{"gene":"OGFOD1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2014,"finding":"OGFOD1 is a prolyl hydroxylase that catalyzes trans-3 prolyl hydroxylation of Pro-62 in the small ribosomal protein RPS23 (uS12). OGFOD1 retains high affinity for and forms a stable complex with the hydroxylated RPS23 substrate. Knockdown or catalytic inactivation of OGFOD1 caused stress granule induction, translational arrest, and growth impairment, rescued by wild-type but not catalytically inactive OGFOD1.","method":"In vitro hydroxylation assay, mass spectrometry, Co-IP, knockdown/rescue with catalytic mutants, cell-based phenotypic readouts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis, substrate identified by MS, functional rescue with catalytic mutant, replicated across yeast homolog studies","pmids":["24550447"],"is_preprint":false},{"year":2015,"finding":"Crystal structures of human OGFOD1 in complex with broad-spectrum 2OG oxygenase inhibitors (NOG and 2,4-PDCA) were solved to 2.1 and 2.6 Å resolution, respectively, revealing the structural basis for trans-3 prolyl hydroxylation of uS12/RPS23 Pro-62 and differences between prolyl-3 and prolyl-4 hydroxylase active sites that can be exploited for selective inhibitor development.","method":"X-ray crystallography (crystal structures of OGFOD1 with inhibitors), structural comparison with PHDs and Tpa1p","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple crystal structures solved to high resolution, functional active-site analysis, corroborated by parallel Tpa1p structures","pmids":["25728928"],"is_preprint":false},{"year":2010,"finding":"OGFOD1 localizes to stress granules and associates via co-immunoprecipitation with stress granule proteins G3BP1, USP10, Caprin1, and YB-1, as well as the ribosome, in both unstressed and stressed cells. OGFOD1 also interacts with eIF2α and the eIF2α kinase HRI. Overexpression of OGFOD1 increased phosphorylated eIF2α levels and accelerated apoptosis, while OGFOD1 knockdown reduced eIF2α phosphorylation and accelerated polyribosome re-accumulation after stress.","method":"Co-immunoprecipitation, overexpression and knockdown (siRNA), polyribosome sedimentation assays, immunofluorescence for stress granule localization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with multiple partners, KD and OE with defined phenotypic readouts, single lab","pmids":["20154146"],"is_preprint":false},{"year":2010,"finding":"OGFOD1 catalytic activity (dependent on an iron-binding residue) is required for expression of ATPAF1 mRNA; OGFOD1 gene silencing confers resistance to ischemic cell death, and reintroduction of catalytically inactive OGFOD1 mutants fails to restore ATPAF1 expression, while ATPAF1 reintroduction into OGFOD1 KO cells re-induces ischemic cell death.","method":"Gene silencing (KO), cDNA microarray, re-introduction of wild-type vs. catalytic mutant OGFOD1, ATPAF1 rescue experiment","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined phenotype, catalytic mutant rescue, downstream gene (ATPAF1) rescue, single lab","pmids":["20579638"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of S. cerevisiae Tpa1 (OGFOD1 ortholog) as binary complex with Fe(III) and ternary complex with Fe(III) and 2-oxoglutarate revealed that both the N- and C-terminal domains have the double-stranded beta-helix fold similar to prolyl 4-hydroxylases; Fe(III) and 2OG binding occurs only in the N-terminal domain. Tpa1 also binds poly(rA), suggesting direct interaction with mRNA.","method":"X-ray crystallography, poly(rA) binding assay","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — crystal structure with bound cofactors, poly(rA) binding assay; ortholog study, single lab","pmids":["20040577"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of S. cerevisiae Tpa1 (OGFOD1 ortholog) demonstrated a prolyl-4-hydroxylase-like N-terminal active site. Integrity of the Tpa1 active site and presence of its partner Yor051c/Ett1 (Nro1 ortholog) are both essential for correct translation termination, and Tpa1 represses expression of genes regulated by the Hap1 transcription factor, connecting its catalytic activity to hypoxia/oxygen sensing.","method":"X-ray crystallography, active site mutagenesis, genetic deletion with translation termination readout, gene expression assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — structure plus active site mutagenesis plus functional genetics, ortholog study, single lab","pmids":["20630870"],"is_preprint":false},{"year":2014,"finding":"S. cerevisiae Tpa1 (OGFOD1 ortholog) directly repairs methylated DNA in vitro (both single- and double-stranded), dependent on its Fe(II)/2OG dioxygenase cofactor-binding residues. Genetic epistasis showed that tpa1Δmag1Δ double mutants are highly susceptible to methylation toxicity, placing Tpa1 in a parallel pathway to base excision repair.","method":"In vitro DNA repair assay with purified Tpa1, active-site mutagenesis, genetic epistasis (double and triple mutant analysis)","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro repair assay with purified protein and mutagenesis, genetic epistasis; ortholog study, single lab","pmids":["25381260"],"is_preprint":false},{"year":2019,"finding":"Deletion of OGFOD1 in human cardiomyocytes decreases translation of specific proteins (e.g., RNA-binding proteins) and alters mRNA splicing. The poor correlation between mRNA and protein changes indicates posttranscriptional regulation as the primary consequence. Loss of OGFOD1 shifts the cardiac proteome toward higher levels of sarcomeric proteins (cardiac troponins, titin, cardiac myosin binding protein C), and OGFOD1 expression decreases during cardiomyocyte differentiation.","method":"OGFOD1 deletion in iPSC-derived cardiomyocytes, RNA-seq, quantitative proteomics, correlation analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with multi-omic readout (proteomics + RNA-seq), single lab","pmids":["31112528"],"is_preprint":false},{"year":2021,"finding":"OGFOD1 directly binds to the C-terminal domain (CTD) of RNA Polymerase II and alters its phosphorylation status. CDK7 and CDK9 phosphorylate OGFOD1 at Ser-256; a non-phosphorylatable Ser256 mutant fails to enhance transcriptional activation and tumor growth. OGFOD1 elimination reduced tumor development.","method":"Co-IP (OGFOD1–RNA Pol II CTD), phosphorylation assay with CDK7/CDK9, phospho-mutant (S256A) rescue, in vitro and in vivo tumor growth assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown by Co-IP, kinase assay with specific mutant, functional rescue; single lab","pmids":["34298635"],"is_preprint":false},{"year":2022,"finding":"OGFOD1 deletion in mice increases myocardial beta-alanine levels and alters purine/pyrimidine metabolism. OGFOD1 KO hearts show 41% reduction in infarct size and 34% improvement in cardiac function after ischemia-reperfusion. Treatment of WT hearts with carnosine (a beta-alanine metabolite) recapitulates part of the protection, while carnosine treatment of KO hearts has no additional effect, consistent with beta-alanine accumulation mediating cardioprotection.","method":"Knockout mouse model, quantitative proteomics (TMT-LC-MS/MS), metabolomics, ex vivo and in vivo ischemia-reperfusion injury models, carnosine pharmacological rescue","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with proteomics and metabolomics, functional I/R readout, pharmacological rescue; single lab","pmids":["34668514"],"is_preprint":false},{"year":2022,"finding":"OGFOD1 knockdown in lung cancer cells induces cell cycle arrest via depletion of CDK1, CDK2, and cyclin B1 (CCNB1) mRNAs and nuclear accumulation of p21Cip1. CDK1 reduction is post-transcriptional and involves the RNA-binding protein HuR; CDK2 and CCNB1 depletion results from decreased transcription mediated by OGFOD1.","method":"siRNA knockdown, mRNA stability assays, RT-qPCR, immunofluorescence for p21 localization, RNP-IP or co-regulation with HuR","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with mechanistic dissection of post-transcriptional vs. transcriptional regulation and involvement of HuR; single lab","pmids":["36464654"],"is_preprint":false},{"year":2024,"finding":"OGFOD1 inhibition by FG4592 (a PHD inhibitor that was identified via target prediction and molecular docking as a novel OGFOD1 inhibitor) decreases infarct volume after ischemic stroke. OGFOD1 knockdown protects against ischemia/reperfusion injury by activating the unfolded protein response (UPR) and autophagy in a HIF-1α-independent manner. Blocking UPR attenuated the neuroprotection, pro-autophagy, and anti-apoptosis effects of FG4592.","method":"Molecular docking, OGFOD1 knockdown in vitro/in vivo, mouse ischemic stroke model, UPR/autophagy pathway inhibition, HIF-1α KD and pharmacological blockade","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined pathway readout (UPR, autophagy), pharmacological and genetic pathway blockade; single lab, molecular docking is computational","pmids":["38454480"],"is_preprint":false},{"year":2025,"finding":"OGFOD1 upregulates global protein synthesis in AML cells by adjusting ribosomal fidelity through its dioxygenase activity (Pro-62 hydroxylation of RPS23). Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis, and improved survival in chemoresistant AML animal models while sparing normal hematopoiesis.","method":"In vivo patient-derived xenograft models, OGFOD1 genetic inhibition, proteomics, translation assays","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO/KD with functional translation readout in AML models; single study but multiple orthogonal methods","pmids":["40961937"],"is_preprint":false},{"year":2026,"finding":"OGFOD1 silencing in hepatocytes subjected to hypoxia/reoxygenation decreases SPARC protein levels without changing SPARC mRNA levels (identified through combined transcriptomics and proteomics), and SPARC overexpression rescues the effects of OGFOD1 silencing on apoptosis and oxidative stress, placing SPARC downstream of OGFOD1 in a post-transcriptional regulatory pathway.","method":"siRNA silencing in H/R hepatocyte model and HIRI rat model, combined transcriptomics and proteomics, SPARC overexpression rescue","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multi-omic mechanistic dissection, downstream rescue experiment; single lab","pmids":["41558616"],"is_preprint":false}],"current_model":"OGFOD1 is a 2-oxoglutarate- and Fe(II)-dependent dioxygenase that catalyzes trans-3 prolyl hydroxylation of Pro-62 on the small ribosomal subunit protein RPS23 (uS12), thereby modulating ribosomal fidelity, global and selective protein translation, and stress responses; it also localizes to stress granules, interacts with eIF2α and its kinase HRI to regulate eIF2α phosphorylation, binds the RNA Pol II CTD and is phosphorylated by CDK7/CDK9 to enhance transcription, and its loss broadly alters the proteome and confers protection against ischemia-reperfusion injury, cardiac hypertrophy, and chemoresistance."},"narrative":{"mechanistic_narrative":"OGFOD1 is a Fe(II)- and 2-oxoglutarate-dependent prolyl hydroxylase that controls protein synthesis by post-translationally modifying the translation machinery and tuning ribosomal fidelity [PMID:24550447, PMID:40961937]. It catalyzes trans-3 prolyl hydroxylation of Pro-62 in the small ribosomal subunit protein RPS23 (uS12), retaining high affinity for the hydroxylated product; loss of this catalytic activity triggers stress granule induction, translational arrest, and growth impairment, and the phenotype is rescued only by catalytically active enzyme [PMID:24550447]. Crystal structures of the human enzyme with 2OG-oxygenase inhibitors define a prolyl-3-hydroxylase active site distinct from prolyl-4-hydroxylases [PMID:25728928]. Beyond ribosome modification, OGFOD1 localizes to stress granules and associates with the ribosome and stress granule proteins, and interacts with eIF2α and its kinase HRI to set the level of eIF2α phosphorylation and the pace of polyribosome recovery after stress [PMID:20154146]. It also directly binds the RNA Pol II C-terminal domain and is phosphorylated at Ser-256 by CDK7/CDK9, which is required for its enhancement of transcriptional activation and tumor growth [PMID:34298635]. Functionally, OGFOD1 loss reshapes the proteome largely at the post-transcriptional level, controlling translation and stability of specific targets including cell-cycle regulators (CDK1 via HuR, with CDK2/CCNB1 reduced transcriptionally) and tissue-specific factors [PMID:31112528, PMID:36464654], and confers protection against ischemia-reperfusion injury through UPR/autophagy activation and altered β-alanine metabolism [PMID:34668514, PMID:38454480], and supports global protein synthesis in chemoresistant AML [PMID:40961937]. Studies of the yeast ortholog Tpa1 establish a conserved double-stranded β-helix dioxygenase architecture coupled to translation termination and oxygen/hypoxia-responsive gene regulation [PMID:20040577, PMID:20630870].","teleology":[{"year":2009,"claim":"Defining the enzymatic scaffold: it was unknown how this 2OG-oxygenase family member was organized, and structures of the yeast ortholog Tpa1 revealed a bilobed double-stranded β-helix fold with cofactor binding restricted to the N-terminal domain, plus poly(rA) binding hinting at mRNA association.","evidence":"X-ray crystallography of S. cerevisiae Tpa1 with Fe(III) and 2OG, poly(rA) binding assay","pmids":["20040577"],"confidence":"Medium","gaps":["Catalytic substrate not identified in this work","Ortholog study; human enzyme not addressed","Functional role of the inactive C-terminal domain unresolved"]},{"year":2010,"claim":"Linking catalysis to translation and oxygen sensing: Tpa1 active-site integrity and its partner Ett1/Nro1 were shown to be essential for correct translation termination and for repression of Hap1-regulated hypoxic genes, connecting the dioxygenase to translation and oxygen-responsive transcription.","evidence":"Crystallography, active-site mutagenesis, genetic deletion with translation termination and gene-expression readouts in yeast","pmids":["20630870"],"confidence":"Medium","gaps":["Direct catalytic substrate still unidentified","Mechanism connecting termination to oxygen sensing unclear","Human relevance inferred from ortholog"]},{"year":2010,"claim":"Placing the human protein in the stress-response network: OGFOD1 was found in stress granules and bound to the ribosome, eIF2α, and HRI, with its level controlling eIF2α phosphorylation and translational recovery—establishing a role in the integrated stress response.","evidence":"Reciprocal Co-IP, siRNA knockdown and overexpression, polyribosome sedimentation, immunofluorescence","pmids":["20154146"],"confidence":"Medium","gaps":["Whether eIF2α/HRI effects require catalytic activity not resolved","Single lab","Direct vs. indirect nature of HRI interaction not dissected"]},{"year":2010,"claim":"Tying catalysis to a downstream transcript and an ischemic phenotype: OGFOD1 catalytic activity was shown to be required for ATPAF1 expression and ischemic cell death, with catalytic-mutant and ATPAF1 rescue experiments establishing causality.","evidence":"Gene silencing, cDNA microarray, wild-type vs. catalytic-mutant reintroduction, ATPAF1 rescue","pmids":["20579638"],"confidence":"Medium","gaps":["Direct substrate connecting catalysis to ATPAF1 unknown","Mechanism of transcript-specific regulation unclear","Single lab"]},{"year":2014,"claim":"Identifying the physiological substrate: it was unknown what OGFOD1 hydroxylates, and in vitro assays with MS established RPS23 (uS12) Pro-62 as the trans-3 prolyl hydroxylation target, with catalytic-mutant rescue tying the modification to stress granule and growth phenotypes.","evidence":"In vitro hydroxylation assay, mass spectrometry, Co-IP, knockdown/rescue with catalytic mutants","pmids":["24550447"],"confidence":"High","gaps":["How Pro-62 hydroxylation alters ribosome function mechanistically not fully defined","Whether other substrates exist not excluded"]},{"year":2014,"claim":"Establishing a non-ribosomal catalytic capacity in the ortholog: Tpa1 was shown to directly repair methylated DNA in vitro in a cofactor-dependent manner and to act in a pathway parallel to base excision repair.","evidence":"In vitro DNA repair assay with purified Tpa1, active-site mutagenesis, genetic epistasis","pmids":["25381260"],"confidence":"Medium","gaps":["Whether human OGFOD1 has analogous DNA-repair activity untested","Physiological significance versus RPS23 hydroxylation unclear","Ortholog study"]},{"year":2015,"claim":"Defining the structural basis of substrate specificity: human OGFOD1 structures with broad-spectrum 2OG-oxygenase inhibitors revealed the prolyl-3 hydroxylase active site and its distinctions from prolyl-4 hydroxylases, enabling selective inhibitor design.","evidence":"X-ray crystallography of human OGFOD1 with NOG and 2,4-PDCA, structural comparison","pmids":["25728928"],"confidence":"High","gaps":["No structure with RPS23 substrate bound","Selective inhibitors not yet developed in this work"]},{"year":2019,"claim":"Demonstrating proteome-wide post-transcriptional control: OGFOD1 deletion in cardiomyocytes selectively altered translation and splicing with poor mRNA-protein correlation, establishing post-transcriptional regulation as its primary cellular consequence and a role in cardiac proteome composition.","evidence":"OGFOD1 deletion in iPSC-cardiomyocytes, RNA-seq, quantitative proteomics, correlation analysis","pmids":["31112528"],"confidence":"Medium","gaps":["Which targets are direct consequences of RPS23 hydroxylation unclear","Mechanism of selective translational control undefined","Single lab"]},{"year":2021,"claim":"Uncovering a transcriptional arm: OGFOD1 was shown to bind the RNA Pol II CTD and to be phosphorylated by CDK7/CDK9 at Ser-256, with a non-phosphorylatable mutant failing to enhance transcription and tumor growth.","evidence":"Co-IP, CDK7/CDK9 phosphorylation assay, S256A phospho-mutant rescue, tumor growth assays","pmids":["34298635"],"confidence":"Medium","gaps":["Relationship between CTD binding and prolyl hydroxylase activity unresolved","Whether OGFOD1 hydroxylates a transcriptional target unknown","Single lab"]},{"year":2022,"claim":"Connecting OGFOD1 to cell-cycle control and cancer: knockdown induced arrest through post-transcriptional CDK1 loss (via HuR) and transcriptional CDK2/CCNB1 depletion with p21 nuclear accumulation, dissecting dual regulatory modes.","evidence":"siRNA knockdown, mRNA stability assays, RT-qPCR, p21 immunofluorescence, RNP-IP with HuR","pmids":["36464654"],"confidence":"Medium","gaps":["Direct molecular link between OGFOD1 catalysis and HuR-mediated regulation unknown","Single cancer model","Single lab"]},{"year":2022,"claim":"Defining a metabolic basis for cardioprotection: OGFOD1 knockout mice showed β-alanine accumulation, reduced infarct size, and improved function after ischemia-reperfusion, with carnosine rescue implicating β-alanine metabolism in the protection.","evidence":"Knockout mouse, TMT proteomics, metabolomics, ex vivo/in vivo ischemia-reperfusion, carnosine pharmacological rescue","pmids":["34668514"],"confidence":"Medium","gaps":["How OGFOD1 catalysis controls β-alanine metabolism unclear","Link between RPS23 hydroxylation and metabolic phenotype undefined","Single lab"]},{"year":2024,"claim":"Mapping the protective signaling output and a druggable target: OGFOD1 knockdown protected against ischemic stroke by activating UPR and autophagy independently of HIF-1α, and FG4592 was identified as an OGFOD1 inhibitor.","evidence":"Molecular docking, OGFOD1 knockdown in vitro/in vivo, mouse ischemic stroke model, UPR/autophagy blockade, HIF-1α knockdown","pmids":["38454480"],"confidence":"Medium","gaps":["FG4592 binding to OGFOD1 is computational/pharmacological, not structurally confirmed","Mechanism linking inhibition to UPR activation unclear","Single lab"]},{"year":2025,"claim":"Establishing therapeutic relevance in leukemia: OGFOD1 was shown to drive global protein synthesis in AML through RPS23 Pro-62 hydroxylation, and its inhibition impaired translation and improved survival in chemoresistant models while sparing normal hematopoiesis.","evidence":"Patient-derived xenografts, genetic inhibition, proteomics, translation assays","pmids":["40961937"],"confidence":"Medium","gaps":["Therapeutic window in patients untested","Selective inhibitor not yet available","Single study"]},{"year":2026,"claim":"Extending post-transcriptional control to hepatic ischemia: OGFOD1 silencing reduced SPARC protein without changing its mRNA, and SPARC overexpression rescued apoptosis and oxidative stress, placing SPARC downstream in a post-transcriptional pathway.","evidence":"siRNA silencing in H/R hepatocytes and HIRI rat model, combined transcriptomics/proteomics, SPARC overexpression rescue","pmids":["41558616"],"confidence":"Medium","gaps":["Mechanism by which OGFOD1 controls SPARC translation/stability unknown","Whether RPS23 hydroxylation mediates this effect untested","Single lab"]},{"year":null,"claim":"It remains unresolved how RPS23 Pro-62 hydroxylation mechanistically connects the enzyme's many downstream phenotypes—selective translation, transcriptional enhancement via Pol II CTD, metabolic and UPR/autophagy outputs—and whether the transcriptional and DNA-related activities require its catalytic function.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of OGFOD1 bound to RPS23","Catalytic dependence of CTD-binding and metabolic phenotypes not established","Direct mechanism linking ribosomal modification to transcript-specific regulation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[2,11]}],"complexes":[],"partners":["RPS23","EIF2S1","EIF2AK1","G3BP1","USP10","CAPRIN1","YBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N543","full_name":"Prolyl 3-hydroxylase OGFOD1","aliases":["2-oxoglutarate and iron-dependent oxygenase domain-containing protein 1","Termination and polyadenylation 1 homolog","uS12 prolyl 3-hydroxylase"],"length_aa":542,"mass_kda":63.2,"function":"Prolyl 3-hydroxylase that catalyzes 3-hydroxylation of 'Pro-62' of small ribosomal subunit uS12 (RPS23), thereby regulating protein translation termination efficiency. Involved in stress granule formation","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q8N543/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OGFOD1","classification":"Not Classified","n_dependent_lines":33,"n_total_lines":1208,"dependency_fraction":0.027317880794701987},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OGFOD1","total_profiled":1310},"omim":[{"mim_id":"617412","title":"BRACHYCEPHALY, TRICHOMEGALY, AND DEVELOPMENTAL DELAY; BTDD","url":"https://www.omim.org/entry/617412"},{"mim_id":"615857","title":"2-OXOGLUTARATE- AND IRON-DEPENDENT OXYGENASE DOMAIN-CONTAINING PROTEIN 1; OGFOD1","url":"https://www.omim.org/entry/615857"},{"mim_id":"603683","title":"RIBOSOMAL PROTEIN S23; RPS23","url":"https://www.omim.org/entry/603683"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OGFOD1"},"hgnc":{"alias_symbol":["KIAA1612","FLJ10826","TPA1"],"prev_symbol":[]},"alphafold":{"accession":"Q8N543","domains":[{"cath_id":"2.60.120.620","chopping":"29-239","consensus_level":"high","plddt":96.9282,"start":29,"end":239},{"cath_id":"2.60.120.620","chopping":"257-367_432-542","consensus_level":"high","plddt":94.8804,"start":257,"end":542}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N543","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N543-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N543-F1-predicted_aligned_error_v6.png","plddt_mean":86.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OGFOD1","jax_strain_url":"https://www.jax.org/strain/search?query=OGFOD1"},"sequence":{"accession":"Q8N543","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N543.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N543/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N543"}},"corpus_meta":[{"pmid":"24550447","id":"PMC_24550447","title":"OGFOD1 catalyzes prolyl hydroxylation of RPS23 and is involved in translation control and stress granule formation.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24550447","citation_count":99,"is_preprint":false},{"pmid":"20154146","id":"PMC_20154146","title":"OGFOD1, a novel modulator of eukaryotic translation initiation factor 2alpha phosphorylation and the cellular response to stress.","date":"2010","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20154146","citation_count":63,"is_preprint":false},{"pmid":"25728928","id":"PMC_25728928","title":"Structure of the ribosomal oxygenase OGFOD1 provides insights into the regio- and stereoselectivity of prolyl hydroxylases.","date":"2015","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/25728928","citation_count":33,"is_preprint":false},{"pmid":"20630870","id":"PMC_20630870","title":"Structural and functional insights into Saccharomyces cerevisiae Tpa1, a putative prolylhydroxylase influencing translation termination and transcription.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20630870","citation_count":29,"is_preprint":false},{"pmid":"20579638","id":"PMC_20579638","title":"OGFOD1, a member of the 2-oxoglutarate and iron dependent dioxygenase family, functions in ischemic signaling.","date":"2010","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/20579638","citation_count":26,"is_preprint":false},{"pmid":"25381260","id":"PMC_25381260","title":"A role for Saccharomyces cerevisiae Tpa1 protein in direct alkylation repair.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25381260","citation_count":24,"is_preprint":false},{"pmid":"20040577","id":"PMC_20040577","title":"Crystal structure of Tpa1 from Saccharomyces cerevisiae, a component of the messenger ribonucleoprotein complex.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/20040577","citation_count":24,"is_preprint":false},{"pmid":"7658466","id":"PMC_7658466","title":"The tpa-1 gene of Caenorhabditis elegans encodes two proteins similar to Ca(2+)-independent protein kinase Cs: evidence by complete genomic and complementary DNA sequences of the tpa-1 gene.","date":"1995","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7658466","citation_count":19,"is_preprint":false},{"pmid":"31112528","id":"PMC_31112528","title":"The ribosomal prolyl-hydroxylase OGFOD1 decreases during cardiac differentiation and modulates translation and splicing.","date":"2019","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/31112528","citation_count":14,"is_preprint":false},{"pmid":"32002629","id":"PMC_32002629","title":"OGFOD1 negatively regulated by miR-1224-5p promotes proliferation in human papillomavirus-infected laryngeal papillomas.","date":"2020","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/32002629","citation_count":10,"is_preprint":false},{"pmid":"34668514","id":"PMC_34668514","title":"Ogfod1 deletion increases cardiac beta-alanine levels and protects mice against ischaemia- reperfusion injury.","date":"2022","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/34668514","citation_count":9,"is_preprint":false},{"pmid":"38454480","id":"PMC_38454480","title":"Inhibition of OGFOD1 by FG4592 confers neuroprotection by activating unfolded protein response and autophagy after ischemic stroke.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38454480","citation_count":9,"is_preprint":false},{"pmid":"34298635","id":"PMC_34298635","title":"Phosphorylation of OGFOD1 by Cell Cycle-Dependent Kinase 7/9 Enhances the Transcriptional Activity of RNA Polymerase II in Breast Cancer Cells.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34298635","citation_count":6,"is_preprint":false},{"pmid":"36464654","id":"PMC_36464654","title":"The prolyl hydroxylase OGFOD1 promotes cancer cell proliferation by regulating the expression of cell cycle regulators.","date":"2022","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/36464654","citation_count":5,"is_preprint":false},{"pmid":"37084634","id":"PMC_37084634","title":"OGFOD1 modulates the transcriptional and proteomic landscapes to alter isoproterenol-induced hypertrophy susceptibility.","date":"2023","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/37084634","citation_count":3,"is_preprint":false},{"pmid":"38843265","id":"PMC_38843265","title":"Deleting the ribosomal prolyl hydroxylase OGFOD1 protects mice against diet-induced obesity and insulin resistance.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38843265","citation_count":2,"is_preprint":false},{"pmid":"38238075","id":"PMC_38238075","title":"A Necessary Role for PKC-2 and TPA-1 in Olfactory Memory and Synaptic AMPAR Trafficking in Caenorhabditis elegans.","date":"2024","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38238075","citation_count":2,"is_preprint":false},{"pmid":"40961937","id":"PMC_40961937","title":"OGFOD1 enables AML chemo- and nutrient stress resistance by regulating protein synthesis.","date":"2025","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40961937","citation_count":1,"is_preprint":false},{"pmid":"42088572","id":"PMC_42088572","title":"OGFOD1: a critical mediator of chemoresistance in acute myeloid leukemia.","date":"2026","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42088572","citation_count":0,"is_preprint":false},{"pmid":"38602331","id":"PMC_38602331","title":"Nematicidal Activity of 20-Deoxyingenol-3-angelate from Euphorbia peplus Latex Through Protein Kinase C Isotype TPA-1.","date":"2024","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38602331","citation_count":0,"is_preprint":false},{"pmid":"41558616","id":"PMC_41558616","title":"Silencing OGFOD1 ameliorates hepatic ischemia-reperfusion injury through abrogating oxidative stress and apoptosis via downregulating SPARC.","date":"2026","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41558616","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11930,"output_tokens":3917,"usd":0.047273,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11731,"output_tokens":5164,"usd":0.093878,"stage2_stop_reason":"end_turn"},"total_usd":0.141151,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"OGFOD1 is a prolyl hydroxylase that catalyzes trans-3 prolyl hydroxylation of Pro-62 in the small ribosomal protein RPS23 (uS12). OGFOD1 retains high affinity for and forms a stable complex with the hydroxylated RPS23 substrate. Knockdown or catalytic inactivation of OGFOD1 caused stress granule induction, translational arrest, and growth impairment, rescued by wild-type but not catalytically inactive OGFOD1.\",\n      \"method\": \"In vitro hydroxylation assay, mass spectrometry, Co-IP, knockdown/rescue with catalytic mutants, cell-based phenotypic readouts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with mutagenesis, substrate identified by MS, functional rescue with catalytic mutant, replicated across yeast homolog studies\",\n      \"pmids\": [\"24550447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structures of human OGFOD1 in complex with broad-spectrum 2OG oxygenase inhibitors (NOG and 2,4-PDCA) were solved to 2.1 and 2.6 Å resolution, respectively, revealing the structural basis for trans-3 prolyl hydroxylation of uS12/RPS23 Pro-62 and differences between prolyl-3 and prolyl-4 hydroxylase active sites that can be exploited for selective inhibitor development.\",\n      \"method\": \"X-ray crystallography (crystal structures of OGFOD1 with inhibitors), structural comparison with PHDs and Tpa1p\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple crystal structures solved to high resolution, functional active-site analysis, corroborated by parallel Tpa1p structures\",\n      \"pmids\": [\"25728928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"OGFOD1 localizes to stress granules and associates via co-immunoprecipitation with stress granule proteins G3BP1, USP10, Caprin1, and YB-1, as well as the ribosome, in both unstressed and stressed cells. OGFOD1 also interacts with eIF2α and the eIF2α kinase HRI. Overexpression of OGFOD1 increased phosphorylated eIF2α levels and accelerated apoptosis, while OGFOD1 knockdown reduced eIF2α phosphorylation and accelerated polyribosome re-accumulation after stress.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown (siRNA), polyribosome sedimentation assays, immunofluorescence for stress granule localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with multiple partners, KD and OE with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"20154146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"OGFOD1 catalytic activity (dependent on an iron-binding residue) is required for expression of ATPAF1 mRNA; OGFOD1 gene silencing confers resistance to ischemic cell death, and reintroduction of catalytically inactive OGFOD1 mutants fails to restore ATPAF1 expression, while ATPAF1 reintroduction into OGFOD1 KO cells re-induces ischemic cell death.\",\n      \"method\": \"Gene silencing (KO), cDNA microarray, re-introduction of wild-type vs. catalytic mutant OGFOD1, ATPAF1 rescue experiment\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined phenotype, catalytic mutant rescue, downstream gene (ATPAF1) rescue, single lab\",\n      \"pmids\": [\"20579638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of S. cerevisiae Tpa1 (OGFOD1 ortholog) as binary complex with Fe(III) and ternary complex with Fe(III) and 2-oxoglutarate revealed that both the N- and C-terminal domains have the double-stranded beta-helix fold similar to prolyl 4-hydroxylases; Fe(III) and 2OG binding occurs only in the N-terminal domain. Tpa1 also binds poly(rA), suggesting direct interaction with mRNA.\",\n      \"method\": \"X-ray crystallography, poly(rA) binding assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with bound cofactors, poly(rA) binding assay; ortholog study, single lab\",\n      \"pmids\": [\"20040577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of S. cerevisiae Tpa1 (OGFOD1 ortholog) demonstrated a prolyl-4-hydroxylase-like N-terminal active site. Integrity of the Tpa1 active site and presence of its partner Yor051c/Ett1 (Nro1 ortholog) are both essential for correct translation termination, and Tpa1 represses expression of genes regulated by the Hap1 transcription factor, connecting its catalytic activity to hypoxia/oxygen sensing.\",\n      \"method\": \"X-ray crystallography, active site mutagenesis, genetic deletion with translation termination readout, gene expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure plus active site mutagenesis plus functional genetics, ortholog study, single lab\",\n      \"pmids\": [\"20630870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"S. cerevisiae Tpa1 (OGFOD1 ortholog) directly repairs methylated DNA in vitro (both single- and double-stranded), dependent on its Fe(II)/2OG dioxygenase cofactor-binding residues. Genetic epistasis showed that tpa1Δmag1Δ double mutants are highly susceptible to methylation toxicity, placing Tpa1 in a parallel pathway to base excision repair.\",\n      \"method\": \"In vitro DNA repair assay with purified Tpa1, active-site mutagenesis, genetic epistasis (double and triple mutant analysis)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro repair assay with purified protein and mutagenesis, genetic epistasis; ortholog study, single lab\",\n      \"pmids\": [\"25381260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Deletion of OGFOD1 in human cardiomyocytes decreases translation of specific proteins (e.g., RNA-binding proteins) and alters mRNA splicing. The poor correlation between mRNA and protein changes indicates posttranscriptional regulation as the primary consequence. Loss of OGFOD1 shifts the cardiac proteome toward higher levels of sarcomeric proteins (cardiac troponins, titin, cardiac myosin binding protein C), and OGFOD1 expression decreases during cardiomyocyte differentiation.\",\n      \"method\": \"OGFOD1 deletion in iPSC-derived cardiomyocytes, RNA-seq, quantitative proteomics, correlation analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with multi-omic readout (proteomics + RNA-seq), single lab\",\n      \"pmids\": [\"31112528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"OGFOD1 directly binds to the C-terminal domain (CTD) of RNA Polymerase II and alters its phosphorylation status. CDK7 and CDK9 phosphorylate OGFOD1 at Ser-256; a non-phosphorylatable Ser256 mutant fails to enhance transcriptional activation and tumor growth. OGFOD1 elimination reduced tumor development.\",\n      \"method\": \"Co-IP (OGFOD1–RNA Pol II CTD), phosphorylation assay with CDK7/CDK9, phospho-mutant (S256A) rescue, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown by Co-IP, kinase assay with specific mutant, functional rescue; single lab\",\n      \"pmids\": [\"34298635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OGFOD1 deletion in mice increases myocardial beta-alanine levels and alters purine/pyrimidine metabolism. OGFOD1 KO hearts show 41% reduction in infarct size and 34% improvement in cardiac function after ischemia-reperfusion. Treatment of WT hearts with carnosine (a beta-alanine metabolite) recapitulates part of the protection, while carnosine treatment of KO hearts has no additional effect, consistent with beta-alanine accumulation mediating cardioprotection.\",\n      \"method\": \"Knockout mouse model, quantitative proteomics (TMT-LC-MS/MS), metabolomics, ex vivo and in vivo ischemia-reperfusion injury models, carnosine pharmacological rescue\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with proteomics and metabolomics, functional I/R readout, pharmacological rescue; single lab\",\n      \"pmids\": [\"34668514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OGFOD1 knockdown in lung cancer cells induces cell cycle arrest via depletion of CDK1, CDK2, and cyclin B1 (CCNB1) mRNAs and nuclear accumulation of p21Cip1. CDK1 reduction is post-transcriptional and involves the RNA-binding protein HuR; CDK2 and CCNB1 depletion results from decreased transcription mediated by OGFOD1.\",\n      \"method\": \"siRNA knockdown, mRNA stability assays, RT-qPCR, immunofluorescence for p21 localization, RNP-IP or co-regulation with HuR\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with mechanistic dissection of post-transcriptional vs. transcriptional regulation and involvement of HuR; single lab\",\n      \"pmids\": [\"36464654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OGFOD1 inhibition by FG4592 (a PHD inhibitor that was identified via target prediction and molecular docking as a novel OGFOD1 inhibitor) decreases infarct volume after ischemic stroke. OGFOD1 knockdown protects against ischemia/reperfusion injury by activating the unfolded protein response (UPR) and autophagy in a HIF-1α-independent manner. Blocking UPR attenuated the neuroprotection, pro-autophagy, and anti-apoptosis effects of FG4592.\",\n      \"method\": \"Molecular docking, OGFOD1 knockdown in vitro/in vivo, mouse ischemic stroke model, UPR/autophagy pathway inhibition, HIF-1α KD and pharmacological blockade\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined pathway readout (UPR, autophagy), pharmacological and genetic pathway blockade; single lab, molecular docking is computational\",\n      \"pmids\": [\"38454480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OGFOD1 upregulates global protein synthesis in AML cells by adjusting ribosomal fidelity through its dioxygenase activity (Pro-62 hydroxylation of RPS23). Inhibiting OGFOD1 impaired translation processing, decreased protein synthesis, and improved survival in chemoresistant AML animal models while sparing normal hematopoiesis.\",\n      \"method\": \"In vivo patient-derived xenograft models, OGFOD1 genetic inhibition, proteomics, translation assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO/KD with functional translation readout in AML models; single study but multiple orthogonal methods\",\n      \"pmids\": [\"40961937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"OGFOD1 silencing in hepatocytes subjected to hypoxia/reoxygenation decreases SPARC protein levels without changing SPARC mRNA levels (identified through combined transcriptomics and proteomics), and SPARC overexpression rescues the effects of OGFOD1 silencing on apoptosis and oxidative stress, placing SPARC downstream of OGFOD1 in a post-transcriptional regulatory pathway.\",\n      \"method\": \"siRNA silencing in H/R hepatocyte model and HIRI rat model, combined transcriptomics and proteomics, SPARC overexpression rescue\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multi-omic mechanistic dissection, downstream rescue experiment; single lab\",\n      \"pmids\": [\"41558616\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OGFOD1 is a 2-oxoglutarate- and Fe(II)-dependent dioxygenase that catalyzes trans-3 prolyl hydroxylation of Pro-62 on the small ribosomal subunit protein RPS23 (uS12), thereby modulating ribosomal fidelity, global and selective protein translation, and stress responses; it also localizes to stress granules, interacts with eIF2α and its kinase HRI to regulate eIF2α phosphorylation, binds the RNA Pol II CTD and is phosphorylated by CDK7/CDK9 to enhance transcription, and its loss broadly alters the proteome and confers protection against ischemia-reperfusion injury, cardiac hypertrophy, and chemoresistance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OGFOD1 is a Fe(II)- and 2-oxoglutarate-dependent prolyl hydroxylase that controls protein synthesis by post-translationally modifying the translation machinery and tuning ribosomal fidelity [#0, #12]. It catalyzes trans-3 prolyl hydroxylation of Pro-62 in the small ribosomal subunit protein RPS23 (uS12), retaining high affinity for the hydroxylated product; loss of this catalytic activity triggers stress granule induction, translational arrest, and growth impairment, and the phenotype is rescued only by catalytically active enzyme [#0]. Crystal structures of the human enzyme with 2OG-oxygenase inhibitors define a prolyl-3-hydroxylase active site distinct from prolyl-4-hydroxylases [#1]. Beyond ribosome modification, OGFOD1 localizes to stress granules and associates with the ribosome and stress granule proteins, and interacts with eIF2\\u03b1 and its kinase HRI to set the level of eIF2\\u03b1 phosphorylation and the pace of polyribosome recovery after stress [#2]. It also directly binds the RNA Pol II C-terminal domain and is phosphorylated at Ser-256 by CDK7/CDK9, which is required for its enhancement of transcriptional activation and tumor growth [#8]. Functionally, OGFOD1 loss reshapes the proteome largely at the post-transcriptional level, controlling translation and stability of specific targets including cell-cycle regulators (CDK1 via HuR, with CDK2/CCNB1 reduced transcriptionally) and tissue-specific factors [#7, #10], and confers protection against ischemia-reperfusion injury through UPR/autophagy activation and altered \\u03b2-alanine metabolism [#9, #11], and supports global protein synthesis in chemoresistant AML [#12]. Studies of the yeast ortholog Tpa1 establish a conserved double-stranded \\u03b2-helix dioxygenase architecture coupled to translation termination and oxygen/hypoxia-responsive gene regulation [#4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining the enzymatic scaffold: it was unknown how this 2OG-oxygenase family member was organized, and structures of the yeast ortholog Tpa1 revealed a bilobed double-stranded \\u03b2-helix fold with cofactor binding restricted to the N-terminal domain, plus poly(rA) binding hinting at mRNA association.\",\n      \"evidence\": \"X-ray crystallography of S. cerevisiae Tpa1 with Fe(III) and 2OG, poly(rA) binding assay\",\n      \"pmids\": [\"20040577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic substrate not identified in this work\", \"Ortholog study; human enzyme not addressed\", \"Functional role of the inactive C-terminal domain unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linking catalysis to translation and oxygen sensing: Tpa1 active-site integrity and its partner Ett1/Nro1 were shown to be essential for correct translation termination and for repression of Hap1-regulated hypoxic genes, connecting the dioxygenase to translation and oxygen-responsive transcription.\",\n      \"evidence\": \"Crystallography, active-site mutagenesis, genetic deletion with translation termination and gene-expression readouts in yeast\",\n      \"pmids\": [\"20630870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalytic substrate still unidentified\", \"Mechanism connecting termination to oxygen sensing unclear\", \"Human relevance inferred from ortholog\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placing the human protein in the stress-response network: OGFOD1 was found in stress granules and bound to the ribosome, eIF2\\u03b1, and HRI, with its level controlling eIF2\\u03b1 phosphorylation and translational recovery\\u2014establishing a role in the integrated stress response.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown and overexpression, polyribosome sedimentation, immunofluorescence\",\n      \"pmids\": [\"20154146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether eIF2\\u03b1/HRI effects require catalytic activity not resolved\", \"Single lab\", \"Direct vs. indirect nature of HRI interaction not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tying catalysis to a downstream transcript and an ischemic phenotype: OGFOD1 catalytic activity was shown to be required for ATPAF1 expression and ischemic cell death, with catalytic-mutant and ATPAF1 rescue experiments establishing causality.\",\n      \"evidence\": \"Gene silencing, cDNA microarray, wild-type vs. catalytic-mutant reintroduction, ATPAF1 rescue\",\n      \"pmids\": [\"20579638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate connecting catalysis to ATPAF1 unknown\", \"Mechanism of transcript-specific regulation unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying the physiological substrate: it was unknown what OGFOD1 hydroxylates, and in vitro assays with MS established RPS23 (uS12) Pro-62 as the trans-3 prolyl hydroxylation target, with catalytic-mutant rescue tying the modification to stress granule and growth phenotypes.\",\n      \"evidence\": \"In vitro hydroxylation assay, mass spectrometry, Co-IP, knockdown/rescue with catalytic mutants\",\n      \"pmids\": [\"24550447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Pro-62 hydroxylation alters ribosome function mechanistically not fully defined\", \"Whether other substrates exist not excluded\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing a non-ribosomal catalytic capacity in the ortholog: Tpa1 was shown to directly repair methylated DNA in vitro in a cofactor-dependent manner and to act in a pathway parallel to base excision repair.\",\n      \"evidence\": \"In vitro DNA repair assay with purified Tpa1, active-site mutagenesis, genetic epistasis\",\n      \"pmids\": [\"25381260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether human OGFOD1 has analogous DNA-repair activity untested\", \"Physiological significance versus RPS23 hydroxylation unclear\", \"Ortholog study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defining the structural basis of substrate specificity: human OGFOD1 structures with broad-spectrum 2OG-oxygenase inhibitors revealed the prolyl-3 hydroxylase active site and its distinctions from prolyl-4 hydroxylases, enabling selective inhibitor design.\",\n      \"evidence\": \"X-ray crystallography of human OGFOD1 with NOG and 2,4-PDCA, structural comparison\",\n      \"pmids\": [\"25728928\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure with RPS23 substrate bound\", \"Selective inhibitors not yet developed in this work\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating proteome-wide post-transcriptional control: OGFOD1 deletion in cardiomyocytes selectively altered translation and splicing with poor mRNA-protein correlation, establishing post-transcriptional regulation as its primary cellular consequence and a role in cardiac proteome composition.\",\n      \"evidence\": \"OGFOD1 deletion in iPSC-cardiomyocytes, RNA-seq, quantitative proteomics, correlation analysis\",\n      \"pmids\": [\"31112528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which targets are direct consequences of RPS23 hydroxylation unclear\", \"Mechanism of selective translational control undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovering a transcriptional arm: OGFOD1 was shown to bind the RNA Pol II CTD and to be phosphorylated by CDK7/CDK9 at Ser-256, with a non-phosphorylatable mutant failing to enhance transcription and tumor growth.\",\n      \"evidence\": \"Co-IP, CDK7/CDK9 phosphorylation assay, S256A phospho-mutant rescue, tumor growth assays\",\n      \"pmids\": [\"34298635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between CTD binding and prolyl hydroxylase activity unresolved\", \"Whether OGFOD1 hydroxylates a transcriptional target unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connecting OGFOD1 to cell-cycle control and cancer: knockdown induced arrest through post-transcriptional CDK1 loss (via HuR) and transcriptional CDK2/CCNB1 depletion with p21 nuclear accumulation, dissecting dual regulatory modes.\",\n      \"evidence\": \"siRNA knockdown, mRNA stability assays, RT-qPCR, p21 immunofluorescence, RNP-IP with HuR\",\n      \"pmids\": [\"36464654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between OGFOD1 catalysis and HuR-mediated regulation unknown\", \"Single cancer model\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining a metabolic basis for cardioprotection: OGFOD1 knockout mice showed \\u03b2-alanine accumulation, reduced infarct size, and improved function after ischemia-reperfusion, with carnosine rescue implicating \\u03b2-alanine metabolism in the protection.\",\n      \"evidence\": \"Knockout mouse, TMT proteomics, metabolomics, ex vivo/in vivo ischemia-reperfusion, carnosine pharmacological rescue\",\n      \"pmids\": [\"34668514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How OGFOD1 catalysis controls \\u03b2-alanine metabolism unclear\", \"Link between RPS23 hydroxylation and metabolic phenotype undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapping the protective signaling output and a druggable target: OGFOD1 knockdown protected against ischemic stroke by activating UPR and autophagy independently of HIF-1\\u03b1, and FG4592 was identified as an OGFOD1 inhibitor.\",\n      \"evidence\": \"Molecular docking, OGFOD1 knockdown in vitro/in vivo, mouse ischemic stroke model, UPR/autophagy blockade, HIF-1\\u03b1 knockdown\",\n      \"pmids\": [\"38454480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FG4592 binding to OGFOD1 is computational/pharmacological, not structurally confirmed\", \"Mechanism linking inhibition to UPR activation unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing therapeutic relevance in leukemia: OGFOD1 was shown to drive global protein synthesis in AML through RPS23 Pro-62 hydroxylation, and its inhibition impaired translation and improved survival in chemoresistant models while sparing normal hematopoiesis.\",\n      \"evidence\": \"Patient-derived xenografts, genetic inhibition, proteomics, translation assays\",\n      \"pmids\": [\"40961937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Therapeutic window in patients untested\", \"Selective inhibitor not yet available\", \"Single study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extending post-transcriptional control to hepatic ischemia: OGFOD1 silencing reduced SPARC protein without changing its mRNA, and SPARC overexpression rescued apoptosis and oxidative stress, placing SPARC downstream in a post-transcriptional pathway.\",\n      \"evidence\": \"siRNA silencing in H/R hepatocytes and HIRI rat model, combined transcriptomics/proteomics, SPARC overexpression rescue\",\n      \"pmids\": [\"41558616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which OGFOD1 controls SPARC translation/stability unknown\", \"Whether RPS23 hydroxylation mediates this effect untested\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how RPS23 Pro-62 hydroxylation mechanistically connects the enzyme's many downstream phenotypes\\u2014selective translation, transcriptional enhancement via Pol II CTD, metabolic and UPR/autophagy outputs\\u2014and whether the transcriptional and DNA-related activities require its catalytic function.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of OGFOD1 bound to RPS23\", \"Catalytic dependence of CTD-binding and metabolic phenotypes not established\", \"Direct mechanism linking ribosomal modification to transcript-specific regulation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016706\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RPS23\", \"EIF2S1\", \"EIF2AK1\", \"G3BP1\", \"USP10\", \"CAPRIN1\", \"YBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}