{"gene":"EEF1E1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2006,"finding":"AIMP3/EEF1E1 couples oncogenic stresses (growth factor- or Ras-dependent signaling) to p53 activation via differential activation of ATM and ATR kinases, thereby preventing cell transformation; single allelic loss of AIMP3 blocks oncogene-induced p53 activation and leads to chromosomal instability.","method":"Genetic knockdown and heterozygous mouse cells; oncogene transformation assays (Ras, Myc); chromosomal analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic loss-of-function with defined cellular phenotypes (transformation, chromosomal instability) and pathway placement (ATM/ATR→p53), single lab but multiple orthogonal assays","pmids":["16849534"],"is_preprint":false},{"year":2008,"finding":"Crystal structure of AIMP3/p18 at 2.0 Å resolution reveals two distinct domains: a 56-aa N-terminal domain (two helices + three antiparallel β-strands) and a 111-aa C-terminal domain (five-helix bundle + coiled region), linked by a 7-aa peptide containing a 3(10) helix. Mutagenesis of the C-terminal putative binding site abolished interaction with ATM and abrogated AIMP3's ability to activate p53, identifying critical residues for tumor-suppressive activity.","method":"X-ray crystallography (2.0 Å); site-directed mutagenesis; co-immunoprecipitation with ATM; p53 activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional validation (ATM interaction, p53 activation) in one rigorous study","pmids":["18343821"],"is_preprint":false},{"year":2010,"finding":"Overexpression of AIMP3 causes proteasome-dependent degradation of mature lamin A (but not lamin C, prelamin A, or progerin), leading to an imbalance in lamin A isoform stoichiometry, nuclear morphology defects, accelerated cellular senescence, and a progeroid phenotype in transgenic mice.","method":"AIMP3 transgenic mouse generation; western blotting; proteasome inhibitor treatment; cellular senescence assays; nuclear morphology analysis","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model plus in vitro mechanistic follow-up with proteasome inhibition, single lab","pmids":["20726853"],"is_preprint":false},{"year":2012,"finding":"AIMP3/p18 specifically binds Met-tRNA(i)(Met) (charged initiator tRNA) but not uncharged or lysine-charged tRNA(i)(Met), and discriminates Met-tRNA(i)(Met) from Met-charged elongator tRNA. AIMP3 and methionyl-tRNA synthetase (MRS) non-competitively interact with eIF2γ, recruiting active eIF2γ to the MRS-AIMP3 complex to mediate transfer of Met-tRNA(i)(Met) to the eIF2 complex for translation initiation. AIMP3 knockdown reduces Met-tRNA(i)(Met) bound to eIF2 and decreases global protein synthesis.","method":"In vitro binding assays (filter-binding); pull-down assay; siRNA knockdown; protein synthesis measurement","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of tRNA binding with specificity controls, pull-down for eIF2γ interaction, functional knockdown confirming reduced protein synthesis; multiple orthogonal methods in one study","pmids":["22867704"],"is_preprint":false},{"year":2018,"finding":"AIMP3 deletion in mouse embryonic stem cells (mESCs) leads to accumulation of DNA double-strand breaks (blocking homologous recombination repair), p53 pathway activation, and loss of self-renewal and tri-lineage differentiation capacity; p53 knockdown rescues stemness loss caused by AIMP3 depletion, placing AIMP3 upstream of p53 in mESC genome maintenance.","method":"Conditional knockout (AIMP3f/f; CreERT2 mESCs); microarray; γH2AX staining; homologous recombination assay; p53 knockdown epistasis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with genetic epistasis (p53 rescue), multiple phenotypic readouts, single lab","pmids":["30250065"],"is_preprint":false},{"year":2018,"finding":"Systemic AIMP3 deletion in adult mice causes spontaneous DNA double-strand breaks (COMET assay, γH2AX induction), delayed γH2AX removal, and significantly reduced homologous recombination activity associated with reduced RPA and Rad51 foci formation, establishing AIMP3 as a component of the HR DNA repair pathway.","method":"Conditional knockout mice (tamoxifen-induced); COMET assay; γH2AX immunostaining; RPA/Rad51 foci formation; HR assay in MEFs and knockdown cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional KO combined with multiple in vitro DNA repair assays, single lab","pmids":["30302025"],"is_preprint":false},{"year":2019,"finding":"HIF1α suppresses AIMP3 expression under hypoxia, thereby preventing AIMP3-induced mitochondrial respiration enhancement and autophagy suppression; Notch3 positively regulates AIMP3. AIMP3 overexpression under hypoxia increases mitochondrial respiration and suppresses autophagy, leading to stem cell senescence; AIMP3 downregulation ameliorates MSC senescence.","method":"RNA sequencing; AIMP3 overexpression and knockdown in hpMSCs and adipose-derived MSCs from AIMP3-transgenic mice; mitochondrial respiration assay; autophagy flux analysis; HIF1α and Notch3 manipulation","journal":"Aging cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with metabolic readouts and regulatory factor identification, single lab","pmids":["30706629"],"is_preprint":false},{"year":2021,"finding":"AIMP3 overexpression in human aortic smooth muscle cells (HASMCs) decreases lamin A protein expression, disrupts nuclear morphology, and induces cellular senescence (increased p16), recapitulating a laminopathy-like phenotype consistent with the mechanism identified in the progeroid mouse model.","method":"AIMP3 transfection into HASMCs; western blotting for lamin A, p16, AIMP3; nuclear morphology histological analysis; comparison with AIMP3 transgenic and aged mice","journal":"Experimental gerontology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment with protein-level readouts, no mechanistic dissection beyond earlier studies; single lab","pmids":["34274427"],"is_preprint":false},{"year":2021,"finding":"AIMP3 inhibits lung adenocarcinoma cell proliferation and migration in a p53-dependent manner; miR-96-5p directly targets AIMP3 mRNA to suppress its expression, and ectopic miR-96-5p promotes cancer cell proliferation and migration partially through AIMP3 suppression, defining a miR-96-5p–AIMP3–p53 axis.","method":"miR-96-5p target validation (luciferase or direct targeting assay implied); AIMP3 overexpression; p53 dependency assay; xenograft in vivo assay; immunohistochemistry on NSCLC samples","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — direct targeting of AIMP3 by miR-96-5p established, p53 dependency asserted but mechanistic follow-up limited in abstract; single lab","pmids":["33538115"],"is_preprint":false},{"year":2023,"finding":"EEF1E1 promotes glioma cell proliferation by downregulating PTEN, thereby suppressing the PTEN/AKT signaling pathway and modulating downstream cyclin-related cell cycle proteins; EEF1E1 knockdown arrests glioma cells in G1/S phase and reduces proliferation in vitro and in vivo.","method":"siRNA knockdown; cell cycle assay; CCK-8, colony formation, EdU assays; western blotting for PTEN/AKT/cyclin proteins; animal xenograft studies; brain slice coculture","journal":"Molecular carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function with pathway-level readouts but no direct mechanistic demonstration of how EEF1E1 regulates PTEN; single lab","pmids":["37589446"],"is_preprint":false},{"year":2024,"finding":"EEF1E1 knockdown via siRNA counteracts D-galactose-induced myoblast senescence (reduced p21, p53, β-galactosidase, muscle protein degradation markers) and improves muscle differentiation efficiency; EEF1E1 reduction is associated with increased SIRT1 levels and enhanced autophagy, placing EEF1E1 upstream of the SIRT1-autophagy axis in myoblast senescence.","method":"siRNA knockdown; recombinant EEF1E1 protein treatment; senescence-associated β-galactosidase assay; western blotting (p21, p53, SIRT1, autophagy markers); aged mouse model; plasma proteomics","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA knockdown with multiple phenotypic readouts but mechanistic link to SIRT1/autophagy is associative; single lab","pmids":["39276001"],"is_preprint":false},{"year":2025,"finding":"Cardiomyocyte-specific conditional knockout of AIMP3 in mice causes lethal cardiomyopathy without affecting MetRS localization, aminoacylation efficiency, or global protein synthesis. Instead, AIMP3 is essential for homocysteine editing by MetRS (a proofreading reaction preventing homocysteine misincorporation); loss of this editing activity causes homocysteine accumulation, reactive oxygen species production, protein aggregation, mitochondrial dysfunction, autophagy, and cardiomyocyte death.","method":"Cardiomyocyte-specific conditional knockout mice; MetRS aminoacylation and localization assays; homocysteine editing assay; ROS measurement; protein aggregation assay; mitochondrial function assay; autophagy analysis","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo conditional KO with rigorous negative controls ruling out translation initiation/elongation defects, direct biochemical demonstration of homocysteine editing function, multiple orthogonal mechanistic readouts","pmids":["40562875"],"is_preprint":false},{"year":2025,"finding":"EEF1E1 undergoes liquid-liquid phase separation (LLPS) condensate formation in hepatocellular carcinoma cells; EEF1E1 silencing reduces cancer stem cell marker expression (CD133, EpCAM, SOX2) and enhances DNA damage (γH2AX) by activating the PTEN/AKT pathway; inhibition of LLPS with 1,6-hexanediol partially reverses the effects of EEF1E1 on tumor cells.","method":"EEF1E1 knockdown (siRNA); LLPS condensate visualization; 1,6-hexanediol LLPS inhibition; western blotting (PTEN, AKT, γH2AX, CSC markers); in vivo and in vitro tumor assays","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — LLPS observation and knockdown phenotype, but mechanistic basis of phase separation and causal link to PTEN/AKT not fully resolved; single lab","pmids":["39884379"],"is_preprint":false}],"current_model":"AIMP3/EEF1E1 is a multifunctional scaffolding protein of the multi-aminoacyl-tRNA synthetase complex that: (1) anchors methionyl-tRNA synthetase (MetRS) and mediates transfer of Met-tRNA(i)(Met) to eIF2γ for translation initiation, and is now shown to be essential for MetRS homocysteine proofreading/editing activity, preventing mistranslation-induced cardiomyopathy; (2) activates p53 via ATM/ATR in response to DNA damage and oncogenic stress, acting as a tumor suppressor; (3) promotes proteasome-dependent degradation of mature lamin A, driving cellular senescence and a progeroid phenotype; and (4) participates in homologous recombination-mediated DNA double-strand break repair, with its loss causing genomic instability."},"narrative":{"mechanistic_narrative":"EEF1E1 (AIMP3/p18) is a multifunctional scaffolding protein that bridges translation initiation, genome surveillance, and the p53 tumor-suppressor response [PMID:16849534, PMID:22867704]. Within the translational machinery it specifically binds charged initiator Met-tRNA(i)(Met), discriminating it from elongator and uncharged species, and together with methionyl-tRNA synthetase (MetRS) non-competitively engages eIF2γ to transfer Met-tRNA(i)(Met) to the eIF2 complex for initiation [PMID:22867704]. Its crystal structure resolves an N-terminal and a five-helix-bundle C-terminal domain, the latter carrying the binding surface required for ATM interaction and p53 activation [PMID:18343821]. Through differential activation of ATM and ATR, EEF1E1 couples oncogenic and DNA-damage stress to p53, acting as a tumor suppressor whose allelic loss permits oncogene-induced transformation and chromosomal instability [PMID:16849534, PMID:18343821]. It is additionally required for homologous-recombination repair of DNA double-strand breaks, with its loss causing accumulation of breaks, reduced RPA/Rad51 foci, and p53-dependent loss of stem-cell self-renewal [PMID:30250065, PMID:30302025]. A distinct activity is its proofreading role: in cardiomyocytes EEF1E1 is essential for MetRS-mediated homocysteine editing—independent of aminoacylation or global translation—and its loss causes homocysteine accumulation, ROS, protein aggregation, and lethal cardiomyopathy [PMID:40562875]. EEF1E1 overexpression also drives proteasome-dependent degradation of mature lamin A, producing nuclear morphology defects, cellular senescence, and a progeroid phenotype [PMID:20726853].","teleology":[{"year":2006,"claim":"Established that EEF1E1/AIMP3 functions as a stress-responsive tumor suppressor by linking oncogenic signaling to p53 activation, answering whether this aminoacyl-tRNA synthetase complex component has a role beyond translation.","evidence":"Genetic knockdown and heterozygous mouse cells with oncogene transformation and chromosomal instability assays","pmids":["16849534"],"confidence":"Medium","gaps":["Did not define the structural basis of ATM/ATR engagement","Direct vs indirect activation of ATM/ATR not resolved"]},{"year":2008,"claim":"Resolved the domain architecture of AIMP3 and pinpointed the C-terminal surface required for ATM binding and p53 activation, providing the structural basis for its tumor-suppressive activity.","evidence":"2.0 Å X-ray crystallography with site-directed mutagenesis, ATM co-immunoprecipitation, and p53 activation assays","pmids":["18343821"],"confidence":"High","gaps":["No co-structure with ATM","Does not address translation or HR functions"]},{"year":2010,"claim":"Identified a senescence-promoting activity whereby AIMP3 selectively destabilizes mature lamin A, connecting the protein to nuclear architecture and aging.","evidence":"AIMP3 transgenic mice, western blotting, proteasome inhibition, and senescence/nuclear morphology assays","pmids":["20726853"],"confidence":"Medium","gaps":["Mechanism by which AIMP3 targets lamin A to the proteasome unidentified","Whether endogenous AIMP3 regulates lamin A unknown"]},{"year":2012,"claim":"Defined the molecular function of AIMP3 in translation initiation by showing it binds initiator Met-tRNA with strict specificity and channels it to eIF2 via MetRS and eIF2γ.","evidence":"In vitro filter-binding and pull-down assays with siRNA knockdown and protein synthesis measurement","pmids":["22867704"],"confidence":"High","gaps":["Structural basis of tRNA discrimination not solved","In vivo requirement for initiation not tested in this study"]},{"year":2018,"claim":"Established AIMP3 as a component of homologous-recombination DSB repair acting upstream of p53, explaining the chromosomal instability seen on its loss.","evidence":"Conditional knockout mESCs and adult mice, γH2AX/COMET assays, RPA/Rad51 foci, HR assays, and p53 epistasis","pmids":["30250065","30302025"],"confidence":"Medium","gaps":["Direct molecular partner within the HR machinery not identified","Whether HR role is separable from translation/p53 roles unclear"]},{"year":2019,"claim":"Linked AIMP3 to metabolic control of stem-cell senescence, showing it enhances mitochondrial respiration and suppresses autophagy under regulation by HIF1α and Notch3.","evidence":"RNA-seq, gain/loss-of-function in MSCs, mitochondrial respiration and autophagy flux assays with HIF1α/Notch3 manipulation","pmids":["30706629"],"confidence":"Medium","gaps":["Molecular mechanism connecting AIMP3 to mitochondrial respiration not defined","Causal link to autophagy machinery associative"]},{"year":2021,"claim":"Extended the lamin A/senescence and p53-dependent tumor-suppressor models to vascular smooth muscle and lung adenocarcinoma, including regulation by miR-96-5p.","evidence":"AIMP3 overexpression in HASMCs and lung cancer cells, miR-96-5p targeting, p53 dependency, and xenograft assays","pmids":["34274427","33538115"],"confidence":"Low","gaps":["Largely overexpression-based without mechanistic dissection","miR-96-5p–AIMP3–p53 axis not validated by endogenous loss-of-function"]},{"year":2023,"claim":"Reported a context-dependent pro-tumor role in glioma and hepatocellular carcinoma via PTEN/AKT suppression and condensate formation, contrasting with the tumor-suppressor role in other tissues.","evidence":"siRNA knockdown, cell-cycle and proliferation assays, PTEN/AKT western blotting, LLPS visualization with 1,6-hexanediol, and xenografts","pmids":["37589446","39884379"],"confidence":"Low","gaps":["Direct mechanism of PTEN downregulation not shown","Causal basis and biophysical determinants of phase separation unresolved"]},{"year":2024,"claim":"Implicated EEF1E1 in myoblast senescence upstream of a SIRT1-autophagy axis, broadening its senescence role to skeletal muscle.","evidence":"siRNA knockdown and recombinant protein treatment with SA-β-gal, p21/p53/SIRT1 blotting, autophagy markers, and aged mouse model","pmids":["39276001"],"confidence":"Low","gaps":["Mechanistic link to SIRT1/autophagy is associative","Whether effect is translation- or p53-mediated not separated"]},{"year":2025,"claim":"Revealed a translation-independent proofreading function: AIMP3 is essential for MetRS homocysteine editing, with loss causing mistranslation-driven lethal cardiomyopathy, redefining its role within the synthetase complex.","evidence":"Cardiomyocyte-specific conditional knockout mice with aminoacylation/localization controls, homocysteine editing, ROS, aggregation, and mitochondrial assays","pmids":["40562875"],"confidence":"High","gaps":["Structural basis for how AIMP3 enables MetRS editing not defined","Relevance of editing function to non-cardiac tissues untested"]},{"year":null,"claim":"How AIMP3's distinct activities—initiator-tRNA channeling, MetRS proofreading, ATM/p53 signaling, HR repair, lamin A turnover, and context-dependent tumor roles—are partitioned and coordinated within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model linking the cytoplasmic synthetase functions to nuclear p53/HR functions","Determinants of tumor-suppressor versus pro-tumor behavior across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":["multi-aminoacyl-tRNA synthetase complex"],"partners":["MARS1","EIF2S3","ATM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O43324","full_name":"Eukaryotic translation elongation factor 1 epsilon-1","aliases":["Aminoacyl tRNA synthetase complex-interacting multifunctional protein 3","Elongation factor p18","Multisynthase complex auxiliary component p18"],"length_aa":174,"mass_kda":19.8,"function":"Positive modulator of ATM response to DNA damage","subcellular_location":"Cytoplasm; Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/O43324/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EEF1E1","classification":"Not Classified","n_dependent_lines":84,"n_total_lines":1208,"dependency_fraction":0.0695364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EEF1E1","total_profiled":1310},"omim":[{"mim_id":"609206","title":"EUKARYOTIC TRANSLATION ELONGATION FACTOR 1, EPSILON-1; EEF1E1","url":"https://www.omim.org/entry/609206"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EEF1E1"},"hgnc":{"alias_symbol":["AIMP3"],"prev_symbol":["P18"]},"alphafold":{"accession":"O43324","domains":[{"cath_id":"1.20.1050.10","chopping":"2-150","consensus_level":"medium","plddt":93.5831,"start":2,"end":150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43324","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43324-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43324-F1-predicted_aligned_error_v6.png","plddt_mean":92.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EEF1E1","jax_strain_url":"https://www.jax.org/strain/search?query=EEF1E1"},"sequence":{"accession":"O43324","fasta_url":"https://rest.uniprot.org/uniprotkb/O43324.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43324/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43324"}},"corpus_meta":[{"pmid":"30858199","id":"PMC_30858199","title":"TCR Affinity Biases Th Cell Differentiation by Regulating CD25, Eef1e1, and Gbp2.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/30858199","citation_count":56,"is_preprint":false},{"pmid":"16849534","id":"PMC_16849534","title":"AIMP3 haploinsufficiency disrupts oncogene-induced p53 activation and genomic stability.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16849534","citation_count":55,"is_preprint":false},{"pmid":"25465621","id":"PMC_25465621","title":"miR-543 and miR-590-3p regulate human mesenchymal stem cell aging via direct targeting of AIMP3/p18.","date":"2014","source":"Age (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/25465621","citation_count":53,"is_preprint":false},{"pmid":"20726853","id":"PMC_20726853","title":"Downregulation of lamin A by tumor suppressor AIMP3/p18 leads to a progeroid phenotype in mice.","date":"2010","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/20726853","citation_count":40,"is_preprint":false},{"pmid":"22867704","id":"PMC_22867704","title":"AIMP3/p18 controls translational initiation by mediating the delivery of charged initiator tRNA to initiation complex.","date":"2012","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22867704","citation_count":37,"is_preprint":false},{"pmid":"18343821","id":"PMC_18343821","title":"Determination of three-dimensional structure and residues of the novel tumor suppressor AIMP3/p18 required for the interaction with ATM.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18343821","citation_count":36,"is_preprint":false},{"pmid":"30706629","id":"PMC_30706629","title":"HIF1α-mediated AIMP3 suppression delays stem cell aging via the induction of autophagy.","date":"2019","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/30706629","citation_count":33,"is_preprint":false},{"pmid":"24917520","id":"PMC_24917520","title":"Loss of expression of the tumour suppressor gene AIMP3 predicts survival following radiotherapy in muscle-invasive bladder cancer.","date":"2014","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24917520","citation_count":21,"is_preprint":false},{"pmid":"30250065","id":"PMC_30250065","title":"AIMP3 depletion causes genome instability and loss of stemness in mouse embryonic stem cells.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30250065","citation_count":16,"is_preprint":false},{"pmid":"39884379","id":"PMC_39884379","title":"Phase separation of EEF1E1 promotes tumor stemness via PTEN/AKT-mediated DNA repair in hepatocellular carcinoma.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/39884379","citation_count":12,"is_preprint":false},{"pmid":"39276001","id":"PMC_39276001","title":"High-Intensity Interval Training Mitigates Sarcopenia and Suppresses the Myoblast Senescence Regulator EEF1E1.","date":"2024","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/39276001","citation_count":11,"is_preprint":false},{"pmid":"33538115","id":"PMC_33538115","title":"AIMP3 inhibits cell growth and metastasis of lung adenocarcinoma through activating a miR-96-5p-AIMP3-p53 axis.","date":"2021","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33538115","citation_count":11,"is_preprint":false},{"pmid":"30302025","id":"PMC_30302025","title":"AIMP3 Deletion Induces Acute Radiation Syndrome-like Phenotype in Mice.","date":"2018","source":"Scientific 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gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/34274427","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10221,"output_tokens":3722,"usd":0.043247,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11513,"output_tokens":3693,"usd":0.074945,"stage2_stop_reason":"end_turn"},"total_usd":0.118192,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"AIMP3/EEF1E1 couples oncogenic stresses (growth factor- or Ras-dependent signaling) to p53 activation via differential activation of ATM and ATR kinases, thereby preventing cell transformation; single allelic loss of AIMP3 blocks oncogene-induced p53 activation and leads to chromosomal instability.\",\n      \"method\": \"Genetic knockdown and heterozygous mouse cells; oncogene transformation assays (Ras, Myc); chromosomal analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic loss-of-function with defined cellular phenotypes (transformation, chromosomal instability) and pathway placement (ATM/ATR→p53), single lab but multiple orthogonal assays\",\n      \"pmids\": [\"16849534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of AIMP3/p18 at 2.0 Å resolution reveals two distinct domains: a 56-aa N-terminal domain (two helices + three antiparallel β-strands) and a 111-aa C-terminal domain (five-helix bundle + coiled region), linked by a 7-aa peptide containing a 3(10) helix. Mutagenesis of the C-terminal putative binding site abolished interaction with ATM and abrogated AIMP3's ability to activate p53, identifying critical residues for tumor-suppressive activity.\",\n      \"method\": \"X-ray crystallography (2.0 Å); site-directed mutagenesis; co-immunoprecipitation with ATM; p53 activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional validation (ATM interaction, p53 activation) in one rigorous study\",\n      \"pmids\": [\"18343821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Overexpression of AIMP3 causes proteasome-dependent degradation of mature lamin A (but not lamin C, prelamin A, or progerin), leading to an imbalance in lamin A isoform stoichiometry, nuclear morphology defects, accelerated cellular senescence, and a progeroid phenotype in transgenic mice.\",\n      \"method\": \"AIMP3 transgenic mouse generation; western blotting; proteasome inhibitor treatment; cellular senescence assays; nuclear morphology analysis\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model plus in vitro mechanistic follow-up with proteasome inhibition, single lab\",\n      \"pmids\": [\"20726853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AIMP3/p18 specifically binds Met-tRNA(i)(Met) (charged initiator tRNA) but not uncharged or lysine-charged tRNA(i)(Met), and discriminates Met-tRNA(i)(Met) from Met-charged elongator tRNA. AIMP3 and methionyl-tRNA synthetase (MRS) non-competitively interact with eIF2γ, recruiting active eIF2γ to the MRS-AIMP3 complex to mediate transfer of Met-tRNA(i)(Met) to the eIF2 complex for translation initiation. AIMP3 knockdown reduces Met-tRNA(i)(Met) bound to eIF2 and decreases global protein synthesis.\",\n      \"method\": \"In vitro binding assays (filter-binding); pull-down assay; siRNA knockdown; protein synthesis measurement\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of tRNA binding with specificity controls, pull-down for eIF2γ interaction, functional knockdown confirming reduced protein synthesis; multiple orthogonal methods in one study\",\n      \"pmids\": [\"22867704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AIMP3 deletion in mouse embryonic stem cells (mESCs) leads to accumulation of DNA double-strand breaks (blocking homologous recombination repair), p53 pathway activation, and loss of self-renewal and tri-lineage differentiation capacity; p53 knockdown rescues stemness loss caused by AIMP3 depletion, placing AIMP3 upstream of p53 in mESC genome maintenance.\",\n      \"method\": \"Conditional knockout (AIMP3f/f; CreERT2 mESCs); microarray; γH2AX staining; homologous recombination assay; p53 knockdown epistasis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with genetic epistasis (p53 rescue), multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"30250065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Systemic AIMP3 deletion in adult mice causes spontaneous DNA double-strand breaks (COMET assay, γH2AX induction), delayed γH2AX removal, and significantly reduced homologous recombination activity associated with reduced RPA and Rad51 foci formation, establishing AIMP3 as a component of the HR DNA repair pathway.\",\n      \"method\": \"Conditional knockout mice (tamoxifen-induced); COMET assay; γH2AX immunostaining; RPA/Rad51 foci formation; HR assay in MEFs and knockdown cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional KO combined with multiple in vitro DNA repair assays, single lab\",\n      \"pmids\": [\"30302025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HIF1α suppresses AIMP3 expression under hypoxia, thereby preventing AIMP3-induced mitochondrial respiration enhancement and autophagy suppression; Notch3 positively regulates AIMP3. AIMP3 overexpression under hypoxia increases mitochondrial respiration and suppresses autophagy, leading to stem cell senescence; AIMP3 downregulation ameliorates MSC senescence.\",\n      \"method\": \"RNA sequencing; AIMP3 overexpression and knockdown in hpMSCs and adipose-derived MSCs from AIMP3-transgenic mice; mitochondrial respiration assay; autophagy flux analysis; HIF1α and Notch3 manipulation\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with metabolic readouts and regulatory factor identification, single lab\",\n      \"pmids\": [\"30706629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AIMP3 overexpression in human aortic smooth muscle cells (HASMCs) decreases lamin A protein expression, disrupts nuclear morphology, and induces cellular senescence (increased p16), recapitulating a laminopathy-like phenotype consistent with the mechanism identified in the progeroid mouse model.\",\n      \"method\": \"AIMP3 transfection into HASMCs; western blotting for lamin A, p16, AIMP3; nuclear morphology histological analysis; comparison with AIMP3 transgenic and aged mice\",\n      \"journal\": \"Experimental gerontology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment with protein-level readouts, no mechanistic dissection beyond earlier studies; single lab\",\n      \"pmids\": [\"34274427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AIMP3 inhibits lung adenocarcinoma cell proliferation and migration in a p53-dependent manner; miR-96-5p directly targets AIMP3 mRNA to suppress its expression, and ectopic miR-96-5p promotes cancer cell proliferation and migration partially through AIMP3 suppression, defining a miR-96-5p–AIMP3–p53 axis.\",\n      \"method\": \"miR-96-5p target validation (luciferase or direct targeting assay implied); AIMP3 overexpression; p53 dependency assay; xenograft in vivo assay; immunohistochemistry on NSCLC samples\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct targeting of AIMP3 by miR-96-5p established, p53 dependency asserted but mechanistic follow-up limited in abstract; single lab\",\n      \"pmids\": [\"33538115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EEF1E1 promotes glioma cell proliferation by downregulating PTEN, thereby suppressing the PTEN/AKT signaling pathway and modulating downstream cyclin-related cell cycle proteins; EEF1E1 knockdown arrests glioma cells in G1/S phase and reduces proliferation in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown; cell cycle assay; CCK-8, colony formation, EdU assays; western blotting for PTEN/AKT/cyclin proteins; animal xenograft studies; brain slice coculture\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function with pathway-level readouts but no direct mechanistic demonstration of how EEF1E1 regulates PTEN; single lab\",\n      \"pmids\": [\"37589446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EEF1E1 knockdown via siRNA counteracts D-galactose-induced myoblast senescence (reduced p21, p53, β-galactosidase, muscle protein degradation markers) and improves muscle differentiation efficiency; EEF1E1 reduction is associated with increased SIRT1 levels and enhanced autophagy, placing EEF1E1 upstream of the SIRT1-autophagy axis in myoblast senescence.\",\n      \"method\": \"siRNA knockdown; recombinant EEF1E1 protein treatment; senescence-associated β-galactosidase assay; western blotting (p21, p53, SIRT1, autophagy markers); aged mouse model; plasma proteomics\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA knockdown with multiple phenotypic readouts but mechanistic link to SIRT1/autophagy is associative; single lab\",\n      \"pmids\": [\"39276001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cardiomyocyte-specific conditional knockout of AIMP3 in mice causes lethal cardiomyopathy without affecting MetRS localization, aminoacylation efficiency, or global protein synthesis. Instead, AIMP3 is essential for homocysteine editing by MetRS (a proofreading reaction preventing homocysteine misincorporation); loss of this editing activity causes homocysteine accumulation, reactive oxygen species production, protein aggregation, mitochondrial dysfunction, autophagy, and cardiomyocyte death.\",\n      \"method\": \"Cardiomyocyte-specific conditional knockout mice; MetRS aminoacylation and localization assays; homocysteine editing assay; ROS measurement; protein aggregation assay; mitochondrial function assay; autophagy analysis\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo conditional KO with rigorous negative controls ruling out translation initiation/elongation defects, direct biochemical demonstration of homocysteine editing function, multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"40562875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"EEF1E1 undergoes liquid-liquid phase separation (LLPS) condensate formation in hepatocellular carcinoma cells; EEF1E1 silencing reduces cancer stem cell marker expression (CD133, EpCAM, SOX2) and enhances DNA damage (γH2AX) by activating the PTEN/AKT pathway; inhibition of LLPS with 1,6-hexanediol partially reverses the effects of EEF1E1 on tumor cells.\",\n      \"method\": \"EEF1E1 knockdown (siRNA); LLPS condensate visualization; 1,6-hexanediol LLPS inhibition; western blotting (PTEN, AKT, γH2AX, CSC markers); in vivo and in vitro tumor assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — LLPS observation and knockdown phenotype, but mechanistic basis of phase separation and causal link to PTEN/AKT not fully resolved; single lab\",\n      \"pmids\": [\"39884379\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AIMP3/EEF1E1 is a multifunctional scaffolding protein of the multi-aminoacyl-tRNA synthetase complex that: (1) anchors methionyl-tRNA synthetase (MetRS) and mediates transfer of Met-tRNA(i)(Met) to eIF2γ for translation initiation, and is now shown to be essential for MetRS homocysteine proofreading/editing activity, preventing mistranslation-induced cardiomyopathy; (2) activates p53 via ATM/ATR in response to DNA damage and oncogenic stress, acting as a tumor suppressor; (3) promotes proteasome-dependent degradation of mature lamin A, driving cellular senescence and a progeroid phenotype; and (4) participates in homologous recombination-mediated DNA double-strand break repair, with its loss causing genomic instability.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EEF1E1 (AIMP3/p18) is a multifunctional scaffolding protein that bridges translation initiation, genome surveillance, and the p53 tumor-suppressor response [#0, #3]. Within the translational machinery it specifically binds charged initiator Met-tRNA(i)(Met), discriminating it from elongator and uncharged species, and together with methionyl-tRNA synthetase (MetRS) non-competitively engages eIF2\\u03b3 to transfer Met-tRNA(i)(Met) to the eIF2 complex for initiation [#3]. Its crystal structure resolves an N-terminal and a five-helix-bundle C-terminal domain, the latter carrying the binding surface required for ATM interaction and p53 activation [#1]. Through differential activation of ATM and ATR, EEF1E1 couples oncogenic and DNA-damage stress to p53, acting as a tumor suppressor whose allelic loss permits oncogene-induced transformation and chromosomal instability [#0, #1]. It is additionally required for homologous-recombination repair of DNA double-strand breaks, with its loss causing accumulation of breaks, reduced RPA/Rad51 foci, and p53-dependent loss of stem-cell self-renewal [#4, #5]. A distinct activity is its proofreading role: in cardiomyocytes EEF1E1 is essential for MetRS-mediated homocysteine editing\\u2014independent of aminoacylation or global translation\\u2014and its loss causes homocysteine accumulation, ROS, protein aggregation, and lethal cardiomyopathy [#11]. EEF1E1 overexpression also drives proteasome-dependent degradation of mature lamin A, producing nuclear morphology defects, cellular senescence, and a progeroid phenotype [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that EEF1E1/AIMP3 functions as a stress-responsive tumor suppressor by linking oncogenic signaling to p53 activation, answering whether this aminoacyl-tRNA synthetase complex component has a role beyond translation.\",\n      \"evidence\": \"Genetic knockdown and heterozygous mouse cells with oncogene transformation and chromosomal instability assays\",\n      \"pmids\": [\"16849534\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not define the structural basis of ATM/ATR engagement\", \"Direct vs indirect activation of ATM/ATR not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the domain architecture of AIMP3 and pinpointed the C-terminal surface required for ATM binding and p53 activation, providing the structural basis for its tumor-suppressive activity.\",\n      \"evidence\": \"2.0 \\u00c5 X-ray crystallography with site-directed mutagenesis, ATM co-immunoprecipitation, and p53 activation assays\",\n      \"pmids\": [\"18343821\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No co-structure with ATM\", \"Does not address translation or HR functions\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified a senescence-promoting activity whereby AIMP3 selectively destabilizes mature lamin A, connecting the protein to nuclear architecture and aging.\",\n      \"evidence\": \"AIMP3 transgenic mice, western blotting, proteasome inhibition, and senescence/nuclear morphology assays\",\n      \"pmids\": [\"20726853\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which AIMP3 targets lamin A to the proteasome unidentified\", \"Whether endogenous AIMP3 regulates lamin A unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the molecular function of AIMP3 in translation initiation by showing it binds initiator Met-tRNA with strict specificity and channels it to eIF2 via MetRS and eIF2\\u03b3.\",\n      \"evidence\": \"In vitro filter-binding and pull-down assays with siRNA knockdown and protein synthesis measurement\",\n      \"pmids\": [\"22867704\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis of tRNA discrimination not solved\", \"In vivo requirement for initiation not tested in this study\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established AIMP3 as a component of homologous-recombination DSB repair acting upstream of p53, explaining the chromosomal instability seen on its loss.\",\n      \"evidence\": \"Conditional knockout mESCs and adult mice, \\u03b3H2AX/COMET assays, RPA/Rad51 foci, HR assays, and p53 epistasis\",\n      \"pmids\": [\"30250065\", \"30302025\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular partner within the HR machinery not identified\", \"Whether HR role is separable from translation/p53 roles unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked AIMP3 to metabolic control of stem-cell senescence, showing it enhances mitochondrial respiration and suppresses autophagy under regulation by HIF1\\u03b1 and Notch3.\",\n      \"evidence\": \"RNA-seq, gain/loss-of-function in MSCs, mitochondrial respiration and autophagy flux assays with HIF1\\u03b1/Notch3 manipulation\",\n      \"pmids\": [\"30706629\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Molecular mechanism connecting AIMP3 to mitochondrial respiration not defined\", \"Causal link to autophagy machinery associative\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the lamin A/senescence and p53-dependent tumor-suppressor models to vascular smooth muscle and lung adenocarcinoma, including regulation by miR-96-5p.\",\n      \"evidence\": \"AIMP3 overexpression in HASMCs and lung cancer cells, miR-96-5p targeting, p53 dependency, and xenograft assays\",\n      \"pmids\": [\"34274427\", \"33538115\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Largely overexpression-based without mechanistic dissection\", \"miR-96-5p\\u2013AIMP3\\u2013p53 axis not validated by endogenous loss-of-function\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reported a context-dependent pro-tumor role in glioma and hepatocellular carcinoma via PTEN/AKT suppression and condensate formation, contrasting with the tumor-suppressor role in other tissues.\",\n      \"evidence\": \"siRNA knockdown, cell-cycle and proliferation assays, PTEN/AKT western blotting, LLPS visualization with 1,6-hexanediol, and xenografts\",\n      \"pmids\": [\"37589446\", \"39884379\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct mechanism of PTEN downregulation not shown\", \"Causal basis and biophysical determinants of phase separation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated EEF1E1 in myoblast senescence upstream of a SIRT1-autophagy axis, broadening its senescence role to skeletal muscle.\",\n      \"evidence\": \"siRNA knockdown and recombinant protein treatment with SA-\\u03b2-gal, p21/p53/SIRT1 blotting, autophagy markers, and aged mouse model\",\n      \"pmids\": [\"39276001\"],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanistic link to SIRT1/autophagy is associative\", \"Whether effect is translation- or p53-mediated not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a translation-independent proofreading function: AIMP3 is essential for MetRS homocysteine editing, with loss causing mistranslation-driven lethal cardiomyopathy, redefining its role within the synthetase complex.\",\n      \"evidence\": \"Cardiomyocyte-specific conditional knockout mice with aminoacylation/localization controls, homocysteine editing, ROS, aggregation, and mitochondrial assays\",\n      \"pmids\": [\"40562875\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Structural basis for how AIMP3 enables MetRS editing not defined\", \"Relevance of editing function to non-cardiac tissues untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AIMP3's distinct activities\\u2014initiator-tRNA channeling, MetRS proofreading, ATM/p53 signaling, HR repair, lamin A turnover, and context-dependent tumor roles\\u2014are partitioned and coordinated within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model linking the cytoplasmic synthetase functions to nuclear p53/HR functions\", \"Determinants of tumor-suppressor versus pro-tumor behavior across tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-72766\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"multi-aminoacyl-tRNA synthetase complex\"],\n    \"partners\": [\"MARS1\", \"EIF2S3\", \"ATM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}