{"gene":"MAGOH","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"MAGOH is a component of the splicing-dependent exon-exon junction complex (EJC), binding directly and avidly to Y14 (RBM8A) and TAP (mRNA export factor), but not to other known EJC components such as Aly/REF or RNPS1. MAGOH associates with mRNAs produced by splicing ~20 nucleotides upstream of exon-exon junctions and remains bound after nuclear export.","method":"GST pulldown, co-immunoprecipitation, UV crosslinking/immunoprecipitation of mRNPs","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP and direct binding assays, replicated by multiple subsequent studies","pmids":["11707413"],"is_preprint":false},{"year":2000,"finding":"MAGOH directly interacts with RBM8A (Y14/RBM8), identified via yeast two-hybrid screen and confirmed by GST fusion protein pulldown assay.","method":"Yeast two-hybrid, GST pulldown","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two orthogonal methods (Y2H + GST pulldown), independently replicated in subsequent structural and biochemical studies","pmids":["10662555"],"is_preprint":false},{"year":2003,"finding":"High-resolution crystal structure of the Y14-MAGOH core complex reveals that MAGOH has an unusual flat six-stranded anti-parallel beta sheet packed against two helices, and binds with high affinity to the RNP motif RNA-binding domain (RBD) of Y14, completely masking its RNA binding surface, explaining how the EJC maintains stable, RNA sequence-independent association at splice junctions.","method":"X-ray crystallography, biochemical binding assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with biochemical validation, foundational structural study","pmids":["12781131"],"is_preprint":false},{"year":2010,"finding":"Magoh controls mouse cerebral cortical size by regulating neural stem cell (NSC) division. Magoh haploinsufficiency causes microcephaly through depletion of intermediate neural progenitors and neuronal apoptosis due to defective mitosis, including disrupted mitotic spindle orientation and integrity, abnormal chromosome number, and genomic instability. A key function of Magoh is to control levels of the microcephaly-associated protein Lis1 during neurogenesis.","method":"Mouse genetics (haploinsufficiency model), in utero rescue experiments, live imaging, immunofluorescence","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, in utero rescue, multiple orthogonal readouts","pmids":["20364144"],"is_preprint":false},{"year":2013,"finding":"Both MAGOH and its paralog MAGOHB interact with other EJC core components, incorporate into mRNA-bound EJCs, and activate nonsense-mediated decay (NMD). Simultaneous depletion of MAGOH and MAGOHB, but not individual depletions, impairs NMD in human cells.","method":"siRNA knockdown, RNA immunoprecipitation, NMD reporter assays","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, NMD reporters, siRNA), single lab","pmids":["23917022"],"is_preprint":false},{"year":2013,"finding":"MAGOH is required for normal melanoblast development; Magoh haploinsufficiency causes mitotic arrest in melanoblasts and reduction of epidermal (but not dermal) melanoblast populations without increased apoptosis, demonstrating a role in melanoblast proliferation.","method":"Mouse genetics, flow cytometry, siRNA knockdown in melanoma cell lines, immunostaining","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic haploinsufficiency model with specific cellular phenotype, multiple methods in single lab","pmids":["23333945"],"is_preprint":false},{"year":2013,"finding":"RBM8A (Y14) and MAGOH co-localize to the centrosome in human A549 cells (in addition to nuclei), where they form a complex as detected by proximity ligation in situ assay. GFP-PLK1 also co-localizes with RBM8A at centrosomes, implicating the RBM8A-MAGOH complex in M-phase progression via direct centrosomal localization.","method":"Immunostaining, proximity ligation in situ assay, fluorescent-tagged protein overexpression","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization demonstrated by multiple methods in single lab, functional consequence inferred but not directly tested by rescue","pmids":["23949737"],"is_preprint":false},{"year":2009,"finding":"MAGOH inhibits STAT3 transcriptional activation by interfering with the formation of the STAT3-Y14 complex. MAGOH co-immunoprecipitates with Y14, and siRNA-mediated reduction of MAGOH enhances IL-6-induced STAT3 target gene expression.","method":"Co-immunoprecipitation, siRNA knockdown, luciferase reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP with functional readout (gene expression), single lab","pmids":["19254694"],"is_preprint":false},{"year":2011,"finding":"Mouse Magoh is a dosage suppressor of a temperature-sensitive Cdc2 (Cdk1) mutant, and RNAi depletion of Magoh causes cold-sensitive cell cycle defects and synthetic enhancement of the Cdc2 ts phenotype similar to Cks2 depletion. Magoh RNAi causes defects in Cdc2 and Cks protein expression, and these effects are modulated by introns of Cks genes, indicating Magoh regulates Cdk activity through EJC-dependent mRNA processing.","method":"Genetic epistasis (suppressor screen), RNAi, cell cycle analysis","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with defined pathway, RNAi phenotype, single lab with multiple approaches","pmids":["21210908"],"is_preprint":false},{"year":2014,"finding":"MAGOH inhibits phosphorylation of RBM8A (Y14) in vitro and in vivo. Most endogenous RBM8A is phosphorylated (at serine residues 166 and 168) prior to complex formation with MAGOH, and MAGOH binding inhibits further phosphorylation.","method":"Phos-tag gel analysis, site-directed mutagenesis, in vitro kinase assay, cell-cycle analysis","journal":"Experimental biology and medicine (Maywood, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo phosphorylation assays with mutagenesis, single lab","pmids":["25349214"],"is_preprint":false},{"year":2019,"finding":"The stability of MAGOH protein depends on its heterodimer formation with Y14 and on nuclear localization: a Magoh L136R mutation that disrupts heterodimer formation causes faster protein degradation. Y14 L118R, which also fails to form heterodimers but retains nuclear localization, is more stable than Magoh L136R, showing nuclear localization provides additional stabilization independent of complex formation.","method":"Cycloheximide chase assay, mutagenesis, immunofluorescence, co-immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (chase assay, mutagenesis, localization), single lab","pmids":["30826064"],"is_preprint":false},{"year":2020,"finding":"Homozygous magoh mutations in zebrafish cause muscle disorganization, neural cell death, and motor neuron outgrowth defects, and dysregulate mRNAs subject to EJC-dependent NMD, including a novel class with 3'UTR introns located <50 nt downstream of a stop codon. foxo3b mRNA is an NMD target regulated by the EJC, and loss of foxo3b function in EJC mutant embryos rescues motor axon growth defects.","method":"Zebrafish genetics (homozygous mutant), RNA-seq, genetic epistasis (foxo3b loss-of-function rescue)","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with molecular mechanism (NMD), transcriptome-wide analysis, and functional rescue in model organism","pmids":["32502192"],"is_preprint":false},{"year":2020,"finding":"Conditional Magoh ablation from interneuron progenitors (but not post-mitotic neurons) depletes cortical interneuron number. Magoh deficiency delays progenitor mitotic progression in a dosage-sensitive fashion. p53 ablation in Magoh haploinsufficient progenitors fully rescues apoptosis and interneuron number; in Magoh homozygotes, p53 loss fails to rescue interneuron number or mitotic delay.","method":"Conditional knockout (Cre-lox), live imaging, transcriptome analysis, genetic epistasis (p53 ablation)","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with live imaging, genetic epistasis (p53), transcriptome analysis, multiple cell types and dosages","pmids":["31857347"],"is_preprint":false},{"year":2022,"finding":"Magoh I90T mutation (equivalent to a Drosophila mago nashi mutant) reduces binding to Y14, causing cytoplasmic mislocalization of Magoh and impaired EJC formation. Magoh G18R mutation does not affect Y14 binding but reduces association with spliced mRNAs, also impairing EJC incorporation.","method":"Site-directed mutagenesis, co-immunoprecipitation, immunofluorescence, UV crosslinking/RNA immunoprecipitation","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with multiple functional readouts (binding, localization, mRNA association), single lab","pmids":["35430764"],"is_preprint":false},{"year":2024,"finding":"MAGOH promotes gastric cancer progression by inhibiting hnRNPA1 expression, which reduces hnRNPA1 binding to RON mRNA, thereby promoting formation of the alternative splice isoform RONΔ160 and activating the PI3K/AKT signaling pathway.","method":"RNA pulldown, RNA immunoprecipitation (RIP), RNA-seq, in vitro and in vivo functional assays, siRNA knockdown","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown and RIP with functional pathway readout, single lab","pmids":["38268030"],"is_preprint":false},{"year":2025,"finding":"PYM1 binds the RBM8A/MAGOH heterodimer of the EJC core and mediates translation-independent EJC destabilization; EJCs lacking PYM1 interaction show no defect in translation-dependent disassembly but accumulate on non-canonical sites including intronless transcripts or transcripts with fewer and longer exons.","method":"CLIP-seq, knockdown, reporter assays, EJC occupancy profiling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide occupancy profiling with functional knockdown, preprint not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"MAGOH-Δ37, an alternatively spliced isoform of MAGOH lacking exon 37, does not interact with known EJC proteins (EIF4A3, RBM8A, RNPS1, SAP18), indicating it functions independently of the EJC. Both MAGOH and MAGOH-Δ37 associate with ubiquitin and are upregulated upon proteasomal inhibition, suggesting involvement in the ubiquitin-proteasome system.","method":"Co-immunoprecipitation, mass spectrometry interactome capture, proteasome inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and MS in single study, novel isoform, single lab","pmids":["40889427"],"is_preprint":false},{"year":2026,"finding":"Individual knockout of MAGOH or MAGOHB each maintains core EJC functions but causes significant growth defects, demonstrating non-redundant roles in proliferation. MAGOH loss uniquely downregulates the mitochondrial ADP/ATP carrier SLC25A4, while MAGOHB loss specifically impairs PI3K-Akt signaling.","method":"CRISPR/Cas9 knockout, quantitative proteomics, cell proliferation assays","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with proteomics, single lab, paralog-specific functional distinctions","pmids":["41956154"],"is_preprint":false},{"year":2024,"finding":"Depletion of MAGOH (an EJC core component) perturbs junctional distribution and localized translation of Zo-1 and Scrib mRNAs at cell-cell junctions, as well as junctional accumulation of their protein products, implicating MAGOH in localizing specific mRNAs for translation at epithelial cell junctions.","method":"siRNA knockdown, smFISH, live imaging, epithelial cell polarity assays in Drosophila and human cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, localization phenotype without direct rescue or mechanistic pathway placement for MAGOH specifically","pmids":[],"is_preprint":true},{"year":2016,"finding":"MAGOH and MAGOHB knockdown in melanoma cells decreases NMD activity, leading to upregulation of the pro-apoptotic protein GADD45A and subsequent apoptosis. The effect on apoptosis is enhanced by simultaneous knockdown of both paralogs.","method":"siRNA knockdown, NMD reporter assay, flow cytometry, Western blot","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NMD reporter assay with defined downstream target (GADD45A), multiple knockdown conditions, single lab","pmids":["36497117"],"is_preprint":false}],"current_model":"MAGOH is a core component of the exon junction complex (EJC) that forms a tight, stable heterodimer with Y14 (RBM8A) — a structure resolved crystallographically — and is deposited on mRNAs ~20 nt upstream of exon-exon junctions during splicing; within this complex, MAGOH directly contacts Y14's RNA-binding surface to maintain stable, sequence-independent mRNA association and regulates multiple downstream post-transcriptional processes including nonsense-mediated mRNA decay (functionally redundant with its paralog MAGOHB), mRNA nuclear export, and localized translation at cell junctions, while also playing a cell-autonomous role in mitotic progression in neural stem cells, melanoblasts, and interneuron progenitors — in part by regulating Lis1 protein levels — and modulating STAT3 activity by competing with STAT3 for Y14 binding."},"narrative":{"mechanistic_narrative":"MAGOH is a core component of the splicing-dependent exon junction complex (EJC), deposited on mRNAs ~20 nucleotides upstream of exon-exon junctions and retained after nuclear export [PMID:11707413]. It functions as an obligate, high-affinity heterodimer with Y14/RBM8A: crystallographic analysis shows MAGOH adopts a flat six-stranded anti-parallel beta sheet that binds the Y14 RNP RNA-binding domain and completely masks its RNA-binding surface, explaining how the EJC achieves stable, sequence-independent association at splice junctions [PMID:10662555, PMID:12781131]. This heterodimer is required for EJC incorporation and for downstream post-transcriptional functions including nonsense-mediated mRNA decay (NMD), in which MAGOH is functionally redundant with its paralog MAGOHB — only simultaneous depletion of both impairs NMD [PMID:23917022]. Through EJC-dependent control of mRNA fate, MAGOH governs proliferation: in mouse neural stem cells and interneuron progenitors, Magoh dosage controls mitotic spindle integrity and progression, in part by regulating levels of the microcephaly protein Lis1, with haploinsufficiency causing microcephaly via progenitor depletion and p53-dependent apoptosis [PMID:20364144, PMID:31857347]. Parallel mitotic requirements are seen in melanoblasts [PMID:23333945]. In zebrafish, loss of magoh dysregulates EJC/NMD substrates including foxo3b, and foxo3b loss rescues the resulting motor axon defects, linking the molecular NMD function to organismal phenotype [PMID:32502192]. MAGOH also acts beyond canonical EJC roles: it competes with STAT3 for Y14 binding to dampen STAT3 transcriptional activation [PMID:19254694], and its protein stability depends on Y14 heterodimerization and nuclear localization [PMID:30826064].","teleology":[{"year":2000,"claim":"Established the founding physical interaction of MAGOH, defining its principal binding partner before any complex context was known.","evidence":"Yeast two-hybrid screen and GST pulldown identifying direct RBM8A/Y14 binding","pmids":["10662555"],"confidence":"High","gaps":["Did not place the interaction in a functional complex","No structural basis for binding","No RNA association demonstrated"]},{"year":2001,"claim":"Placed MAGOH within the exon junction complex, showing it is deposited co-transcriptionally upstream of splice junctions and retained through export, defining its role in mRNP marking of spliced transcripts.","evidence":"GST pulldown, reciprocal co-IP, and UV crosslinking/IP of mRNPs in human cells","pmids":["11707413"],"confidence":"High","gaps":["Functional consequence of EJC deposition not yet tested","Selectivity for Y14 and TAP over Aly/REF unexplained structurally"]},{"year":2003,"claim":"Resolved the structural logic of the MAGOH-Y14 heterodimer, explaining how the EJC achieves sequence-independent, stable mRNA association.","evidence":"X-ray crystallography of the Y14-MAGOH core with biochemical binding validation","pmids":["12781131"],"confidence":"High","gaps":["Structure of the full assembled EJC on RNA not resolved here","Did not address how the complex is remodeled or disassembled"]},{"year":2010,"claim":"Connected the molecular EJC function to a cell-autonomous role in mitosis, showing Magoh dosage controls cortical neural stem cell division and Lis1 levels, linking it to microcephaly.","evidence":"Mouse haploinsufficiency model with in utero rescue, live imaging and immunofluorescence","pmids":["20364144"],"confidence":"High","gaps":["Mechanism by which Magoh controls Lis1 levels not defined","Whether spindle phenotype is EJC/NMD-dependent unresolved"]},{"year":2013,"claim":"Demonstrated functional redundancy with the paralog MAGOHB in NMD, showing both incorporate into EJCs and that NMD requires loss of both.","evidence":"siRNA knockdown, RNA immunoprecipitation, and NMD reporter assays in human cells","pmids":["23917022"],"confidence":"High","gaps":["Did not identify endogenous substrate sets distinguishing the paralogs","Single lab"]},{"year":2013,"claim":"Extended the mitotic proliferation role to a second lineage and localized the MAGOH-Y14 complex to the centrosome alongside PLK1, implicating it directly in M-phase machinery.","evidence":"Mouse genetics and melanoma siRNA (melanoblasts); immunostaining and proximity ligation assay (centrosome)","pmids":["23333945","23949737"],"confidence":"Medium","gaps":["Centrosomal function inferred, not tested by rescue","Link between centrosomal localization and EJC activity unclear"]},{"year":2009,"claim":"Identified a non-EJC regulatory role: MAGOH competes with STAT3 for Y14 binding to restrain STAT3-driven transcription.","evidence":"Co-immunoprecipitation, siRNA knockdown, and luciferase reporter assays","pmids":["19254694"],"confidence":"Medium","gaps":["Direct competition not shown by reconstitution","Physiological contexts where this operates unknown"]},{"year":2011,"claim":"Linked Magoh to cell cycle control through Cdk1/Cks regulation, showing the effect depends on Cks introns and thus EJC-dependent mRNA processing.","evidence":"Genetic suppressor screen of a Cdc2 ts mutant, RNAi, and cell cycle analysis","pmids":["21210908"],"confidence":"Medium","gaps":["Whether regulation is via NMD or splicing not pinned down","Single lab"]},{"year":2014,"claim":"Showed MAGOH binding suppresses Y14 phosphorylation, adding a layer of post-translational regulation to heterodimer assembly.","evidence":"Phos-tag gels, site-directed mutagenesis, in vitro kinase assay, cell-cycle analysis","pmids":["25349214"],"confidence":"Medium","gaps":["Kinase responsible not definitively identified","Functional output of Y14 phosphorylation state unclear"]},{"year":2019,"claim":"Defined the determinants of MAGOH protein stability, showing it requires Y14 heterodimerization and nuclear localization.","evidence":"Cycloheximide chase, mutagenesis (L136R), immunofluorescence, co-IP","pmids":["30826064"],"confidence":"Medium","gaps":["Degradation machinery not identified","Single lab"]},{"year":2020,"claim":"Connected MAGOH's molecular NMD function to organismal phenotype, showing magoh loss dysregulates EJC/NMD substrates including foxo3b, whose removal rescues motor axon defects.","evidence":"Zebrafish homozygous mutants, RNA-seq, and foxo3b loss-of-function genetic epistasis","pmids":["32502192"],"confidence":"High","gaps":["3'UTR-intron NMD class mechanism not fully resolved","Tissue-specific substrate dependence incomplete"]},{"year":2020,"claim":"Dissected the dosage- and p53-dependence of Magoh's mitotic function in interneuron progenitors, separating apoptosis (p53-rescuable) from mitotic delay (not rescued in nulls).","evidence":"Conditional Cre-lox knockout, live imaging, transcriptome analysis, p53 genetic epistasis","pmids":["31857347"],"confidence":"High","gaps":["Molecular cause of p53-independent mitotic delay unknown","Relevant EJC substrates in interneurons not defined"]},{"year":2022,"claim":"Mapped distinct MAGOH residues required for Y14 binding versus mRNA association, separating two functional requirements for EJC incorporation.","evidence":"Site-directed mutagenesis (I90T, G18R), co-IP, immunofluorescence, UV-CLIP/RIP","pmids":["35430764"],"confidence":"Medium","gaps":["Structural basis of G18R mRNA-association defect not resolved","Single lab"]},{"year":2024,"claim":"Identified disease-relevant outputs: MAGOH influences alternative splicing of RON to activate PI3K/AKT in gastric cancer, and EJC depletion perturbs junctional localized translation of Zo-1 and Scrib.","evidence":"RNA pulldown/RIP, RNA-seq, in vivo assays (cancer); siRNA, smFISH, live imaging in Drosophila and human cells (junctions, preprint)","pmids":["38268030"],"confidence":"Medium","gaps":["Junctional translation role rests on a preprint without MAGOH-specific rescue","Direct vs indirect effect on hnRNPA1 not fully separated"]},{"year":2026,"claim":"Showed individual MAGOH and MAGOHB knockouts retain core EJC function yet cause distinct, non-redundant proliferation and proteome defects.","evidence":"CRISPR/Cas9 knockout, quantitative proteomics, proliferation assays","pmids":["41956154"],"confidence":"Medium","gaps":["Mechanism linking MAGOH loss to SLC25A4 downregulation unknown","Reconciliation with earlier full redundancy claims incomplete"]},{"year":null,"claim":"How MAGOH's canonical EJC role is mechanistically coupled to its EJC-independent activities (Lis1 control, STAT3 competition, ubiquitin-proteasome association, junctional translation) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking mitotic, NMD, and signaling functions","EJC-independent isoform (MAGOH-Δ37) function uncharacterized beyond interactome","PYM1-mediated EJC destabilization role awaits peer review"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,13]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[3,12]}],"complexes":["exon junction complex (EJC)"],"partners":["RBM8A","EIF4A3","RNPS1","PYM1","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P61326","full_name":"Protein mago nashi homolog","aliases":[],"length_aa":146,"mass_kda":17.2,"function":"Required for pre-mRNA splicing as component of the spliceosome (PubMed:11991638). Plays a redundant role with MAGOHB as core component of the exon junction complex (EJC) and in the nonsense-mediated decay (NMD) pathway (PubMed:23917022). The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). The MAGOH-RBM8A heterodimer inhibits the ATPase activity of EIF4A3, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The MAGOH-RBM8A heterodimer interacts with the EJC key regulator PYM1 leading to EJC disassembly in the cytoplasm and translation enhancement of EJC-bearing spliced mRNAs by recruiting them to the ribosomal 48S pre-initiation complex. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly","subcellular_location":"Nucleus; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P61326/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MAGOH","classification":"Common Essential","n_dependent_lines":974,"n_total_lines":1208,"dependency_fraction":0.8062913907284768},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MAGOH","total_profiled":1310},"omim":[{"mim_id":"619753","title":"PYM HOMOLOG 1, EXON JUNCTION COMPLEX-ASSOCIATED FACTOR; PYM1","url":"https://www.omim.org/entry/619753"},{"mim_id":"619552","title":"MAGO HOMOLOG B, EXON JUNCTION COMPLEX SUBUNIT; MAGOHB","url":"https://www.omim.org/entry/619552"},{"mim_id":"608546","title":"EUKARYOTIC TRANSLATION INITIATION FACTOR 4A, ISOFORM 3; EIF4A3","url":"https://www.omim.org/entry/608546"},{"mim_id":"606504","title":"CANCER SUSCEPTIBILITY CANDIDATE 3; CASC3","url":"https://www.omim.org/entry/606504"},{"mim_id":"605530","title":"UPF3A REGULATOR OF NONSENSE-MEDIATED mRNA DECAY; UPF3A","url":"https://www.omim.org/entry/605530"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAGOH"},"hgnc":{"alias_symbol":["MAGOHA","MAGOH1"],"prev_symbol":[]},"alphafold":{"accession":"P61326","domains":[{"cath_id":"3.30.1560.10","chopping":"4-140","consensus_level":"high","plddt":94.8082,"start":4,"end":140}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P61326","model_url":"https://alphafold.ebi.ac.uk/files/AF-P61326-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P61326-F1-predicted_aligned_error_v6.png","plddt_mean":93.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAGOH","jax_strain_url":"https://www.jax.org/strain/search?query=MAGOH"},"sequence":{"accession":"P61326","fasta_url":"https://rest.uniprot.org/uniprotkb/P61326.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P61326/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P61326"}},"corpus_meta":[{"pmid":"11707413","id":"PMC_11707413","title":"Magoh, a human homolog of Drosophila mago nashi protein, is a component of the splicing-dependent exon-exon junction complex.","date":"2001","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/11707413","citation_count":182,"is_preprint":false},{"pmid":"20364144","id":"PMC_20364144","title":"The exon junction complex component Magoh controls brain size by regulating neural stem cell division.","date":"2010","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20364144","citation_count":150,"is_preprint":false},{"pmid":"12781131","id":"PMC_12781131","title":"Structure of the Y14-Magoh core of the exon junction complex.","date":"2003","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/12781131","citation_count":104,"is_preprint":false},{"pmid":"10662555","id":"PMC_10662555","title":"MAGOH interacts with a novel RNA-binding protein.","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10662555","citation_count":62,"is_preprint":false},{"pmid":"23917022","id":"PMC_23917022","title":"Two mammalian MAGOH genes contribute to exon junction complex composition and nonsense-mediated decay.","date":"2013","source":"RNA biology","url":"https://pubmed.ncbi.nlm.nih.gov/23917022","citation_count":48,"is_preprint":false},{"pmid":"23333945","id":"PMC_23333945","title":"The EJC component Magoh regulates proliferation and expansion of neural crest-derived melanocytes.","date":"2013","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/23333945","citation_count":35,"is_preprint":false},{"pmid":"23949737","id":"PMC_23949737","title":"RNA-binding protein RBM8A (Y14) and MAGOH localize to centrosome in human A549 cells.","date":"2013","source":"Histochemistry and cell 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the Tumorigenesis of Gastric Cancer via Inactivation of b-RAF/MEK/ERK Signaling.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33328743","citation_count":19,"is_preprint":false},{"pmid":"31857347","id":"PMC_31857347","title":"Dosage-dependent requirements of Magoh for cortical interneuron generation and survival.","date":"2020","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31857347","citation_count":16,"is_preprint":false},{"pmid":"21210908","id":"PMC_21210908","title":"Genetic analyses using a mouse cell cycle mutant identifies magoh as a novel gene involved in Cdk regulation.","date":"2011","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/21210908","citation_count":15,"is_preprint":false},{"pmid":"38268030","id":"PMC_38268030","title":"MAGOH promotes gastric cancer progression via hnRNPA1 expression inhibition-mediated RONΔ160/PI3K/AKT signaling 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MAGOH associates with mRNAs produced by splicing ~20 nucleotides upstream of exon-exon junctions and remains bound after nuclear export.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation, UV crosslinking/immunoprecipitation of mRNPs\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP and direct binding assays, replicated by multiple subsequent studies\",\n      \"pmids\": [\"11707413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MAGOH directly interacts with RBM8A (Y14/RBM8), identified via yeast two-hybrid screen and confirmed by GST fusion protein pulldown assay.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two orthogonal methods (Y2H + GST pulldown), independently replicated in subsequent structural and biochemical studies\",\n      \"pmids\": [\"10662555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"High-resolution crystal structure of the Y14-MAGOH core complex reveals that MAGOH has an unusual flat six-stranded anti-parallel beta sheet packed against two helices, and binds with high affinity to the RNP motif RNA-binding domain (RBD) of Y14, completely masking its RNA binding surface, explaining how the EJC maintains stable, RNA sequence-independent association at splice junctions.\",\n      \"method\": \"X-ray crystallography, biochemical binding assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with biochemical validation, foundational structural study\",\n      \"pmids\": [\"12781131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Magoh controls mouse cerebral cortical size by regulating neural stem cell (NSC) division. Magoh haploinsufficiency causes microcephaly through depletion of intermediate neural progenitors and neuronal apoptosis due to defective mitosis, including disrupted mitotic spindle orientation and integrity, abnormal chromosome number, and genomic instability. A key function of Magoh is to control levels of the microcephaly-associated protein Lis1 during neurogenesis.\",\n      \"method\": \"Mouse genetics (haploinsufficiency model), in utero rescue experiments, live imaging, immunofluorescence\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype, in utero rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"20364144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Both MAGOH and its paralog MAGOHB interact with other EJC core components, incorporate into mRNA-bound EJCs, and activate nonsense-mediated decay (NMD). Simultaneous depletion of MAGOH and MAGOHB, but not individual depletions, impairs NMD in human cells.\",\n      \"method\": \"siRNA knockdown, RNA immunoprecipitation, NMD reporter assays\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, NMD reporters, siRNA), single lab\",\n      \"pmids\": [\"23917022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAGOH is required for normal melanoblast development; Magoh haploinsufficiency causes mitotic arrest in melanoblasts and reduction of epidermal (but not dermal) melanoblast populations without increased apoptosis, demonstrating a role in melanoblast proliferation.\",\n      \"method\": \"Mouse genetics, flow cytometry, siRNA knockdown in melanoma cell lines, immunostaining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic haploinsufficiency model with specific cellular phenotype, multiple methods in single lab\",\n      \"pmids\": [\"23333945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBM8A (Y14) and MAGOH co-localize to the centrosome in human A549 cells (in addition to nuclei), where they form a complex as detected by proximity ligation in situ assay. GFP-PLK1 also co-localizes with RBM8A at centrosomes, implicating the RBM8A-MAGOH complex in M-phase progression via direct centrosomal localization.\",\n      \"method\": \"Immunostaining, proximity ligation in situ assay, fluorescent-tagged protein overexpression\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization demonstrated by multiple methods in single lab, functional consequence inferred but not directly tested by rescue\",\n      \"pmids\": [\"23949737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAGOH inhibits STAT3 transcriptional activation by interfering with the formation of the STAT3-Y14 complex. MAGOH co-immunoprecipitates with Y14, and siRNA-mediated reduction of MAGOH enhances IL-6-induced STAT3 target gene expression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, luciferase reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP with functional readout (gene expression), single lab\",\n      \"pmids\": [\"19254694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mouse Magoh is a dosage suppressor of a temperature-sensitive Cdc2 (Cdk1) mutant, and RNAi depletion of Magoh causes cold-sensitive cell cycle defects and synthetic enhancement of the Cdc2 ts phenotype similar to Cks2 depletion. Magoh RNAi causes defects in Cdc2 and Cks protein expression, and these effects are modulated by introns of Cks genes, indicating Magoh regulates Cdk activity through EJC-dependent mRNA processing.\",\n      \"method\": \"Genetic epistasis (suppressor screen), RNAi, cell cycle analysis\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with defined pathway, RNAi phenotype, single lab with multiple approaches\",\n      \"pmids\": [\"21210908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAGOH inhibits phosphorylation of RBM8A (Y14) in vitro and in vivo. Most endogenous RBM8A is phosphorylated (at serine residues 166 and 168) prior to complex formation with MAGOH, and MAGOH binding inhibits further phosphorylation.\",\n      \"method\": \"Phos-tag gel analysis, site-directed mutagenesis, in vitro kinase assay, cell-cycle analysis\",\n      \"journal\": \"Experimental biology and medicine (Maywood, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo phosphorylation assays with mutagenesis, single lab\",\n      \"pmids\": [\"25349214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The stability of MAGOH protein depends on its heterodimer formation with Y14 and on nuclear localization: a Magoh L136R mutation that disrupts heterodimer formation causes faster protein degradation. Y14 L118R, which also fails to form heterodimers but retains nuclear localization, is more stable than Magoh L136R, showing nuclear localization provides additional stabilization independent of complex formation.\",\n      \"method\": \"Cycloheximide chase assay, mutagenesis, immunofluorescence, co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (chase assay, mutagenesis, localization), single lab\",\n      \"pmids\": [\"30826064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Homozygous magoh mutations in zebrafish cause muscle disorganization, neural cell death, and motor neuron outgrowth defects, and dysregulate mRNAs subject to EJC-dependent NMD, including a novel class with 3'UTR introns located <50 nt downstream of a stop codon. foxo3b mRNA is an NMD target regulated by the EJC, and loss of foxo3b function in EJC mutant embryos rescues motor axon growth defects.\",\n      \"method\": \"Zebrafish genetics (homozygous mutant), RNA-seq, genetic epistasis (foxo3b loss-of-function rescue)\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with molecular mechanism (NMD), transcriptome-wide analysis, and functional rescue in model organism\",\n      \"pmids\": [\"32502192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional Magoh ablation from interneuron progenitors (but not post-mitotic neurons) depletes cortical interneuron number. Magoh deficiency delays progenitor mitotic progression in a dosage-sensitive fashion. p53 ablation in Magoh haploinsufficient progenitors fully rescues apoptosis and interneuron number; in Magoh homozygotes, p53 loss fails to rescue interneuron number or mitotic delay.\",\n      \"method\": \"Conditional knockout (Cre-lox), live imaging, transcriptome analysis, genetic epistasis (p53 ablation)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with live imaging, genetic epistasis (p53), transcriptome analysis, multiple cell types and dosages\",\n      \"pmids\": [\"31857347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Magoh I90T mutation (equivalent to a Drosophila mago nashi mutant) reduces binding to Y14, causing cytoplasmic mislocalization of Magoh and impaired EJC formation. Magoh G18R mutation does not affect Y14 binding but reduces association with spliced mRNAs, also impairing EJC incorporation.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, immunofluorescence, UV crosslinking/RNA immunoprecipitation\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with multiple functional readouts (binding, localization, mRNA association), single lab\",\n      \"pmids\": [\"35430764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MAGOH promotes gastric cancer progression by inhibiting hnRNPA1 expression, which reduces hnRNPA1 binding to RON mRNA, thereby promoting formation of the alternative splice isoform RONΔ160 and activating the PI3K/AKT signaling pathway.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation (RIP), RNA-seq, in vitro and in vivo functional assays, siRNA knockdown\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown and RIP with functional pathway readout, single lab\",\n      \"pmids\": [\"38268030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PYM1 binds the RBM8A/MAGOH heterodimer of the EJC core and mediates translation-independent EJC destabilization; EJCs lacking PYM1 interaction show no defect in translation-dependent disassembly but accumulate on non-canonical sites including intronless transcripts or transcripts with fewer and longer exons.\",\n      \"method\": \"CLIP-seq, knockdown, reporter assays, EJC occupancy profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide occupancy profiling with functional knockdown, preprint not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MAGOH-Δ37, an alternatively spliced isoform of MAGOH lacking exon 37, does not interact with known EJC proteins (EIF4A3, RBM8A, RNPS1, SAP18), indicating it functions independently of the EJC. Both MAGOH and MAGOH-Δ37 associate with ubiquitin and are upregulated upon proteasomal inhibition, suggesting involvement in the ubiquitin-proteasome system.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry interactome capture, proteasome inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and MS in single study, novel isoform, single lab\",\n      \"pmids\": [\"40889427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Individual knockout of MAGOH or MAGOHB each maintains core EJC functions but causes significant growth defects, demonstrating non-redundant roles in proliferation. MAGOH loss uniquely downregulates the mitochondrial ADP/ATP carrier SLC25A4, while MAGOHB loss specifically impairs PI3K-Akt signaling.\",\n      \"method\": \"CRISPR/Cas9 knockout, quantitative proteomics, cell proliferation assays\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with proteomics, single lab, paralog-specific functional distinctions\",\n      \"pmids\": [\"41956154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Depletion of MAGOH (an EJC core component) perturbs junctional distribution and localized translation of Zo-1 and Scrib mRNAs at cell-cell junctions, as well as junctional accumulation of their protein products, implicating MAGOH in localizing specific mRNAs for translation at epithelial cell junctions.\",\n      \"method\": \"siRNA knockdown, smFISH, live imaging, epithelial cell polarity assays in Drosophila and human cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, localization phenotype without direct rescue or mechanistic pathway placement for MAGOH specifically\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAGOH and MAGOHB knockdown in melanoma cells decreases NMD activity, leading to upregulation of the pro-apoptotic protein GADD45A and subsequent apoptosis. The effect on apoptosis is enhanced by simultaneous knockdown of both paralogs.\",\n      \"method\": \"siRNA knockdown, NMD reporter assay, flow cytometry, Western blot\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NMD reporter assay with defined downstream target (GADD45A), multiple knockdown conditions, single lab\",\n      \"pmids\": [\"36497117\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAGOH is a core component of the exon junction complex (EJC) that forms a tight, stable heterodimer with Y14 (RBM8A) — a structure resolved crystallographically — and is deposited on mRNAs ~20 nt upstream of exon-exon junctions during splicing; within this complex, MAGOH directly contacts Y14's RNA-binding surface to maintain stable, sequence-independent mRNA association and regulates multiple downstream post-transcriptional processes including nonsense-mediated mRNA decay (functionally redundant with its paralog MAGOHB), mRNA nuclear export, and localized translation at cell junctions, while also playing a cell-autonomous role in mitotic progression in neural stem cells, melanoblasts, and interneuron progenitors — in part by regulating Lis1 protein levels — and modulating STAT3 activity by competing with STAT3 for Y14 binding.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAGOH is a core component of the splicing-dependent exon junction complex (EJC), deposited on mRNAs ~20 nucleotides upstream of exon-exon junctions and retained after nuclear export [#0]. It functions as an obligate, high-affinity heterodimer with Y14/RBM8A: crystallographic analysis shows MAGOH adopts a flat six-stranded anti-parallel beta sheet that binds the Y14 RNP RNA-binding domain and completely masks its RNA-binding surface, explaining how the EJC achieves stable, sequence-independent association at splice junctions [#1, #2]. This heterodimer is required for EJC incorporation and for downstream post-transcriptional functions including nonsense-mediated mRNA decay (NMD), in which MAGOH is functionally redundant with its paralog MAGOHB \\u2014 only simultaneous depletion of both impairs NMD [#4]. Through EJC-dependent control of mRNA fate, MAGOH governs proliferation: in mouse neural stem cells and interneuron progenitors, Magoh dosage controls mitotic spindle integrity and progression, in part by regulating levels of the microcephaly protein Lis1, with haploinsufficiency causing microcephaly via progenitor depletion and p53-dependent apoptosis [#3, #12]. Parallel mitotic requirements are seen in melanoblasts [#5]. In zebrafish, loss of magoh dysregulates EJC/NMD substrates including foxo3b, and foxo3b loss rescues the resulting motor axon defects, linking the molecular NMD function to organismal phenotype [#11]. MAGOH also acts beyond canonical EJC roles: it competes with STAT3 for Y14 binding to dampen STAT3 transcriptional activation [#7], and its protein stability depends on Y14 heterodimerization and nuclear localization [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the founding physical interaction of MAGOH, defining its principal binding partner before any complex context was known.\",\n      \"evidence\": \"Yeast two-hybrid screen and GST pulldown identifying direct RBM8A/Y14 binding\",\n      \"pmids\": [\"10662555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not place the interaction in a functional complex\", \"No structural basis for binding\", \"No RNA association demonstrated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed MAGOH within the exon junction complex, showing it is deposited co-transcriptionally upstream of splice junctions and retained through export, defining its role in mRNP marking of spliced transcripts.\",\n      \"evidence\": \"GST pulldown, reciprocal co-IP, and UV crosslinking/IP of mRNPs in human cells\",\n      \"pmids\": [\"11707413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of EJC deposition not yet tested\", \"Selectivity for Y14 and TAP over Aly/REF unexplained structurally\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the structural logic of the MAGOH-Y14 heterodimer, explaining how the EJC achieves sequence-independent, stable mRNA association.\",\n      \"evidence\": \"X-ray crystallography of the Y14-MAGOH core with biochemical binding validation\",\n      \"pmids\": [\"12781131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full assembled EJC on RNA not resolved here\", \"Did not address how the complex is remodeled or disassembled\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected the molecular EJC function to a cell-autonomous role in mitosis, showing Magoh dosage controls cortical neural stem cell division and Lis1 levels, linking it to microcephaly.\",\n      \"evidence\": \"Mouse haploinsufficiency model with in utero rescue, live imaging and immunofluorescence\",\n      \"pmids\": [\"20364144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which Magoh controls Lis1 levels not defined\", \"Whether spindle phenotype is EJC/NMD-dependent unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated functional redundancy with the paralog MAGOHB in NMD, showing both incorporate into EJCs and that NMD requires loss of both.\",\n      \"evidence\": \"siRNA knockdown, RNA immunoprecipitation, and NMD reporter assays in human cells\",\n      \"pmids\": [\"23917022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify endogenous substrate sets distinguishing the paralogs\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the mitotic proliferation role to a second lineage and localized the MAGOH-Y14 complex to the centrosome alongside PLK1, implicating it directly in M-phase machinery.\",\n      \"evidence\": \"Mouse genetics and melanoma siRNA (melanoblasts); immunostaining and proximity ligation assay (centrosome)\",\n      \"pmids\": [\"23333945\", \"23949737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Centrosomal function inferred, not tested by rescue\", \"Link between centrosomal localization and EJC activity unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified a non-EJC regulatory role: MAGOH competes with STAT3 for Y14 binding to restrain STAT3-driven transcription.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown, and luciferase reporter assays\",\n      \"pmids\": [\"19254694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct competition not shown by reconstitution\", \"Physiological contexts where this operates unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked Magoh to cell cycle control through Cdk1/Cks regulation, showing the effect depends on Cks introns and thus EJC-dependent mRNA processing.\",\n      \"evidence\": \"Genetic suppressor screen of a Cdc2 ts mutant, RNAi, and cell cycle analysis\",\n      \"pmids\": [\"21210908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether regulation is via NMD or splicing not pinned down\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed MAGOH binding suppresses Y14 phosphorylation, adding a layer of post-translational regulation to heterodimer assembly.\",\n      \"evidence\": \"Phos-tag gels, site-directed mutagenesis, in vitro kinase assay, cell-cycle analysis\",\n      \"pmids\": [\"25349214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible not definitively identified\", \"Functional output of Y14 phosphorylation state unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the determinants of MAGOH protein stability, showing it requires Y14 heterodimerization and nuclear localization.\",\n      \"evidence\": \"Cycloheximide chase, mutagenesis (L136R), immunofluorescence, co-IP\",\n      \"pmids\": [\"30826064\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Degradation machinery not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected MAGOH's molecular NMD function to organismal phenotype, showing magoh loss dysregulates EJC/NMD substrates including foxo3b, whose removal rescues motor axon defects.\",\n      \"evidence\": \"Zebrafish homozygous mutants, RNA-seq, and foxo3b loss-of-function genetic epistasis\",\n      \"pmids\": [\"32502192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"3'UTR-intron NMD class mechanism not fully resolved\", \"Tissue-specific substrate dependence incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Dissected the dosage- and p53-dependence of Magoh's mitotic function in interneuron progenitors, separating apoptosis (p53-rescuable) from mitotic delay (not rescued in nulls).\",\n      \"evidence\": \"Conditional Cre-lox knockout, live imaging, transcriptome analysis, p53 genetic epistasis\",\n      \"pmids\": [\"31857347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cause of p53-independent mitotic delay unknown\", \"Relevant EJC substrates in interneurons not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped distinct MAGOH residues required for Y14 binding versus mRNA association, separating two functional requirements for EJC incorporation.\",\n      \"evidence\": \"Site-directed mutagenesis (I90T, G18R), co-IP, immunofluorescence, UV-CLIP/RIP\",\n      \"pmids\": [\"35430764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of G18R mRNA-association defect not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified disease-relevant outputs: MAGOH influences alternative splicing of RON to activate PI3K/AKT in gastric cancer, and EJC depletion perturbs junctional localized translation of Zo-1 and Scrib.\",\n      \"evidence\": \"RNA pulldown/RIP, RNA-seq, in vivo assays (cancer); siRNA, smFISH, live imaging in Drosophila and human cells (junctions, preprint)\",\n      \"pmids\": [\"38268030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Junctional translation role rests on a preprint without MAGOH-specific rescue\", \"Direct vs indirect effect on hnRNPA1 not fully separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed individual MAGOH and MAGOHB knockouts retain core EJC function yet cause distinct, non-redundant proliferation and proteome defects.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, quantitative proteomics, proliferation assays\",\n      \"pmids\": [\"41956154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking MAGOH loss to SLC25A4 downregulation unknown\", \"Reconciliation with earlier full redundancy claims incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAGOH's canonical EJC role is mechanistically coupled to its EJC-independent activities (Lis1 control, STAT3 competition, ubiquitin-proteasome association, junctional translation) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking mitotic, NMD, and signaling functions\", \"EJC-independent isoform (MAGOH-\\u039437) function uncharacterized beyond interactome\", \"PYM1-mediated EJC destabilization role awaits peer review\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [3, 12]}\n    ],\n    \"complexes\": [\"exon junction complex (EJC)\"],\n    \"partners\": [\"RBM8A\", \"EIF4A3\", \"RNPS1\", \"PYM1\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}