shRNA knockdown, co-immunoprecipitation, nuclear localization assay, c-Abl inhibitor (STI571), acetylation Western blot","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 — epistasis with shRNA plus Co-IP and pathway inhibitor, single lab","pmids":["19766113"],"is_preprint":false},{"year":2009,"finding":"ING2 upregulation in colon cancer drives MMP13 expression and enhances cellular invasion; this regulation of MMP13 is mediated by the ING2-HDAC1-mSin3A complex, as co-expression of these complex members further induces MMP13.","method":"Microarray, siRNA knockdown, overexpression, in vitro invasion assay, EMSA/luciferase for NF-κB binding to ING2 promoter","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional invasion assay plus complex co-expression data, single lab","pmids":["19437536"],"is_preprint":false},{"year":2021,"finding":"ING2 translocates into the inner mitochondrial fraction in a redox-sensitive manner modulated by 14-3-3η protein; mitochondrial ING2 interacts with mtDNA via TFAM and is required for normal mitochondrial ultrastructure and mitochondrial respiration/OXPHOS activity.","method":"Subcellular fractionation, immunoprecipitation, co-IP with TFAM, oxygen consumption rate assay, siRNA knockdown, electron microscopy","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — fractionation with functional consequence, multiple orthogonal methods, single lab","pmids":["34017078"],"is_preprint":false},{"year":2021,"finding":"In renal tubular epithelial cells, ING2 controls mitochondrial respiration by regulating ubiquitination and stability of the mitochondrial transcription factor MRPL12, thereby modulating mtDNA-encoded respiratory chain component expression.","method":"Co-immunoprecipitation, ubiquitination assay, oxygen consumption rate assay, ING2 overexpression in vivo (kidney-specific), siRNA knockdown","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP with ubiquitination assay and functional respiration readout, in vivo overexpression model","pmids":["34434929"],"is_preprint":false},{"year":2016,"finding":"ING2 acts as a corepressor of the androgen receptor (AR), interacting with AR to inhibit AR-mediated transactivation, induce cell cycle arrest and cellular senescence, and upregulate p16INK4a; ING2 protein levels are increased as a compensatory mechanism when ING1 is deficient.","method":"Co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, Ing1 knockout mouse","journal":"Journal of molecular medicine (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP plus reporter assays and in vivo KO model, single lab","pmids":["27305909"],"is_preprint":false},{"year":2021,"finding":"ING1 and ING2 are recruited to the hTERT core promoter in an androgen-dependent manner and mediate AR-driven transcriptional repression of hTERT at supraphysiological androgen levels; knockdown of ING1/ING2 abolishes this repression.","method":"Chromatin immunoprecipitation (ChIP), siRNA knockdown, luciferase reporter assay with defined negative androgen response element","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP mapping plus functional knockdown, multiple cell models","pmids":["34439179"],"is_preprint":false},{"year":2007,"finding":"ING2 directly interacts with the corepressor Alien both in vivo and in vitro (GST pulldown), and expression of ING2 enhances Alien-mediated transcriptional silencing; the Alien binding domain maps to a central region of Alien.","method":"SELDI-MS proteomic approach, co-immunoprecipitation, GST pulldown, transcriptional reporter assay","journal":"Journal of proteome research","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP/pulldown with partial functional follow-up, single lab","pmids":["17929852"],"is_preprint":false}],"current_model":"ING2 is a chromatin-regulatory tumor suppressor that uses its PHD domain to read the H3K4me3 histone mark and the nuclear phosphoinositide PtdIns(5)P signal, thereby recruiting or stabilizing the mSin3A-HDAC1 repressive complex at target gene promoters; it activates p53 by scaffolding p300-mediated p53 acetylation, regulates DNA replication fork progression through PCNA, undergoes SUMO1 modification (K195) that enhances Sin3A binding, is degraded via Smurf1-mediated ubiquitination, and also localizes to mitochondria where it maintains respiratory chain function through MRPL12 stability."},"narrative":{"teleology":[{"year":2001,"claim":"Establishing ING2 as a p53 activator resolved how the ING family connects to the p53 tumor-suppressive pathway: ING2 enhances p53 transcriptional activity and acetylation at Lys-382, driving G1 arrest and apoptosis after DNA damage.","evidence":"Overexpression, p53 transcriptional reporter, acetylation Western blot, cell cycle and apoptosis assays in human cells","pmids":["11481424"],"confidence":"High","gaps":["Acetyltransferase responsible not identified","Endogenous complex stoichiometry unknown","Mechanism linking ING2 to p53 acetylation not defined"]},{"year":2003,"claim":"Demonstrating that the ING2 PHD finger binds PtdIns(5)P in the nucleus revealed a novel nuclear phosphoinositide signaling input that governs ING2's p53-activating and apoptotic functions.","evidence":"Lipid-binding assays (in vitro and in vivo), PHD finger mutagenesis, p53 activation assays","pmids":["12859901"],"confidence":"High","gaps":["Enzymes controlling nuclear PtdIns(5)P pools not linked to ING2 regulation","Whether PtdIns(5)P and H3K4me binding are mutually exclusive or cooperative unknown"]},{"year":2005,"claim":"Identification of a p53–ING2–p300 ternary complex explained the acetylation mechanism: ING2 scaffolds p300-mediated p53 acetylation, linking this to replicative senescence.","evidence":"Reciprocal co-immunoprecipitation, siRNA knockdown, senescence assays","pmids":["16024799"],"confidence":"High","gaps":["ING2–p300 binding interface not mapped","Whether ING2 directs p300 to chromatin versus soluble p53 unclear"]},{"year":2006,"claim":"Structural and biochemical resolution of H3K4me3 recognition by the PHD domain, combined with its role in tethering the mSin3A–HDAC1 complex to promoters, established ING2 as a histone-mark reader linking active chromatin marks to transcriptional repression.","evidence":"2.0 Å crystal structure, binding assays, aromatic cage mutagenesis (Y215/W238), ChIP, Co-IP with mSin3A–HDAC1","pmids":["16728974","16728977"],"confidence":"High","gaps":["How a mark of active transcription (H3K4me3) is reconciled with repressive HDAC recruitment not fully resolved","Genome-wide binding profile not determined"]},{"year":2006,"claim":"ING2 was placed upstream of chromatin remodeling in UV-induced nucleotide excision repair, showing it promotes histone H4 acetylation, chromatin relaxation, and XPA recruitment to photolesions, with the leucine zipper–like motif essential for p53 association and repair.","evidence":"Host-cell reactivation assay, siRNA, histone acetylation and chromatin accessibility assays, domain deletion mutagenesis","pmids":["16488987","16782091"],"confidence":"Medium","gaps":["Whether ING2 directly recruits a HAT for H4 acetylation in NER unknown","Repair function not validated by in vivo damage assays in knockout models"]},{"year":2008,"claim":"Discovery that ING2 participates in TGF-β signaling through a SnoN–ING2–Smad2 complex broadened its role beyond p53 to include Smad-dependent transcription and cell cycle arrest.","evidence":"Co-immunoprecipitation, siRNA, transcriptional reporter assays","pmids":["18334480"],"confidence":"Medium","gaps":["Chromatin target genes of the SnoN–ING2–Smad2 complex not defined","Whether the Sin3A–HDAC1 complex is involved in this axis unclear"]},{"year":2009,"claim":"Linking ING2 to PCNA and DNA replication fork progression revealed a replication-intrinsic function: ING2 controls PCNA loading onto chromatin, and its loss causes reduced replication rate, endoreduplication, and sister chromatid exchange.","evidence":"DNA fiber spreading, co-immunoprecipitation, chromatin fractionation, siRNA","pmids":["19730436"],"confidence":"Medium","gaps":["Mechanism by which ING2 promotes PCNA loading not resolved","Whether PHD domain H3K4me3 reading is required for replication function unknown"]},{"year":2010,"claim":"Post-translational regulation of ING2 was defined: SUMO1 modification at K195 enhances Sin3A binding and promoter occupancy, while Smurf1-mediated ubiquitination targets ING2 for proteasomal degradation, revealing opposing PTM switches that tune ING2 activity.","evidence":"In vitro and in vivo sumoylation/ubiquitination assays, mutagenesis, Co-IP, ChIP, proteasome inhibitor treatment","pmids":["20676127","20621832"],"confidence":"Medium","gaps":["Signals triggering Smurf1-mediated degradation not identified","Interplay between sumoylation and ubiquitination not examined"]},{"year":2010,"claim":"Ing2 knockout mice developed soft-tissue sarcomas and male infertility with meiotic arrest and deregulated chromatin acetylation, providing in vivo genetic proof of tumor suppressor function and a requirement for HDAC1-mediated chromatin regulation in spermatogenesis.","evidence":"Germline knockout, histopathology, p53 double-knockout rescue, immunofluorescence","pmids":["21124965"],"confidence":"High","gaps":["Tumor spectrum and latency not fully characterized","Direct transcriptional targets in spermatogenesis not identified"]},{"year":2013,"claim":"Genome-level demonstration that PtdIns(5)P binding is required for ING2 promoter occupancy at a subset of DNA damage–responsive targets refined the lipid-signaling model from a general activator to a site-selective chromatin-targeting mechanism.","evidence":"ChIP combined with PtdIns(5)P depletion and lipid-binding assays","pmids":["23823870"],"confidence":"Medium","gaps":["Full repertoire of PtdIns(5)P-dependent ING2 target genes not mapped","Whether PtdIns(5)P binding alters PHD domain conformation not resolved"]},{"year":2021,"claim":"Discovery of ING2 translocation to mitochondria, where it interacts with mtDNA via TFAM and stabilizes MRPL12 to maintain OXPHOS, revealed a non-nuclear function that extends ING2's role to mitochondrial homeostasis.","evidence":"Subcellular fractionation, Co-IP with TFAM and MRPL12, OCR assay, electron microscopy, siRNA, kidney-specific in vivo overexpression","pmids":["34017078","34434929"],"confidence":"Medium","gaps":["Mitochondrial import signal or translocase pathway not identified","Whether mitochondrial ING2 retains PHD-dependent functions unknown","Physiological stimuli triggering mitochondrial translocation beyond redox changes not defined"]},{"year":null,"claim":"The interplay between ING2's nuclear chromatin functions and its mitochondrial roles, the full genome-wide target repertoire of ING2-associated repressive complexes, and how PtdIns(5)P and H3K4me3 binding are coordinated on the same PHD domain remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No genome-wide occupancy map integrating histone mark and lipid-dependent targeting","Structural basis for dual PHD ligand recognition (H3K4me3 vs PtdIns(5)P) not determined","Relative contribution of nuclear vs mitochondrial ING2 to tumor suppression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,5,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8,9,18,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,3,9,12]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,6,11]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[19,20]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,5,9,13]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,3,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,9,22]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8]}],"complexes":["mSin3A-HDAC1","p53-p300-ING2","SnoN-ING2-Smad2"],"partners":["HDAC1","SIN3A","TP53","EP300","PCNA","SMURF1","TFAM","MRPL12"],"other_free_text":[]},"mechanistic_narrative":"ING2 is a chromatin-regulatory tumor suppressor that integrates histone mark recognition, nuclear lipid signaling, and transcriptional repression to control cell proliferation, DNA damage responses, and differentiation. Its PHD domain binds H3K4me3/me2 with high affinity and simultaneously senses the nuclear phosphoinositide PtdIns(5)P, directing the mSin3A–HDAC1 repressive complex to target promoters such as p21 and proliferation genes in response to DNA damage [PMID:16728974, PMID:12859901, PMID:23823870]. ING2 also scaffolds p53–p300 interaction through its N-terminal leucine zipper–like motif, promoting p53 acetylation at Lys-382 to activate p53-dependent apoptosis, senescence, and nucleotide excision repair [PMID:11481424, PMID:16024799, PMID:16782091]. Beyond nuclear chromatin functions, ING2 translocates to mitochondria in a redox-sensitive manner, where it maintains respiratory chain activity by stabilizing MRPL12 and interacting with mtDNA via TFAM [PMID:34017078, PMID:34434929]."},"prefetch_data":{"uniprot":{"accession":"Q9H160","full_name":"Inhibitor of growth protein 2","aliases":["Inhibitor of growth 1-like protein","ING1Lp","p32","p33ING2"],"length_aa":280,"mass_kda":32.8,"function":"Seems to be involved in p53/TP53 activation and p53/TP53-dependent apoptotic pathways, probably by enhancing acetylation of p53/TP53. Component of a mSin3A-like corepressor complex, which is probably involved in deacetylation of nucleosomal histones. ING2 activity seems to be modulated by binding to phosphoinositides (PtdInsPs)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9H160/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ING2","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HDAC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ING2","total_profiled":1310},"omim":[{"mim_id":"620287","title":"TRANSMEMBRANE PROTEIN 71; TMEM71","url":"https://www.omim.org/entry/620287"},{"mim_id":"608525","title":"INHIBITOR OF GROWTH 5; ING5","url":"https://www.omim.org/entry/608525"},{"mim_id":"608524","title":"INHIBITOR OF GROWTH 4; ING4","url":"https://www.omim.org/entry/608524"},{"mim_id":"604215","title":"INHIBITOR OF GROWTH 2; ING2","url":"https://www.omim.org/entry/604215"},{"mim_id":"602810","title":"HISTONE GENE CLUSTER 1, H3 HISTONE FAMILY, MEMBER A; HIST1H3A","url":"https://www.omim.org/entry/602810"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ING2"},"hgnc":{"alias_symbol":["p33ING2"],"prev_symbol":["ING1L"]},"alphafold":{"accession":"Q9H160","domains":[{"cath_id":"1.10.287","chopping":"11-126","consensus_level":"medium","plddt":91.932,"start":11,"end":126},{"cath_id":"3.30.40.10","chopping":"209-263","consensus_level":"medium","plddt":86.7787,"start":209,"end":263}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H160","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H160-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H160-F1-predicted_aligned_error_v6.png","plddt_mean":75.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ING2","jax_strain_url":"https://www.jax.org/strain/search?query=ING2"},"sequence":{"accession":"Q9H160","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H160.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H160/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H160"}},"corpus_meta":[{"pmid":"16728974","id":"PMC_16728974","title":"ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16728974","citation_count":750,"is_preprint":false},{"pmid":"16728977","id":"PMC_16728977","title":"Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16728977","citation_count":564,"is_preprint":false},{"pmid":"12859901","id":"PMC_12859901","title":"The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor.","date":"2003","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12859901","citation_count":439,"is_preprint":false},{"pmid":"11481424","id":"PMC_11481424","title":"DNA damage-inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of 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\"year\": 2006,\n      \"finding\": \"The PHD domain of ING2 is a specific, high-affinity binding module for trimethylated and dimethylated histone H3 lysine 4 (H3K4me3/me2), and ING2 as a native subunit of the mSin3a-HDAC1 histone deacetylase complex uses this interaction to stabilize the repressive complex at promoters of proliferation genes in response to DNA damage.\",\n      \"method\": \"Biochemical binding assays, co-immunoprecipitation, chromatin immunoprecipitation, loss-of-function experiments with PHD domain mutants\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (binding assays, ChIP, mutagenesis, Co-IP), replicated in companion structural paper same issue\",\n      \"pmids\": [\"16728974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure (2.0 Å) of the mouse ING2 PHD finger in complex with H3K4me3 peptide revealed that trimethylated Lys4 is recognized by aromatic cage residues Y215 and W238, and mutagenesis of these binding-site residues disrupts H3K4me3 interaction in vitro and impairs ING2-induced apoptosis in vivo.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, site-directed mutagenesis, apoptosis assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution structure with mutagenesis and functional validation\",\n      \"pmids\": [\"16728977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The PHD finger of ING2 binds phosphoinositides, particularly phosphatidylinositol 5-phosphate (PtdIns(5)P), in vitro and in vivo in the nucleus, and this interaction regulates ING2's ability to activate p53 and p53-dependent apoptotic pathways.\",\n      \"method\": \"Lipid-binding assays, in vivo PtdIns(5)P interaction, p53 activation assays, PHD finger mutagenesis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple methods (in vitro binding, in vivo interaction, functional assays), high-citation foundational paper\",\n      \"pmids\": [\"12859901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ING2 (p33ING2) enhances p53 transcriptional activity and increases acetylation of p53 at Lys-382, negatively regulating cell growth through p53-dependent G1 cell cycle arrest and apoptosis in response to DNA damage.\",\n      \"method\": \"Overexpression, p53 transcriptional assay, Western blot for acetylated p53, cell cycle analysis, apoptosis assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, independently replicated\",\n      \"pmids\": [\"11481424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ING2 complexes with p53 and the histone acetyltransferase p300, enhancing their interaction and acting as a cofactor for p300-mediated acetylation of p53, thereby promoting p53-dependent replicative senescence.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, senescence assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, siRNA and overexpression with defined senescence phenotype\",\n      \"pmids\": [\"16024799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"HDAC inhibitor SAHA causes dissociation of ING2 from the Sin3 deacetylase complex, and loss of ING2 disrupts in vivo binding of the Sin3 complex to the p21 promoter.\",\n      \"method\": \"Mass spectrometry of complex composition after SAHA treatment, chromatin immunoprecipitation\",\n      \"journal\": \"Chemistry & biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-based complex analysis plus ChIP, single lab\",\n      \"pmids\": [\"20142042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ING2 is required for UV-induced nucleotide excision repair in melanoma cells; it promotes rapid histone H4 acetylation, chromatin relaxation, and recruitment of damage-recognition protein XPA to photolesions, functioning upstream of chromatin remodeling in NER.\",\n      \"method\": \"Host-cell reactivation assay, siRNA knockdown, histone acetylation assay, chromatin accessibility assay, XPA recruitment by ChIP/immunofluorescence\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional repair assay plus chromatin endpoints, single lab\",\n      \"pmids\": [\"16488987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The leucine zipper-like (LZL) motif in the N-terminus of ING2 is required for association with p53 (but not p300), and its deletion abolishes ING2-dependent DNA repair, apoptosis, and chromatin remodeling after UV irradiation, placing ING2 as a scaffold mediating p53–p300 interaction.\",\n      \"method\": \"Deletion mutagenesis, co-immunoprecipitation, host-cell reactivation assay, apoptosis assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mapping by mutagenesis with multiple functional readouts, single lab\",\n      \"pmids\": [\"16782091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ING2 promotes TGF-β-induced transcription and cell cycle arrest; it interacts with the transcriptional modulator SnoN to form a complex with SnoN–ING2–Smad2, and SnoN is required for ING2-mediated enhancement of TGF-β/Smad-dependent transcription.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP showing complex plus reciprocal siRNA/overexpression functional assays, single lab\",\n      \"pmids\": [\"18334480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ING2 is sumoylated by SUMO1 on lysine 195 both in vitro and in vivo, and this sumoylation enhances ING2 association with Sin3A and is required for ING2 binding to specific gene promoters (e.g., TMEM71) to mediate Sin3A/HDAC-dependent transcriptional repression.\",\n      \"method\": \"In vitro sumoylation assay, in vivo SUMO modification, co-immunoprecipitation, chromatin immunoprecipitation, mutagenesis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro and in vivo PTM mapping with mutagenesis and functional ChIP, single lab\",\n      \"pmids\": [\"20676127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The HECT-type ubiquitin ligase Smurf1 directly interacts with ING2 via its HECT domain, polyubiquitinates ING2 requiring the C-terminal PHD domain of ING2, and targets ING2 for proteasomal degradation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, domain mapping\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP, ubiquitination assay, domain mapping; single lab\",\n      \"pmids\": [\"20621832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ING2 interacts with proliferating cell nuclear antigen (PCNA) and regulates PCNA loading onto chromatin, controlling DNA replication fork progression; ING2 depletion reduces global replication rate and causes endoreduplication and increased sister chromatid exchange.\",\n      \"method\": \"DNA fiber spreading assay, co-immunoprecipitation, chromatin fractionation, siRNA knockdown\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (fiber assay, Co-IP, fractionation), single lab\",\n      \"pmids\": [\"19730436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Direct association of ING2 with nuclear phosphatidylinositol-5-phosphate (PtdIns(5)P) is required for ING2 promoter occupancy and ING2-associated gene repression at a subset of genomic targets in response to DNA damage; PtdIns(5)P depletion attenuates ING2-mediated gene regulation at these sites.\",\n      \"method\": \"Chromatin immunoprecipitation, PtdIns(5)P depletion, lipid-binding assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and lipid manipulation with functional gene regulation readout, single lab\",\n      \"pmids\": [\"23823870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ING2 associates with histone methyltransferase (HMT) activity in vitro and in vivo, methylating histone H3 at a site distinct from K9 but dependent on the methylation state of K4; this HDAC-independent silencing function maps to the ING2 C-terminus.\",\n      \"method\": \"In vitro HMT assay, co-immunoprecipitation, deletion and mutation analysis, reporter silencing assay with TSA\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro enzymatic assay plus domain mapping, single lab\",\n      \"pmids\": [\"18513492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ING2 knockout mice develop soft-tissue sarcomas and show male infertility due to meiotic arrest; in Ing2-null testes, HDAC1 accumulation is lost and chromatin acetylation is deregulated, establishing that ING2 functions through both p53-dependent and chromatin (HDAC1/H3K4me3)-mediated mechanisms in spermatogenesis.\",\n      \"method\": \"Targeted germline knockout, histopathology, immunofluorescence, p53 double-knockout rescue\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with multiple defined phenotypes, partial rescue by p53 co-deletion establishing epistasis\",\n      \"pmids\": [\"21124965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ING2 regulates the G1/S transition by maintaining p21 expression independently of p53; ING2 knockdown accelerates G1-to-S progression and decreases p21 levels, a function not shared by its homolog ING1.\",\n      \"method\": \"siRNA knockdown, flow cytometry cell cycle analysis, Western blot/qPCR for p21\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA with defined cell cycle phenotype and molecular readout, single lab\",\n      \"pmids\": [\"20890119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ING2 is required for C2C12 myoblast differentiation into myotubes; the leucine zipper motif of ING2 promotes differentiation while the PHD domain inhibits it, and the Sin3A-HDAC1 complex that interacts with ING2 is essential for ING2-dependent myogenesis.\",\n      \"method\": \"RNAi knockdown, overexpression of domain mutants, myotube formation assay, Co-IP of Sin3A-HDAC1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — RNAi phenotype plus domain structure-function analysis with complex interaction, single lab\",\n      \"pmids\": [\"22808232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ING2 regulates cell death in response to the alkylating agent MNNG through a MMR/c-Abl→ING2→p73α signaling axis; ING2 induction is dependent on MLH1 and c-Abl, and ING2 associates with p73α in the nucleus, promoting its stabilization and acetylation.\",\n      \"method\": \"shRNA knockdown, co-immunoprecipitation, nuclear localization assay, c-Abl inhibitor (STI571), acetylation Western blot\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — epistasis with shRNA plus Co-IP and pathway inhibitor, single lab\",\n      \"pmids\": [\"19766113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ING2 upregulation in colon cancer drives MMP13 expression and enhances cellular invasion; this regulation of MMP13 is mediated by the ING2-HDAC1-mSin3A complex, as co-expression of these complex members further induces MMP13.\",\n      \"method\": \"Microarray, siRNA knockdown, overexpression, in vitro invasion assay, EMSA/luciferase for NF-κB binding to ING2 promoter\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional invasion assay plus complex co-expression data, single lab\",\n      \"pmids\": [\"19437536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ING2 translocates into the inner mitochondrial fraction in a redox-sensitive manner modulated by 14-3-3η protein; mitochondrial ING2 interacts with mtDNA via TFAM and is required for normal mitochondrial ultrastructure and mitochondrial respiration/OXPHOS activity.\",\n      \"method\": \"Subcellular fractionation, immunoprecipitation, co-IP with TFAM, oxygen consumption rate assay, siRNA knockdown, electron microscopy\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — fractionation with functional consequence, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34017078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In renal tubular epithelial cells, ING2 controls mitochondrial respiration by regulating ubiquitination and stability of the mitochondrial transcription factor MRPL12, thereby modulating mtDNA-encoded respiratory chain component expression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, oxygen consumption rate assay, ING2 overexpression in vivo (kidney-specific), siRNA knockdown\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP with ubiquitination assay and functional respiration readout, in vivo overexpression model\",\n      \"pmids\": [\"34434929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ING2 acts as a corepressor of the androgen receptor (AR), interacting with AR to inhibit AR-mediated transactivation, induce cell cycle arrest and cellular senescence, and upregulate p16INK4a; ING2 protein levels are increased as a compensatory mechanism when ING1 is deficient.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, Ing1 knockout mouse\",\n      \"journal\": \"Journal of molecular medicine (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP plus reporter assays and in vivo KO model, single lab\",\n      \"pmids\": [\"27305909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ING1 and ING2 are recruited to the hTERT core promoter in an androgen-dependent manner and mediate AR-driven transcriptional repression of hTERT at supraphysiological androgen levels; knockdown of ING1/ING2 abolishes this repression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), siRNA knockdown, luciferase reporter assay with defined negative androgen response element\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP mapping plus functional knockdown, multiple cell models\",\n      \"pmids\": [\"34439179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ING2 directly interacts with the corepressor Alien both in vivo and in vitro (GST pulldown), and expression of ING2 enhances Alien-mediated transcriptional silencing; the Alien binding domain maps to a central region of Alien.\",\n      \"method\": \"SELDI-MS proteomic approach, co-immunoprecipitation, GST pulldown, transcriptional reporter assay\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP/pulldown with partial functional follow-up, single lab\",\n      \"pmids\": [\"17929852\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ING2 is a chromatin-regulatory tumor suppressor that uses its PHD domain to read the H3K4me3 histone mark and the nuclear phosphoinositide PtdIns(5)P signal, thereby recruiting or stabilizing the mSin3A-HDAC1 repressive complex at target gene promoters; it activates p53 by scaffolding p300-mediated p53 acetylation, regulates DNA replication fork progression through PCNA, undergoes SUMO1 modification (K195) that enhances Sin3A binding, is degraded via Smurf1-mediated ubiquitination, and also localizes to mitochondria where it maintains respiratory chain function through MRPL12 stability.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ING2 is a chromatin-regulatory tumor suppressor that integrates histone mark recognition, nuclear lipid signaling, and transcriptional repression to control cell proliferation, DNA damage responses, and differentiation. Its PHD domain binds H3K4me3/me2 with high affinity and simultaneously senses the nuclear phosphoinositide PtdIns(5)P, directing the mSin3A–HDAC1 repressive complex to target promoters such as p21 and proliferation genes in response to DNA damage [PMID:16728974, PMID:12859901, PMID:23823870]. ING2 also scaffolds p53–p300 interaction through its N-terminal leucine zipper–like motif, promoting p53 acetylation at Lys-382 to activate p53-dependent apoptosis, senescence, and nucleotide excision repair [PMID:11481424, PMID:16024799, PMID:16782091]. Beyond nuclear chromatin functions, ING2 translocates to mitochondria in a redox-sensitive manner, where it maintains respiratory chain activity by stabilizing MRPL12 and interacting with mtDNA via TFAM [PMID:34017078, PMID:34434929].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing ING2 as a p53 activator resolved how the ING family connects to the p53 tumor-suppressive pathway: ING2 enhances p53 transcriptional activity and acetylation at Lys-382, driving G1 arrest and apoptosis after DNA damage.\",\n      \"evidence\": \"Overexpression, p53 transcriptional reporter, acetylation Western blot, cell cycle and apoptosis assays in human cells\",\n      \"pmids\": [\"11481424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase responsible not identified\", \"Endogenous complex stoichiometry unknown\", \"Mechanism linking ING2 to p53 acetylation not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that the ING2 PHD finger binds PtdIns(5)P in the nucleus revealed a novel nuclear phosphoinositide signaling input that governs ING2's p53-activating and apoptotic functions.\",\n      \"evidence\": \"Lipid-binding assays (in vitro and in vivo), PHD finger mutagenesis, p53 activation assays\",\n      \"pmids\": [\"12859901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes controlling nuclear PtdIns(5)P pools not linked to ING2 regulation\", \"Whether PtdIns(5)P and H3K4me binding are mutually exclusive or cooperative unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of a p53–ING2–p300 ternary complex explained the acetylation mechanism: ING2 scaffolds p300-mediated p53 acetylation, linking this to replicative senescence.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, siRNA knockdown, senescence assays\",\n      \"pmids\": [\"16024799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ING2–p300 binding interface not mapped\", \"Whether ING2 directs p300 to chromatin versus soluble p53 unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Structural and biochemical resolution of H3K4me3 recognition by the PHD domain, combined with its role in tethering the mSin3A–HDAC1 complex to promoters, established ING2 as a histone-mark reader linking active chromatin marks to transcriptional repression.\",\n      \"evidence\": \"2.0 Å crystal structure, binding assays, aromatic cage mutagenesis (Y215/W238), ChIP, Co-IP with mSin3A–HDAC1\",\n      \"pmids\": [\"16728974\", \"16728977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a mark of active transcription (H3K4me3) is reconciled with repressive HDAC recruitment not fully resolved\", \"Genome-wide binding profile not determined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"ING2 was placed upstream of chromatin remodeling in UV-induced nucleotide excision repair, showing it promotes histone H4 acetylation, chromatin relaxation, and XPA recruitment to photolesions, with the leucine zipper–like motif essential for p53 association and repair.\",\n      \"evidence\": \"Host-cell reactivation assay, siRNA, histone acetylation and chromatin accessibility assays, domain deletion mutagenesis\",\n      \"pmids\": [\"16488987\", \"16782091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ING2 directly recruits a HAT for H4 acetylation in NER unknown\", \"Repair function not validated by in vivo damage assays in knockout models\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that ING2 participates in TGF-β signaling through a SnoN–ING2–Smad2 complex broadened its role beyond p53 to include Smad-dependent transcription and cell cycle arrest.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA, transcriptional reporter assays\",\n      \"pmids\": [\"18334480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chromatin target genes of the SnoN–ING2–Smad2 complex not defined\", \"Whether the Sin3A–HDAC1 complex is involved in this axis unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linking ING2 to PCNA and DNA replication fork progression revealed a replication-intrinsic function: ING2 controls PCNA loading onto chromatin, and its loss causes reduced replication rate, endoreduplication, and sister chromatid exchange.\",\n      \"evidence\": \"DNA fiber spreading, co-immunoprecipitation, chromatin fractionation, siRNA\",\n      \"pmids\": [\"19730436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ING2 promotes PCNA loading not resolved\", \"Whether PHD domain H3K4me3 reading is required for replication function unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Post-translational regulation of ING2 was defined: SUMO1 modification at K195 enhances Sin3A binding and promoter occupancy, while Smurf1-mediated ubiquitination targets ING2 for proteasomal degradation, revealing opposing PTM switches that tune ING2 activity.\",\n      \"evidence\": \"In vitro and in vivo sumoylation/ubiquitination assays, mutagenesis, Co-IP, ChIP, proteasome inhibitor treatment\",\n      \"pmids\": [\"20676127\", \"20621832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals triggering Smurf1-mediated degradation not identified\", \"Interplay between sumoylation and ubiquitination not examined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Ing2 knockout mice developed soft-tissue sarcomas and male infertility with meiotic arrest and deregulated chromatin acetylation, providing in vivo genetic proof of tumor suppressor function and a requirement for HDAC1-mediated chromatin regulation in spermatogenesis.\",\n      \"evidence\": \"Germline knockout, histopathology, p53 double-knockout rescue, immunofluorescence\",\n      \"pmids\": [\"21124965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tumor spectrum and latency not fully characterized\", \"Direct transcriptional targets in spermatogenesis not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genome-level demonstration that PtdIns(5)P binding is required for ING2 promoter occupancy at a subset of DNA damage–responsive targets refined the lipid-signaling model from a general activator to a site-selective chromatin-targeting mechanism.\",\n      \"evidence\": \"ChIP combined with PtdIns(5)P depletion and lipid-binding assays\",\n      \"pmids\": [\"23823870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full repertoire of PtdIns(5)P-dependent ING2 target genes not mapped\", \"Whether PtdIns(5)P binding alters PHD domain conformation not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery of ING2 translocation to mitochondria, where it interacts with mtDNA via TFAM and stabilizes MRPL12 to maintain OXPHOS, revealed a non-nuclear function that extends ING2's role to mitochondrial homeostasis.\",\n      \"evidence\": \"Subcellular fractionation, Co-IP with TFAM and MRPL12, OCR assay, electron microscopy, siRNA, kidney-specific in vivo overexpression\",\n      \"pmids\": [\"34017078\", \"34434929\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mitochondrial import signal or translocase pathway not identified\", \"Whether mitochondrial ING2 retains PHD-dependent functions unknown\", \"Physiological stimuli triggering mitochondrial translocation beyond redox changes not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The interplay between ING2's nuclear chromatin functions and its mitochondrial roles, the full genome-wide target repertoire of ING2-associated repressive complexes, and how PtdIns(5)P and H3K4me3 binding are coordinated on the same PHD domain remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genome-wide occupancy map integrating histone mark and lipid-dependent targeting\", \"Structural basis for dual PHD ligand recognition (H3K4me3 vs PtdIns(5)P) not determined\", \"Relative contribution of nuclear vs mitochondrial ING2 to tumor suppression unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 5, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 9, 18, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 3, 9, 12]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 6, 11]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [19, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 5, 9, 13]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 3, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 9, 22]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"mSin3A-HDAC1\",\n      \"p53-p300-ING2\",\n      \"SnoN-ING2-Smad2\"\n    ],\n    \"partners\": [\n      \"HDAC1\",\n      \"SIN3A\",\n      \"TP53\",\n      \"EP300\",\n      \"PCNA\",\n      \"SMURF1\",\n      \"TFAM\",\n      \"MRPL12\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}