{"gene":"RBM8A","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2001,"finding":"Y14 (RBM8A) binds stably to sequences immediately upstream of exon-exon junctions on spliced mRNAs in a position-specific manner, as demonstrated by microinjection of pre-mRNAs into Xenopus oocyte nuclei followed by immunoprecipitation of RNase-fragmented cytoplasmic mRNAs. Unlike Aly/REF, Y14 persists on mRNAs in the cytoplasm after nuclear export.","method":"Xenopus oocyte microinjection, immunoprecipitation of RNase-fragmented mRNAs, cytoplasmic fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro/in vivo reconstitution with Xenopus oocyte system, position-mapping by RNase fragmentation, orthogonal comparison with Aly/REF","pmids":["11296238"],"is_preprint":false},{"year":2001,"finding":"Drosophila Y14 interacts with Mago-nashi in vivo, colocalizes with oskar mRNA at the posterior pole of the oocyte, and is required for oskar mRNA localization to the posterior pole; loss of Y14 specifically disrupts posterior oskar mRNA localization without affecting the cytoskeleton.","method":"Immunohistochemistry, genetic loss-of-function (y14 mutant oocytes), in vivo co-localization","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mutant with specific mRNA localization phenotype plus co-localization; replicated by later structural and developmental studies","pmids":["11696323"],"is_preprint":false},{"year":2002,"finding":"Y14 is removed from mRNAs in the cytoplasm by the process of translation; Y14 associates with monosome fractions and remains on untranslated mRNAs, but is displaced from translationally active mRNAs. Blocking translation in vivo (by strong 5' UTR secondary structure) retains Y14 on cytoplasmic mRNAs.","method":"Polysome profiling, in vitro splicing/translation-coupled reporter assay, in vivo 5' UTR secondary structure block","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (polysome fractionation, coupled in vitro system, in vivo reporter), replicated across conditions","pmids":["12121612"],"is_preprint":false},{"year":2003,"finding":"Y14 directly interacts with hUpf3b via a conserved domain of hUpf3b, forming an NMD-activating complex. Tethered function analysis shows that the Y14/hUpf3b interaction is essential for NMD, while the hUpf3b/hUpf2 interaction is not. RNAi knockdown of Y14 impairs degradation of beta-globin NS39 NMD substrate mRNA, and Y14 is required for NMD induced by tethered hUpf3b.","method":"Tethered function assay, RNAi knockdown, co-immunoprecipitation, siRNA repletion, NMD reporter mRNA decay assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (tethering, RNAi, repletion), clearly defined functional hierarchy","pmids":["12718880"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of Drosophila Y14-Mago complex at 2.5 Å reveals that the RBD (RNA recognition motif) of Y14 engages its RNP1 and RNP2 motifs to bind Mago via protein-protein interaction rather than RNA binding. Structure-guided mutagenesis shows that the Y14-Mago association is essential for NMD function and that Mago is also a component of the NMD pathway.","method":"X-ray crystallography (2.5 Å), structure-guided mutagenesis, NMD functional assay","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus functional NMD assay in single study","pmids":["12730685"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of human Y14-Magoh complex shows that Magoh has an unusual flat beta-sheet structure and binds with high affinity to the RNP motif RBD of Y14, completely masking its RNA binding surface, explaining position-specific but RNA sequence-independent EJC association.","method":"X-ray crystallography (high resolution), biochemical binding assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent crystal structure of human complex with biochemical validation, consistent with Drosophila structure (PMID:12730685)","pmids":["12781131"],"is_preprint":false},{"year":2003,"finding":"Crystal structure of Drosophila Mago-Y14 complex at 1.85 Å shows that the canonical RNA-binding surface of the Y14 RRM is engaged in extensive protein-protein interactions with Mago, revealing molecular basis of EJC assembly.","method":"X-ray crystallography (1.85 Å)","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — independent high-resolution structure, third orthogonal crystal structure of the same complex","pmids":["12704080"],"is_preprint":false},{"year":2004,"finding":"PYM interacts directly with Mago-Y14 by means of its N-terminal domain. Crystal structure of the Drosophila PYM-Mago-Y14 ternary complex at 1.9 Å shows PYM caps the Mago-Y14 heterodimerization interface at conserved surface residues. PYM is a cytoplasmic protein excluded from the nucleus by Crm1. Human PYM is active in NMD tethering assays.","method":"X-ray crystallography (1.9 Å), direct binding assay, nuclear exclusion/Crm1 assay, NMD tethering assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus direct binding plus functional NMD assay","pmids":["14968132"],"is_preprint":false},{"year":2005,"finding":"Y14 is phosphorylated at its RS (arginine/serine) dipeptides, likely by SR protein-specific kinases. Phosphorylation abolishes Y14's interaction with EJC components and downstream NMD factors. A non-phosphorylatable Y14 mutant retains NMD activity but sequesters EJC/NMD factors on ribosome-containing mRNPs. Y14 is also methylated at multiple arginine residues in the C-terminal domain, and methylation is antagonized by phosphorylation of RS dipeptides.","method":"Phosphorylation mapping, SR kinase inhibition, non-phosphorylatable/phosphomimetic mutants, co-immunoprecipitation, polysome fractionation, methylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods identifying PTMs and functional consequences, with mutant analysis","pmids":["16100109"],"is_preprint":false},{"year":2006,"finding":"Y14 and nuclear export factor NXF1 form a complex in vivo that preferentially localizes within and around nuclear speckles (SC35 domains), dependent on transcription and full-length NXF1. FRAP/FLIP revealed that roughly half of accumulated BiFC complexes are immobile and this immobile fraction is depleted by ATP in permeabilized cells, indicating an ATP-dependent retention mechanism.","method":"Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation with RNA, FRAP, FLIP, ATP depletion in permeabilized cells","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BiFC plus co-IP plus live-cell dynamics, single lab","pmids":["16431928"],"is_preprint":false},{"year":2007,"finding":"In Drosophila null clonal analysis, Tsunagi/Y14 is essential for restricting oocyte fate to a single cell; Y14 null germline cysts fail to concentrate centrosomes and oocyte-specific components in a single cell. Mago-nashi null germline stem cells fail to differentiate, and mago nashi functions independently of Y14 in germline stem cell differentiation.","method":"Null alleles, clonal analysis, immunostaining for oocyte-specific markers and centrosomes","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — null genetic analysis with clonal dissection, clear epistasis between mago and Y14 in separate cellular processes","pmids":["17628520"],"is_preprint":false},{"year":2008,"finding":"Y14 was identified as a novel STAT3 binding partner via yeast two-hybrid screening. Y14 binds to STAT3 through the C-terminal region of STAT3 in vivo. siRNA-mediated knockdown of endogenous Y14 decreased IL-6-induced STAT3 tyrosine-phosphorylation, nuclear accumulation, DNA-binding activity, and STAT3-dependent gene expression.","method":"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, STAT3 phosphorylation assay, nuclear localization assay, gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional siRNA knockdown, single lab, multiple readouts","pmids":["18503751"],"is_preprint":false},{"year":2009,"finding":"MAGOH, the Y14 partner in the EJC, inhibits STAT3-Y14 complex formation. Endogenous STAT3 co-immunoprecipitates with Y14. siRNA knockdown of MAGOH enhanced IL-6-induced STAT3-dependent gene expression, demonstrating that MAGOH regulates STAT3 transcriptional activation by interfering with the STAT3-Y14 complex.","method":"Co-immunoprecipitation, siRNA knockdown, gene expression assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous co-IP plus siRNA functional assay, single lab","pmids":["19254694"],"is_preprint":false},{"year":2011,"finding":"Y14/Magoh heterodimer interacts with the cytoplasmic PRMT5-containing methylosome. Y14 promotes PRMT5 activity in methylation of Sm proteins of the snRNP core, and Y14 knockdown reduces Sm protein methylation. Y14 overexpression induces formation of a large, active, snRNP-associated methylosome complex.","method":"Co-immunoprecipitation (Y14/Magoh as bait), Sm methylation assay, Y14 knockdown and overexpression, complex fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional methylation assay, single lab","pmids":["21209085"],"is_preprint":false},{"year":2011,"finding":"Y14 contains a nuclear localization signal (YNS) that also confers nuclear export. A 12-amino-acid peptide near Y14's C-terminus is required for association with spliced mRNAs and for Magoh binding. Y14 mutants deficient in Magoh binding can still localize to the nucleus, indicating a Magoh-independent nuclear import pathway.","method":"Deletion/mutant analysis, nuclear localization assays, spliced mRNA association assay, Magoh binding assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic domain mapping with functional localization and binding assays, single lab","pmids":["22355610"],"is_preprint":false},{"year":2012,"finding":"Y14/Magoh heterodimer specifically associates with mRNA-decapping complex components and exoribonucleases. Y14 directly interacts with decapping factor Dcp2 and the 5' cap structure of mRNAs via different but overlapping domains. Y14 inhibits mRNA-decapping activity of Dcp2 in vitro, and Y14 overexpression prolongs reporter mRNA half-life. Y14 depletion disrupts processing body (P-body) formation, while phosphomimetic Y14 overexpression increases P-body number.","method":"Co-immunoprecipitation, in vitro decapping assay, mRNA half-life assay, siRNA depletion, overexpression of phosphomimetic mutant, P-body imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro decapping assay plus co-IP plus functional mRNA stability assay plus cellular imaging, multiple orthogonal methods in one study","pmids":["23115303"],"is_preprint":false},{"year":2012,"finding":"RBM8A insufficiency (compound inheritance of a null allele and regulatory SNPs in the 5' or 3' UTR of RBM8A) causes TAR syndrome. The two regulatory SNPs result in diminished RBM8A transcription in vitro, and Y14 expression is reduced in platelets from TAR individuals.","method":"In vitro transcription reporter assay, Western blot of patient platelets, genetic mapping","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional in vitro transcription assay plus patient protein quantification, large cohort (53/55 cases)","pmids":["22366785"],"is_preprint":false},{"year":2013,"finding":"RBM8A depletion in A549 cells causes accumulation of mitotic cells, failure to progress past G2/M phase after G1/S release, increased sub-G1 population, caspase 3/7 activation, and increased frequency of multipolar or monopolar centrosomes. Silencing of either RBM8A or Magoh results in mutual downregulation of the other protein.","method":"siRNA knockdown, cell cycle analysis (flow cytometry), caspase activity assay, immunostaining of centrosomes, double thymidine block release","journal":"Experimental biology and medicine (Maywood, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with multiple cell cycle and apoptosis readouts, centrosome phenotype, single lab","pmids":["23970407"],"is_preprint":false},{"year":2013,"finding":"RBM8A (Y14) and MAGOH localize to the centrosome in addition to nuclei in human A549 cells. Proximity ligation assay confirmed RBM8A-MAGOH complex formation at the centrosome. GFP-PLK1 co-localizes with Myc-RBM8A at centrosomes, suggesting RBM8A-MAGOH complex is involved in M-phase progression through direct centrosome localization.","method":"Immunostaining, proximity ligation in situ assay, tagged protein expression and co-localization, GFP-PLK1 co-localization","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — localization confirmed by multiple methods (immunostaining, proximity ligation, tagged protein), single lab","pmids":["23949737"],"is_preprint":false},{"year":2013,"finding":"Y14 positively regulates TNF-α-induced NF-κB transcriptional activity. Y14 endogenously associates with RIP1 and TRADD. Y14 lies downstream of TRADD and upstream of RIP1 in this pathway. Y14 significantly enhances the binding between RIP1 and TRADD. These actions are independent of MAGOH/EJC.","method":"siRNA knockdown, NF-κB transcriptional reporter assay, co-immunoprecipitation, epistasis by overexpression/knockdown rescue experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous co-IP plus epistasis rescue experiments plus reporter assay, single lab","pmids":["23817415"],"is_preprint":false},{"year":2015,"finding":"RBM8a overexpression in embryonic cortex stimulates neural progenitor cell (NPC) proliferation and suppresses neuronal differentiation, while RBM8a knockdown reduces NPC proliferation and promotes premature differentiation. RBM8a overexpression suppresses cell cycle exit and maintains NPCs in a proliferative state. RBM8a regulates multiple alternative splicing events and NMD targets implicated in autism spectrum disorder.","method":"In utero electroporation (overexpression and knockdown), BrdU incorporation, immunostaining, genome-wide RNA-seq","journal":"Neural development","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function in vivo with quantitative proliferation/differentiation readouts plus transcriptomic analysis","pmids":["26094033"],"is_preprint":false},{"year":2016,"finding":"An evolutionarily conserved tryptophan residue (Trp-73) of Y14 is critical for mRNA cap binding. The W73V mutant binds mRNAs weakly and fails to protect them from degradation. W73V retains partial NMD activity but cannot interact with translation initiation factors, suppresses reporter mRNA translation in vitro and in vivo, and reduces nascent protein synthesis. Thus, Trp-73 is essential for cap-binding activity and Y14-mediated translation enhancement.","method":"Site-directed mutagenesis, cap-binding assay, mRNA stability assay, co-immunoprecipitation with translation initiation factors, in vitro and in vivo translation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis plus reconstituted in vitro assay plus multiple functional readouts","pmids":["26887951"],"is_preprint":false},{"year":2017,"finding":"Y14 depletion induces expression of an alternatively spliced p53 isoform (p53β) in human cells. Y14, in the context of the EJC, inhibits aberrant exon inclusion during p53 pre-mRNA splicing. Both depletion and overexpression of Y14 increase overall p53 protein levels. Y14 depletion reduces p21 protein levels and increases cell sensitivity to genotoxic agents.","method":"siRNA knockdown, RT-PCR splicing analysis, Western blot, cell viability/sensitivity assay, overexpression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA plus overexpression with splicing and protein level readouts, single lab","pmids":["28361991"],"is_preprint":false},{"year":2018,"finding":"Y14 C-terminal RS repeat-containing region controls Y14 localization: deletion or dephosphorylation-mimic mutants shift localization away from nucleoplasm, and the C-terminal RS repeat sequence itself can direct nucleolar localization. Y14 localization by the C-terminal region is further controlled by MAGOH binding.","method":"Deletion mutants, phosphomimetic/dephosphorylation-mimic mutants, fluorescence microscopy, MAGOH binding assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple mutant constructs with localization readout, single lab","pmids":["29330450"],"is_preprint":false},{"year":2019,"finding":"Y14 depletion differentially affects expression of DNA damage response (DDR) factors and induces R-loops. Mass spectrometry after Y14 immunoprecipitation identified DDR factors as Y14-interacting partners; confirmed interactions with Ku and several DDR factors in an ATM-dependent manner. Y14 co-fractionates with Ku in chromatin-enriched fractions and accumulates on chromatin upon DNA damage. Y14 knockdown delays DDR factor recruitment to damage sites, delays γH2AX foci formation, causes Ku retention on chromatin, and compromises DNA end joining efficiency.","method":"Co-immunoprecipitation coupled with mass spectrometry, chromatin fractionation, γH2AX foci imaging, DNA end joining assay, R-loop detection, siRNA knockdown","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-coupled IP plus chromatin fractionation plus functional DNA repair assay, multiple orthogonal methods","pmids":["30901577"],"is_preprint":false},{"year":2019,"finding":"Stability of Magoh and Y14 proteins depends on their heterodimerization and nuclear localization. Interface-disrupting mutations (Magoh L136R, Y14 L118R) accelerate protein degradation without affecting mRNA levels. Y14 L118R retains nuclear localization and is more stable than Magoh L136R, which loses nuclear localization.","method":"Site-directed mutagenesis, cycloheximide chase assay, subcellular localization, Western blot, RT-PCR","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus protein stability assay, single lab","pmids":["30826064"],"is_preprint":false},{"year":2020,"finding":"Homozygous zebrafish rbm8a mutations cause muscle disorganization, neural cell death, and motor neuron outgrowth defects, and dysregulate NMD targets including transcripts with 3'UTR introns (3'UI) within 50 nt downstream of stop codon. EJC-dependent NMD regulates foxo3b mRNA; loss of foxo3b function in EJC mutants significantly rescues motor axon growth defects, placing RBM8A/EJC upstream of foxo3b in a developmental signaling pathway.","method":"Zebrafish genetic mutants, RNA-seq, NMD reporter assay, genetic epistasis (foxo3b loss-of-function rescue), immunostaining","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with rescue experiment plus transcriptomic analysis in vertebrate model","pmids":["32502192"],"is_preprint":false},{"year":2020,"finding":"Conditional knockout of Rbm8a in neural stem cells causes microcephaly, early postnatal lethality, and altered distribution of excitatory neurons. Rbm8a haploinsufficiency decreases proliferation in ganglionic eminences, reduces parvalbumin+ and neuropeptide Y+ interneurons, and decreases cortical GABA frequency. Conditional KO in NKX2.1 interneuron progenitors reduces progenitor proliferation and alters interneuron distribution.","method":"Conditional knockout mouse (neural stem cell and NKX2.1-specific), immunostaining, electrophysiology (GABA frequency), RNA-seq, BrdU proliferation assay","journal":"Translational psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with multiple orthogonal phenotypic readouts including electrophysiology","pmids":["33154347"],"is_preprint":false},{"year":2021,"finding":"Megakaryocyte-specific Rbm8a knockout mice exhibit marked thrombocytopenia, internal hemorrhage, and splenomegaly. Rbm8a deficiency induces p53 and p21 in megakaryocytes. p53 inhibitor treatment or Trp53 knockout partially restores megakaryocyte differentiation and increases platelet counts, establishing a Y14-p53 regulatory circuit in platelet production.","method":"Megakaryocyte-specific conditional knockout mouse, genetic epistasis (Trp53 knockout), p53 inhibitor treatment, ex vivo megakaryocyte differentiation assay, flow cytometry","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus genetic epistasis rescue (Trp53 KO) plus pharmacological rescue, multiple orthogonal approaches","pmids":["34816104"],"is_preprint":false},{"year":2022,"finding":"RBM8A controls transcript levels of intronless genes and is a global regulator of ribosomal protein transcripts. Acute depletion of RBM8A using the auxin degron system followed by genome-wide nascent transcription analysis (SLAM-seq or equivalent) demonstrated that RBM8A regulates ribosomal protein transcript levels.","method":"CRISPR knockout screen, auxin degron acute depletion, genome-wide nascent transcription analysis, FACS-based reporter assay","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — acute depletion with genome-wide transcriptomic readout, single lab","pmids":["36187487"],"is_preprint":false},{"year":2023,"finding":"Recombinant Y14 undergoes liquid-liquid phase separation (LLPS) in vitro in a manner sensitive to pH, salt concentration, and involving multivalent electrostatic interactions in low-complexity regions. Phospho-mimicry of C-terminal RS dipeptides suppresses phase separation. RNA co-phase separates into Y14 droplets in a concentration-dependent manner. LLPS capacity correlates with Y14 activity in DNA double-strand break repair.","method":"Recombinant protein phase separation assay, domain mapping, phosphomimetic mutants, RNA titration, DSB repair assay","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with multiple domain mutants plus functional correlation with repair activity","pmids":["37001915"],"is_preprint":false},{"year":2024,"finding":"hsa_circ_0081343 binds directly to Rbm8a in the cytoplasm, and knockdown of hsa_circ_0081343 facilitates Rbm8a nuclear localization. Importin13 (Ipo13) recognizes Rbm8a via a functional NLS and transports it across the nuclear membrane. hsa_circ_0081343-mediated nuclear translocation of Rbm8a activates trophoblast autophagy.","method":"RNA pull-down assay, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation (Ipo13-Rbm8a), immunofluorescence, Western blot","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down plus co-IP for nuclear transport interaction, single lab","pmids":["39413593"],"is_preprint":false},{"year":2024,"finding":"RBM8A forms a complex with EIF4A3 in breast cancer cells. The RBM8A/EIF4A3 complex binds IGF1R and IRS-2 mRNA (by RIP-seq) and regulates their expression to activate the PI3K/AKT signaling pathway. TEAD4 is identified as a transcriptional activator of RBM8A by ChIP and dual luciferase reporter assays.","method":"Co-immunoprecipitation, immunofluorescence, RIP-seq, ChIP, dual-luciferase reporter assay, siRNA knockdown, xenograft","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus RIP-seq plus ChIP, single lab","pmids":["39232805"],"is_preprint":false},{"year":2025,"finding":"SRPK1-mediated phosphorylation of Y14 is required for its localization at laser-induced DNA damage sites and function in DSB repair. Phosphorylated Y14 undergoes liquid-liquid phase separation promoted by magnesium in vitro, and Ku70/80 can partition into phosphorylated Y14 condensates. Chelation of divalent cations abolishes Y14 localization at DNA damage sites and NHEJ factor recruitment.","method":"HaloTag-Y14 live-cell imaging at laser damage sites, SRPK1 inhibition, phosphomimetic mutants, in vitro phase separation with phospho-Y14, co-condensation with Ku70/80, divalent cation chelation","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of phase separation plus live-cell imaging plus functional NHEJ assay, multiple orthogonal methods","pmids":["40727937"],"is_preprint":false},{"year":2025,"finding":"RBM8A promotes BBC3 (PUMA) mRNA degradation by interacting with UPF3B. RIP-seq identified BBC3 as a direct RBM8A target, confirmed by RIP-PCR, FISH-IF, and RNA pull-down. Actinomycin D assays showed RBM8A promotes BBC3 mRNA degradation. Co-immunoprecipitation confirmed RBM8A-UPF3B interaction.","method":"RIP-seq, RIP-qPCR, RNA pull-down, FISH-immunofluorescence, actinomycin D mRNA stability assay, co-immunoprecipitation","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple RNA binding methods plus mRNA stability assay plus co-IP, single lab","pmids":["40613240"],"is_preprint":false},{"year":2025,"finding":"RBM8A recruits eIF4A3 to stabilize EGFR mRNA, shielding it from exonucleolytic degradation, thereby sustaining EGFR protein levels and enabling nuclear EGFR-DNA-PKcs complex formation to drive NHEJ-mediated DNA repair and suppress oxaliplatin-induced apoptosis in gastric cancer cells.","method":"siRNA screen, RIP-seq, co-immunoprecipitation (RBM8A-eIF4A3), mRNA stability assay, nuclear EGFR-DNA-PKcs interaction, NHEJ reporter, xenograft model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus RIP-seq plus functional NHEJ and stability assays, single lab","pmids":["41354714"],"is_preprint":false},{"year":2025,"finding":"PYM1 interaction with RBM8A/MAGOH heterodimer is required for translation-independent EJC destabilization but not for translation-dependent disassembly. EJCs lacking PYM1 interaction are enriched on non-canonical sites including intronless transcripts and transcripts with fewer and longer exons. Acute PYM1 depletion modestly inhibits NMD and stabilizes mRNAs localizing to ER-associated TIS granules.","method":"EJC occupancy mapping (iCLIP/eCLIP), acute PYM1 depletion, NMD reporter assay, RNA-seq, auxin degron system","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide occupancy mapping plus functional disassembly and NMD assays, single lab, preprint","pmids":["bio_10.1101_2025.03.13.643037"],"is_preprint":true},{"year":2025,"finding":"In zebrafish, rbm8a deficiency causes accumulation of mRNAs with retained introns including non-canonical Wnt/PCP pathway components. Genetic interaction experiments show reduced rbm8a function interacts with wnt5b, wnt11f2, fzd7a, and vangl2 mutations. Rbm8a deficiency impairs lateral plate mesoderm architecture and hematopoietic gene expression (runx1, gfi1aa), connecting rbm8a to Wnt/PCP-mediated hematopoietic development.","method":"Zebrafish hypomorphic mutants, RNA-seq (intron retention), genetic epistasis with Wnt/PCP pathway mutants, live imaging of lateral plate mesoderm, in situ hybridization","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple pathway mutants plus transcriptomic evidence plus live imaging, peer-reviewed","pmids":["40907933"],"is_preprint":false},{"year":2013,"finding":"Overexpression of RBM8a in mouse hippocampal dentate gyrus leads to increased anxiety-like behavior and abnormal social interaction. RNA immunoprecipitation (RNA-IP) detected that RBM8a binds CaMK2, GluR1, and Egr1 mRNA in neurons, and RBM8a overexpression increases miniature excitatory postsynaptic current (mEPSC) frequency.","method":"Lentiviral overexpression in vivo, behavioral tests, RNA immunoprecipitation, electrophysiology (mEPSC)","journal":"Current molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA-IP for binding plus electrophysiology plus in vivo behavioral readout, single lab","pmids":["23638902"],"is_preprint":false}],"current_model":"RBM8A (Y14) is a core component of the exon junction complex (EJC) that binds spliced mRNA immediately upstream of exon-exon junctions via protein-protein interaction with MAGOH (which occludes Y14's RRM RNA-binding surface), persists on mRNAs through nuclear export until displaced by translating ribosomes, and coordinates multiple downstream processes including nonsense-mediated mRNA decay (through direct interaction with UPF3b), translational enhancement (via mRNA cap binding at Trp-73), mRNA decapping inhibition (through direct inhibition of Dcp2), snRNP biogenesis (by promoting PRMT5-mediated Sm protein methylation), DNA double-strand break repair (through RNA-dependent recruitment of NHEJ factors via SRPK1-phosphorylation-driven phase condensates with Ku70/80), regulation of p53 splicing and the Y14-p53 circuit in megakaryocyte differentiation, and signaling modulation (STAT3 and NF-κB pathways) independent of EJC context."},"narrative":{"mechanistic_narrative":"RBM8A (Y14) is a core subunit of the exon junction complex (EJC) that controls the fate of spliced mRNAs from nuclear processing through cytoplasmic translation, and additionally serves EJC-independent roles in genome maintenance and signaling [PMID:11296238, PMID:12121612]. It binds spliced mRNA in a position-specific but RNA-sequence-independent manner by heterodimerizing with MAGOH, whose flat beta-sheet engages and masks the RNA-binding surface of the Y14 RRM, explaining why deposition is dictated by exon-exon junction position rather than sequence [PMID:11296238, PMID:12781131, PMID:12704080]. Y14 persists on mRNAs through nuclear export and is removed in the cytoplasm by translating ribosomes; PYM caps the Mago-Y14 interface to drive disassembly [PMID:12121612, PMID:14968132]. From this platform Y14 coordinates downstream RNA fates: it activates nonsense-mediated mRNA decay through a direct interaction with UPF3B that is essential for NMD [PMID:12718880, PMID:12730685], enhances translation and protects mRNA via a conserved Trp-73 cap-binding residue [PMID:26887951], and inhibits Dcp2-mediated decapping to stabilize transcripts and modulate P-body formation [PMID:23115303]. Beyond canonical EJC functions, Y14 promotes PRMT5-mediated methylation of Sm proteins during snRNP biogenesis [PMID:21209085], regulates p53 pre-mRNA splicing and protein levels [PMID:28361991], and participates in DNA double-strand break repair, where SRPK1-driven phosphorylation promotes Mg2+-dependent liquid-liquid phase separation that recruits Ku70/80 and NHEJ factors to damage sites [PMID:30901577, PMID:37001915, PMID:40727937]. Phosphorylation of its C-terminal RS dipeptides governs EJC/NMD-factor association, subcellular localization, and phase-separation capacity [PMID:16100109, PMID:29330450, PMID:37001915]. EJC-independent activities include positive regulation of STAT3 and TNF-α-induced NF-κB signaling [PMID:18503751, PMID:23817415]. Developmentally, Y14 maintains neural progenitor proliferation and influences interneuron production and cortical GABAergic signaling [PMID:26094033, PMID:33154347], and operates in a Y14-p53 circuit required for megakaryocyte differentiation and platelet production [PMID:34816104]. RBM8A insufficiency, through compound inheritance of a null allele with hypomorphic regulatory SNPs, causes thrombocytopenia-absent radius (TAR) syndrome [PMID:22366785].","teleology":[{"year":2001,"claim":"Established that Y14 is deposited on spliced mRNA at a fixed position upstream of exon junctions and uniquely persists into the cytoplasm, defining it as a mark of splicing history rather than a sequence-specific binder.","evidence":"Xenopus oocyte microinjection with RNase mapping and cytoplasmic fractionation; in vivo Drosophila genetics showing Mago-nashi interaction and oskar mRNA localization","pmids":["11296238","11696323"],"confidence":"High","gaps":["Did not resolve how position-specific deposition is achieved mechanistically","Cytoplasmic function of persistent Y14 not yet defined"]},{"year":2002,"claim":"Answered how the cytoplasmic EJC mark is erased, showing translation displaces Y14 and links its removal to ribosome transit.","evidence":"Polysome profiling, coupled in vitro splicing/translation, and in vivo 5' UTR structural block","pmids":["12121612"],"confidence":"High","gaps":["Did not identify the factor that physically strips Y14 from translated mRNA"]},{"year":2003,"claim":"Defined the molecular basis of EJC assembly and its coupling to NMD: MAGOH binds the Y14 RRM RNA surface, and the Y14-UPF3b axis is the essential NMD-activating interaction.","evidence":"Multiple independent crystal structures of Y14-Mago(h) and tethered-function/RNAi NMD assays with UPF3b","pmids":["12730685","12781131","12704080","12718880"],"confidence":"High","gaps":["Did not explain how the EJC signals decay across long distances on mRNA"]},{"year":2004,"claim":"Identified PYM as the disassembly factor that caps the Mago-Y14 interface, providing a mechanism for cytoplasmic EJC recycling.","evidence":"Crystal structure of the PYM-Mago-Y14 ternary complex with binding and NMD tethering assays","pmids":["14968132"],"confidence":"High","gaps":["Did not separate translation-dependent from translation-independent disassembly roles of PYM"]},{"year":2005,"claim":"Showed that RS-dipeptide phosphorylation and arginine methylation toggle Y14's ability to engage EJC and NMD factors, establishing post-translational control of complex assembly.","evidence":"Phosphorylation/methylation mapping, SR-kinase inhibition, and non-phosphorylatable mutants with polysome fractionation","pmids":["16100109"],"confidence":"High","gaps":["Specific kinase identity not pinned down at this stage","Physiological triggers of PTM switching unknown"]},{"year":2006,"claim":"Connected Y14 to nuclear mRNA export by demonstrating an NXF1 complex retained in an ATP-dependent manner near nuclear speckles.","evidence":"BiFC, RNA co-IP, and FRAP/FLIP with ATP depletion in permeabilized cells","pmids":["16431928"],"confidence":"Medium","gaps":["Single-lab; molecular basis of ATP-dependent retention not defined","Functional consequence of speckle retention for export not directly tested"]},{"year":2008,"claim":"Extended Y14 beyond RNA metabolism, identifying it as a STAT3 cofactor required for IL-6-induced STAT3 activation.","evidence":"Yeast two-hybrid, co-IP, and siRNA knockdown with STAT3 phosphorylation/transcription readouts","pmids":["18503751"],"confidence":"Medium","gaps":["Single-lab; mechanism of how Y14 promotes STAT3 phosphorylation unclear","EJC dependence not resolved here"]},{"year":2009,"claim":"Showed MAGOH competes with STAT3 for Y14, integrating EJC assembly with signaling output.","evidence":"Endogenous co-IP and MAGOH siRNA knockdown with STAT3-dependent gene expression","pmids":["19254694"],"confidence":"Medium","gaps":["Single-lab; quantitative partitioning of Y14 between EJC and STAT3 pools not determined"]},{"year":2011,"claim":"Linked the Y14/MAGOH heterodimer to snRNP biogenesis by showing it stimulates PRMT5-mediated Sm protein methylation, and mapped a C-terminal element controlling import and mRNA association.","evidence":"Reciprocal co-IP with methylosome, Sm methylation assays, and domain-mapping localization assays","pmids":["21209085","22355610"],"confidence":"Medium","gaps":["Single-lab methylosome data","Magoh-independent import pathway not molecularly defined"]},{"year":2012,"claim":"Revealed Y14 as a direct inhibitor of decapping and stabilizer of mRNA, and established that RBM8A insufficiency causes TAR syndrome.","evidence":"In vitro Dcp2 decapping assays, cap-binding/mRNA half-life assays, P-body imaging; genetic and reporter analysis plus patient platelet Western blots","pmids":["23115303","22366785"],"confidence":"High","gaps":["How decapping inhibition relates to EJC versus free Y14 not separated","Tissue specificity of TAR phenotype not explained mechanistically"]},{"year":2013,"claim":"Documented mitotic and centrosomal roles for the RBM8A-MAGOH complex and an EJC-independent function promoting NF-κB and neuronal mRNA regulation.","evidence":"siRNA cell-cycle/apoptosis assays, centrosome proximity ligation with PLK1, NF-κB reporter with RIP1/TRADD co-IP, and neuronal RNA-IP with electrophysiology","pmids":["23970407","23949737","23817415","23638902"],"confidence":"Medium","gaps":["Centrosomal function molecularly unresolved","Single-lab signaling and behavioral data"]},{"year":2015,"claim":"Established Y14 as a regulator of neural progenitor proliferation versus differentiation through control of alternative splicing and NMD targets.","evidence":"In utero electroporation gain/loss-of-function with BrdU and genome-wide RNA-seq","pmids":["26094033"],"confidence":"High","gaps":["Key effector splicing/NMD targets driving proliferation not individually validated"]},{"year":2016,"claim":"Pinpointed Trp-73 as the cap-binding residue separating Y14's translation-enhancement and mRNA-protection functions from its NMD activity.","evidence":"Site-directed W73V mutagenesis with cap-binding, stability, and in vitro/in vivo translation assays","pmids":["26887951"],"confidence":"High","gaps":["How cap binding is coordinated with MAGOH-masked RRM not structurally resolved"]},{"year":2017,"claim":"Connected Y14 to genome-protective gene regulation by showing EJC-dependent suppression of aberrant p53 splicing and modulation of p21 and genotoxic sensitivity.","evidence":"siRNA/overexpression with RT-PCR splicing analysis, Western blot, and viability assays","pmids":["28361991"],"confidence":"Medium","gaps":["Single-lab; biphasic effect of depletion vs overexpression on p53 unexplained"]},{"year":2019,"claim":"Demonstrated a direct role for Y14 in DNA double-strand break repair via ATM-dependent interaction with Ku and chromatin recruitment of DDR factors.","evidence":"IP-mass spectrometry, chromatin fractionation, γH2AX foci imaging, and DNA end-joining assays with R-loop detection","pmids":["30901577"],"confidence":"High","gaps":["RNA-dependence of recruitment not yet mechanistically defined","Did not yet implicate phase separation"]},{"year":2020,"claim":"Established conserved developmental requirements for RBM8A in vertebrate neurogenesis, muscle, motor neuron, and hematopoietic development, placing it upstream of foxo3b in an NMD-controlled pathway.","evidence":"Zebrafish rbm8a mutants with epistasis (foxo3b rescue) and conditional KO mice with electrophysiology and RNA-seq","pmids":["32502192","33154347"],"confidence":"High","gaps":["Cell-autonomous versus non-autonomous contributions not fully separated"]},{"year":2021,"claim":"Defined a Y14-p53 regulatory circuit as the basis of RBM8A's requirement in platelet production, linking the molecular pathway to the TAR phenotype.","evidence":"Megakaryocyte-specific conditional KO with Trp53 KO epistasis and pharmacological p53 inhibition","pmids":["34816104"],"confidence":"High","gaps":["Molecular route from Y14 loss to p53 induction in megakaryocytes not detailed"]},{"year":2022,"claim":"Identified RBM8A as a global regulator of intronless and ribosomal protein transcript levels using acute depletion.","evidence":"CRISPR screen and auxin-degron acute depletion with genome-wide nascent transcription analysis","pmids":["36187487"],"confidence":"Medium","gaps":["Single-lab; mechanism of intronless transcript regulation not defined"]},{"year":2023,"claim":"Linked Y14's repair function to biophysics, showing recombinant Y14 undergoes phosphorylation-tunable, RNA-responsive liquid-liquid phase separation that correlates with DSB repair activity.","evidence":"In vitro phase-separation assays with domain/phosphomimetic mutants, RNA titration, and DSB repair assays","pmids":["37001915"],"confidence":"High","gaps":["Did not yet identify the kinase or co-condensing repair factors in cells"]},{"year":2024,"claim":"Expanded RBM8A's cytoplasmic targeted-RNA regulation, identifying circRNA/Ipo13-mediated nuclear transport and an eIF4A3 partnership stabilizing growth-signaling mRNAs.","evidence":"RNA pull-down/MS with Ipo13 co-IP in trophoblasts; co-IP, RIP-seq, and ChIP linking RBM8A/EIF4A3 to IGF1R/IRS-2 and TEAD4 regulation in breast cancer","pmids":["39413593","39232805"],"confidence":"Medium","gaps":["Single-lab; generality of eIF4A3-dependent mRNA stabilization across contexts untested"]},{"year":2025,"claim":"Resolved the mechanism of Y14-dependent NHEJ, showing SRPK1 phosphorylation drives Mg2+-dependent condensates that partition Ku70/80, and extended targeted mRNA regulation to UPF3B-dependent BBC3 decay and eIF4A3-mediated EGFR stabilization supporting repair.","evidence":"Live-cell laser-damage imaging with SRPK1 inhibition and in vitro phospho-Y14 co-condensation with Ku70/80; RIP-seq, RNA pull-down, and stability assays for BBC3 and EGFR with NHEJ readouts","pmids":["40727937","40613240","41354714"],"confidence":"High","gaps":["Single-lab cancer-context studies for BBC3/EGFR","How condensate-based repair integrates with canonical EJC pool unclear"]},{"year":2025,"claim":"Connected RBM8A to non-canonical Wnt/PCP signaling and intron retention control in hematopoietic and developmental contexts, and refined PYM1's role in EJC disassembly site selectivity.","evidence":"Zebrafish hypomorphs with Wnt/PCP genetic epistasis and intron-retention RNA-seq; EJC occupancy mapping with acute PYM1 depletion (preprint)","pmids":["40907933","bio_10.1101_2025.03.13.643037"],"confidence":"High","gaps":["Direct splicing targets mediating Wnt/PCP effects not validated","PYM1 disassembly findings remain a preprint"]},{"year":null,"claim":"How Y14 partitions between its EJC-bound pool and its many EJC-independent roles (signaling, snRNP methylation, condensate-based repair) within a single cell, and what determines target and pathway selection, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model for context-dependent activity switching","Quantitative pool partitioning not measured","Structural basis of cap binding within the MAGOH-masked RRM unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,15,21,30,34]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,19,24]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[13,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,22]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[14,23,25,31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[9,23]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[23]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[18]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[24,33]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2,3,13,15]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[24,30,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[20,26,27,37]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,19,32]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[22,29]}],"complexes":["exon junction complex (EJC)","methylosome (PRMT5)"],"partners":["MAGOH","UPF3B","PYM1","EIF4A3","NXF1","STAT3","KU70/80","DCP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5S9","full_name":"RNA-binding protein 8A","aliases":["Binder of OVCA1-1","BOV-1","RNA-binding motif protein 8A","RNA-binding protein Y14","Ribonucleoprotein RBM8A"],"length_aa":174,"mass_kda":19.9,"function":"Required for pre-mRNA splicing as component of the spliceosome (PubMed:28502770, PubMed:29301961). Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. 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 preinitiation complex. Its removal from cytoplasmic mRNAs requires translation initiation from EJC-bearing spliced mRNAs. Associates preferentially with mRNAs produced by splicing. Does not interact with pre-mRNAs, introns, or mRNAs produced from intronless cDNAs. Associates with both nuclear mRNAs and newly exported cytoplasmic mRNAs. The MAGOH-RBM8A heterodimer is a component of the nonsense mediated decay (NMD) pathway. 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/Q9Y5S9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM8A","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000265241","cell_line_id":"CID001492","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"RPL23","stoichiometry":10.0},{"gene":"RPS25","stoichiometry":10.0},{"gene":"RPS28","stoichiometry":10.0},{"gene":"RPL30","stoichiometry":10.0},{"gene":"RPL10A","stoichiometry":10.0},{"gene":"RPL8","stoichiometry":10.0},{"gene":"GNB2L1","stoichiometry":10.0},{"gene":"RPS6","stoichiometry":10.0},{"gene":"RPS8","stoichiometry":10.0},{"gene":"RPS16","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001492","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":"616970","title":"MARVEL DOMAIN-CONTAINING PROTEIN 1; MARVELD1","url":"https://www.omim.org/entry/616970"},{"mim_id":"612875","title":"GONADOTROPIN-RELEASING HORMONE RECEPTOR 2; GNRHR2","url":"https://www.omim.org/entry/612875"},{"mim_id":"606447","title":"RNA-BINDING PROTEIN S1; RNPS1","url":"https://www.omim.org/entry/606447"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM8A"},"hgnc":{"alias_symbol":["ZNRP","BOV-1A","BOV-1B","BOV-1C","Y14"],"prev_symbol":["RBM8"]},"alphafold":{"accession":"Q9Y5S9","domains":[{"cath_id":"3.30.70.330","chopping":"64-150","consensus_level":"medium","plddt":97.0376,"start":64,"end":150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5S9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5S9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5S9-F1-predicted_aligned_error_v6.png","plddt_mean":80.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM8A","jax_strain_url":"https://www.jax.org/strain/search?query=RBM8A"},"sequence":{"accession":"Q9Y5S9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5S9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5S9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5S9"}},"corpus_meta":[{"pmid":"22366785","id":"PMC_22366785","title":"Compound 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Signaling Pathways Contributing to Neurodevelopmental Diseases.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36902031","citation_count":2,"is_preprint":false},{"pmid":"41354714","id":"PMC_41354714","title":"RBM8A confers oxaliplatin resistance in gastric cancer by maintaining EGFR mRNA stability.","date":"2025","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/41354714","citation_count":1,"is_preprint":false},{"pmid":"40267529","id":"PMC_40267529","title":"hsa_circ_0081343 interacts with Rbm8a to inhibit NLRP3-mediated pyroptosis via the PI3K/AKT/HIF-1α pathways.","date":"2025","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/40267529","citation_count":1,"is_preprint":false},{"pmid":"40727937","id":"PMC_40727937","title":"Phosphorylated Y14 condensates as a scaffold for DNA double-strand break 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to sequences immediately upstream of exon-exon junctions on spliced mRNAs in a position-specific manner, as demonstrated by microinjection of pre-mRNAs into Xenopus oocyte nuclei followed by immunoprecipitation of RNase-fragmented cytoplasmic mRNAs. Unlike Aly/REF, Y14 persists on mRNAs in the cytoplasm after nuclear export.\",\n      \"method\": \"Xenopus oocyte microinjection, immunoprecipitation of RNase-fragmented mRNAs, cytoplasmic fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro/in vivo reconstitution with Xenopus oocyte system, position-mapping by RNase fragmentation, orthogonal comparison with Aly/REF\",\n      \"pmids\": [\"11296238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Drosophila Y14 interacts with Mago-nashi in vivo, colocalizes with oskar mRNA at the posterior pole of the oocyte, and is required for oskar mRNA localization to the posterior pole; loss of Y14 specifically disrupts posterior oskar mRNA localization without affecting the cytoskeleton.\",\n      \"method\": \"Immunohistochemistry, genetic loss-of-function (y14 mutant oocytes), in vivo co-localization\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mutant with specific mRNA localization phenotype plus co-localization; replicated by later structural and developmental studies\",\n      \"pmids\": [\"11696323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Y14 is removed from mRNAs in the cytoplasm by the process of translation; Y14 associates with monosome fractions and remains on untranslated mRNAs, but is displaced from translationally active mRNAs. Blocking translation in vivo (by strong 5' UTR secondary structure) retains Y14 on cytoplasmic mRNAs.\",\n      \"method\": \"Polysome profiling, in vitro splicing/translation-coupled reporter assay, in vivo 5' UTR secondary structure block\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (polysome fractionation, coupled in vitro system, in vivo reporter), replicated across conditions\",\n      \"pmids\": [\"12121612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Y14 directly interacts with hUpf3b via a conserved domain of hUpf3b, forming an NMD-activating complex. Tethered function analysis shows that the Y14/hUpf3b interaction is essential for NMD, while the hUpf3b/hUpf2 interaction is not. RNAi knockdown of Y14 impairs degradation of beta-globin NS39 NMD substrate mRNA, and Y14 is required for NMD induced by tethered hUpf3b.\",\n      \"method\": \"Tethered function assay, RNAi knockdown, co-immunoprecipitation, siRNA repletion, NMD reporter mRNA decay assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (tethering, RNAi, repletion), clearly defined functional hierarchy\",\n      \"pmids\": [\"12718880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of Drosophila Y14-Mago complex at 2.5 Å reveals that the RBD (RNA recognition motif) of Y14 engages its RNP1 and RNP2 motifs to bind Mago via protein-protein interaction rather than RNA binding. Structure-guided mutagenesis shows that the Y14-Mago association is essential for NMD function and that Mago is also a component of the NMD pathway.\",\n      \"method\": \"X-ray crystallography (2.5 Å), structure-guided mutagenesis, NMD functional assay\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus functional NMD assay in single study\",\n      \"pmids\": [\"12730685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of human Y14-Magoh complex shows that Magoh has an unusual flat beta-sheet structure and binds with high affinity to the RNP motif RBD of Y14, completely masking its RNA binding surface, explaining position-specific but RNA sequence-independent EJC association.\",\n      \"method\": \"X-ray crystallography (high resolution), biochemical binding assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent crystal structure of human complex with biochemical validation, consistent with Drosophila structure (PMID:12730685)\",\n      \"pmids\": [\"12781131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of Drosophila Mago-Y14 complex at 1.85 Å shows that the canonical RNA-binding surface of the Y14 RRM is engaged in extensive protein-protein interactions with Mago, revealing molecular basis of EJC assembly.\",\n      \"method\": \"X-ray crystallography (1.85 Å)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — independent high-resolution structure, third orthogonal crystal structure of the same complex\",\n      \"pmids\": [\"12704080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PYM interacts directly with Mago-Y14 by means of its N-terminal domain. Crystal structure of the Drosophila PYM-Mago-Y14 ternary complex at 1.9 Å shows PYM caps the Mago-Y14 heterodimerization interface at conserved surface residues. PYM is a cytoplasmic protein excluded from the nucleus by Crm1. Human PYM is active in NMD tethering assays.\",\n      \"method\": \"X-ray crystallography (1.9 Å), direct binding assay, nuclear exclusion/Crm1 assay, NMD tethering assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus direct binding plus functional NMD assay\",\n      \"pmids\": [\"14968132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Y14 is phosphorylated at its RS (arginine/serine) dipeptides, likely by SR protein-specific kinases. Phosphorylation abolishes Y14's interaction with EJC components and downstream NMD factors. A non-phosphorylatable Y14 mutant retains NMD activity but sequesters EJC/NMD factors on ribosome-containing mRNPs. Y14 is also methylated at multiple arginine residues in the C-terminal domain, and methylation is antagonized by phosphorylation of RS dipeptides.\",\n      \"method\": \"Phosphorylation mapping, SR kinase inhibition, non-phosphorylatable/phosphomimetic mutants, co-immunoprecipitation, polysome fractionation, methylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods identifying PTMs and functional consequences, with mutant analysis\",\n      \"pmids\": [\"16100109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Y14 and nuclear export factor NXF1 form a complex in vivo that preferentially localizes within and around nuclear speckles (SC35 domains), dependent on transcription and full-length NXF1. FRAP/FLIP revealed that roughly half of accumulated BiFC complexes are immobile and this immobile fraction is depleted by ATP in permeabilized cells, indicating an ATP-dependent retention mechanism.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC), co-immunoprecipitation with RNA, FRAP, FLIP, ATP depletion in permeabilized cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BiFC plus co-IP plus live-cell dynamics, single lab\",\n      \"pmids\": [\"16431928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila null clonal analysis, Tsunagi/Y14 is essential for restricting oocyte fate to a single cell; Y14 null germline cysts fail to concentrate centrosomes and oocyte-specific components in a single cell. Mago-nashi null germline stem cells fail to differentiate, and mago nashi functions independently of Y14 in germline stem cell differentiation.\",\n      \"method\": \"Null alleles, clonal analysis, immunostaining for oocyte-specific markers and centrosomes\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null genetic analysis with clonal dissection, clear epistasis between mago and Y14 in separate cellular processes\",\n      \"pmids\": [\"17628520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Y14 was identified as a novel STAT3 binding partner via yeast two-hybrid screening. Y14 binds to STAT3 through the C-terminal region of STAT3 in vivo. siRNA-mediated knockdown of endogenous Y14 decreased IL-6-induced STAT3 tyrosine-phosphorylation, nuclear accumulation, DNA-binding activity, and STAT3-dependent gene expression.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, STAT3 phosphorylation assay, nuclear localization assay, gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional siRNA knockdown, single lab, multiple readouts\",\n      \"pmids\": [\"18503751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MAGOH, the Y14 partner in the EJC, inhibits STAT3-Y14 complex formation. Endogenous STAT3 co-immunoprecipitates with Y14. siRNA knockdown of MAGOH enhanced IL-6-induced STAT3-dependent gene expression, demonstrating that MAGOH regulates STAT3 transcriptional activation by interfering with the STAT3-Y14 complex.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, gene expression assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous co-IP plus siRNA functional assay, single lab\",\n      \"pmids\": [\"19254694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Y14/Magoh heterodimer interacts with the cytoplasmic PRMT5-containing methylosome. Y14 promotes PRMT5 activity in methylation of Sm proteins of the snRNP core, and Y14 knockdown reduces Sm protein methylation. Y14 overexpression induces formation of a large, active, snRNP-associated methylosome complex.\",\n      \"method\": \"Co-immunoprecipitation (Y14/Magoh as bait), Sm methylation assay, Y14 knockdown and overexpression, complex fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional methylation assay, single lab\",\n      \"pmids\": [\"21209085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Y14 contains a nuclear localization signal (YNS) that also confers nuclear export. A 12-amino-acid peptide near Y14's C-terminus is required for association with spliced mRNAs and for Magoh binding. Y14 mutants deficient in Magoh binding can still localize to the nucleus, indicating a Magoh-independent nuclear import pathway.\",\n      \"method\": \"Deletion/mutant analysis, nuclear localization assays, spliced mRNA association assay, Magoh binding assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic domain mapping with functional localization and binding assays, single lab\",\n      \"pmids\": [\"22355610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Y14/Magoh heterodimer specifically associates with mRNA-decapping complex components and exoribonucleases. Y14 directly interacts with decapping factor Dcp2 and the 5' cap structure of mRNAs via different but overlapping domains. Y14 inhibits mRNA-decapping activity of Dcp2 in vitro, and Y14 overexpression prolongs reporter mRNA half-life. Y14 depletion disrupts processing body (P-body) formation, while phosphomimetic Y14 overexpression increases P-body number.\",\n      \"method\": \"Co-immunoprecipitation, in vitro decapping assay, mRNA half-life assay, siRNA depletion, overexpression of phosphomimetic mutant, P-body imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro decapping assay plus co-IP plus functional mRNA stability assay plus cellular imaging, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23115303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RBM8A insufficiency (compound inheritance of a null allele and regulatory SNPs in the 5' or 3' UTR of RBM8A) causes TAR syndrome. The two regulatory SNPs result in diminished RBM8A transcription in vitro, and Y14 expression is reduced in platelets from TAR individuals.\",\n      \"method\": \"In vitro transcription reporter assay, Western blot of patient platelets, genetic mapping\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional in vitro transcription assay plus patient protein quantification, large cohort (53/55 cases)\",\n      \"pmids\": [\"22366785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBM8A depletion in A549 cells causes accumulation of mitotic cells, failure to progress past G2/M phase after G1/S release, increased sub-G1 population, caspase 3/7 activation, and increased frequency of multipolar or monopolar centrosomes. Silencing of either RBM8A or Magoh results in mutual downregulation of the other protein.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis (flow cytometry), caspase activity assay, immunostaining of centrosomes, double thymidine block release\",\n      \"journal\": \"Experimental biology and medicine (Maywood, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with multiple cell cycle and apoptosis readouts, centrosome phenotype, single lab\",\n      \"pmids\": [\"23970407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RBM8A (Y14) and MAGOH localize to the centrosome in addition to nuclei in human A549 cells. Proximity ligation assay confirmed RBM8A-MAGOH complex formation at the centrosome. GFP-PLK1 co-localizes with Myc-RBM8A at centrosomes, suggesting RBM8A-MAGOH complex is involved in M-phase progression through direct centrosome localization.\",\n      \"method\": \"Immunostaining, proximity ligation in situ assay, tagged protein expression and co-localization, GFP-PLK1 co-localization\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — localization confirmed by multiple methods (immunostaining, proximity ligation, tagged protein), single lab\",\n      \"pmids\": [\"23949737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Y14 positively regulates TNF-α-induced NF-κB transcriptional activity. Y14 endogenously associates with RIP1 and TRADD. Y14 lies downstream of TRADD and upstream of RIP1 in this pathway. Y14 significantly enhances the binding between RIP1 and TRADD. These actions are independent of MAGOH/EJC.\",\n      \"method\": \"siRNA knockdown, NF-κB transcriptional reporter assay, co-immunoprecipitation, epistasis by overexpression/knockdown rescue experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous co-IP plus epistasis rescue experiments plus reporter assay, single lab\",\n      \"pmids\": [\"23817415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBM8a overexpression in embryonic cortex stimulates neural progenitor cell (NPC) proliferation and suppresses neuronal differentiation, while RBM8a knockdown reduces NPC proliferation and promotes premature differentiation. RBM8a overexpression suppresses cell cycle exit and maintains NPCs in a proliferative state. RBM8a regulates multiple alternative splicing events and NMD targets implicated in autism spectrum disorder.\",\n      \"method\": \"In utero electroporation (overexpression and knockdown), BrdU incorporation, immunostaining, genome-wide RNA-seq\",\n      \"journal\": \"Neural development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function in vivo with quantitative proliferation/differentiation readouts plus transcriptomic analysis\",\n      \"pmids\": [\"26094033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"An evolutionarily conserved tryptophan residue (Trp-73) of Y14 is critical for mRNA cap binding. The W73V mutant binds mRNAs weakly and fails to protect them from degradation. W73V retains partial NMD activity but cannot interact with translation initiation factors, suppresses reporter mRNA translation in vitro and in vivo, and reduces nascent protein synthesis. Thus, Trp-73 is essential for cap-binding activity and Y14-mediated translation enhancement.\",\n      \"method\": \"Site-directed mutagenesis, cap-binding assay, mRNA stability assay, co-immunoprecipitation with translation initiation factors, in vitro and in vivo translation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis plus reconstituted in vitro assay plus multiple functional readouts\",\n      \"pmids\": [\"26887951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Y14 depletion induces expression of an alternatively spliced p53 isoform (p53β) in human cells. Y14, in the context of the EJC, inhibits aberrant exon inclusion during p53 pre-mRNA splicing. Both depletion and overexpression of Y14 increase overall p53 protein levels. Y14 depletion reduces p21 protein levels and increases cell sensitivity to genotoxic agents.\",\n      \"method\": \"siRNA knockdown, RT-PCR splicing analysis, Western blot, cell viability/sensitivity assay, overexpression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA plus overexpression with splicing and protein level readouts, single lab\",\n      \"pmids\": [\"28361991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Y14 C-terminal RS repeat-containing region controls Y14 localization: deletion or dephosphorylation-mimic mutants shift localization away from nucleoplasm, and the C-terminal RS repeat sequence itself can direct nucleolar localization. Y14 localization by the C-terminal region is further controlled by MAGOH binding.\",\n      \"method\": \"Deletion mutants, phosphomimetic/dephosphorylation-mimic mutants, fluorescence microscopy, MAGOH binding assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple mutant constructs with localization readout, single lab\",\n      \"pmids\": [\"29330450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Y14 depletion differentially affects expression of DNA damage response (DDR) factors and induces R-loops. Mass spectrometry after Y14 immunoprecipitation identified DDR factors as Y14-interacting partners; confirmed interactions with Ku and several DDR factors in an ATM-dependent manner. Y14 co-fractionates with Ku in chromatin-enriched fractions and accumulates on chromatin upon DNA damage. Y14 knockdown delays DDR factor recruitment to damage sites, delays γH2AX foci formation, causes Ku retention on chromatin, and compromises DNA end joining efficiency.\",\n      \"method\": \"Co-immunoprecipitation coupled with mass spectrometry, chromatin fractionation, γH2AX foci imaging, DNA end joining assay, R-loop detection, siRNA knockdown\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-coupled IP plus chromatin fractionation plus functional DNA repair assay, multiple orthogonal methods\",\n      \"pmids\": [\"30901577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Stability of Magoh and Y14 proteins depends on their heterodimerization and nuclear localization. Interface-disrupting mutations (Magoh L136R, Y14 L118R) accelerate protein degradation without affecting mRNA levels. Y14 L118R retains nuclear localization and is more stable than Magoh L136R, which loses nuclear localization.\",\n      \"method\": \"Site-directed mutagenesis, cycloheximide chase assay, subcellular localization, Western blot, RT-PCR\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus protein stability assay, single lab\",\n      \"pmids\": [\"30826064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Homozygous zebrafish rbm8a mutations cause muscle disorganization, neural cell death, and motor neuron outgrowth defects, and dysregulate NMD targets including transcripts with 3'UTR introns (3'UI) within 50 nt downstream of stop codon. EJC-dependent NMD regulates foxo3b mRNA; loss of foxo3b function in EJC mutants significantly rescues motor axon growth defects, placing RBM8A/EJC upstream of foxo3b in a developmental signaling pathway.\",\n      \"method\": \"Zebrafish genetic mutants, RNA-seq, NMD reporter assay, genetic epistasis (foxo3b loss-of-function rescue), immunostaining\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with rescue experiment plus transcriptomic analysis in vertebrate model\",\n      \"pmids\": [\"32502192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional knockout of Rbm8a in neural stem cells causes microcephaly, early postnatal lethality, and altered distribution of excitatory neurons. Rbm8a haploinsufficiency decreases proliferation in ganglionic eminences, reduces parvalbumin+ and neuropeptide Y+ interneurons, and decreases cortical GABA frequency. Conditional KO in NKX2.1 interneuron progenitors reduces progenitor proliferation and alters interneuron distribution.\",\n      \"method\": \"Conditional knockout mouse (neural stem cell and NKX2.1-specific), immunostaining, electrophysiology (GABA frequency), RNA-seq, BrdU proliferation assay\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with multiple orthogonal phenotypic readouts including electrophysiology\",\n      \"pmids\": [\"33154347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Megakaryocyte-specific Rbm8a knockout mice exhibit marked thrombocytopenia, internal hemorrhage, and splenomegaly. Rbm8a deficiency induces p53 and p21 in megakaryocytes. p53 inhibitor treatment or Trp53 knockout partially restores megakaryocyte differentiation and increases platelet counts, establishing a Y14-p53 regulatory circuit in platelet production.\",\n      \"method\": \"Megakaryocyte-specific conditional knockout mouse, genetic epistasis (Trp53 knockout), p53 inhibitor treatment, ex vivo megakaryocyte differentiation assay, flow cytometry\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus genetic epistasis rescue (Trp53 KO) plus pharmacological rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"34816104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RBM8A controls transcript levels of intronless genes and is a global regulator of ribosomal protein transcripts. Acute depletion of RBM8A using the auxin degron system followed by genome-wide nascent transcription analysis (SLAM-seq or equivalent) demonstrated that RBM8A regulates ribosomal protein transcript levels.\",\n      \"method\": \"CRISPR knockout screen, auxin degron acute depletion, genome-wide nascent transcription analysis, FACS-based reporter assay\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — acute depletion with genome-wide transcriptomic readout, single lab\",\n      \"pmids\": [\"36187487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Recombinant Y14 undergoes liquid-liquid phase separation (LLPS) in vitro in a manner sensitive to pH, salt concentration, and involving multivalent electrostatic interactions in low-complexity regions. Phospho-mimicry of C-terminal RS dipeptides suppresses phase separation. RNA co-phase separates into Y14 droplets in a concentration-dependent manner. LLPS capacity correlates with Y14 activity in DNA double-strand break repair.\",\n      \"method\": \"Recombinant protein phase separation assay, domain mapping, phosphomimetic mutants, RNA titration, DSB repair assay\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with multiple domain mutants plus functional correlation with repair activity\",\n      \"pmids\": [\"37001915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"hsa_circ_0081343 binds directly to Rbm8a in the cytoplasm, and knockdown of hsa_circ_0081343 facilitates Rbm8a nuclear localization. Importin13 (Ipo13) recognizes Rbm8a via a functional NLS and transports it across the nuclear membrane. hsa_circ_0081343-mediated nuclear translocation of Rbm8a activates trophoblast autophagy.\",\n      \"method\": \"RNA pull-down assay, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation (Ipo13-Rbm8a), immunofluorescence, Western blot\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down plus co-IP for nuclear transport interaction, single lab\",\n      \"pmids\": [\"39413593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RBM8A forms a complex with EIF4A3 in breast cancer cells. The RBM8A/EIF4A3 complex binds IGF1R and IRS-2 mRNA (by RIP-seq) and regulates their expression to activate the PI3K/AKT signaling pathway. TEAD4 is identified as a transcriptional activator of RBM8A by ChIP and dual luciferase reporter assays.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, RIP-seq, ChIP, dual-luciferase reporter assay, siRNA knockdown, xenograft\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus RIP-seq plus ChIP, single lab\",\n      \"pmids\": [\"39232805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SRPK1-mediated phosphorylation of Y14 is required for its localization at laser-induced DNA damage sites and function in DSB repair. Phosphorylated Y14 undergoes liquid-liquid phase separation promoted by magnesium in vitro, and Ku70/80 can partition into phosphorylated Y14 condensates. Chelation of divalent cations abolishes Y14 localization at DNA damage sites and NHEJ factor recruitment.\",\n      \"method\": \"HaloTag-Y14 live-cell imaging at laser damage sites, SRPK1 inhibition, phosphomimetic mutants, in vitro phase separation with phospho-Y14, co-condensation with Ku70/80, divalent cation chelation\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of phase separation plus live-cell imaging plus functional NHEJ assay, multiple orthogonal methods\",\n      \"pmids\": [\"40727937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM8A promotes BBC3 (PUMA) mRNA degradation by interacting with UPF3B. RIP-seq identified BBC3 as a direct RBM8A target, confirmed by RIP-PCR, FISH-IF, and RNA pull-down. Actinomycin D assays showed RBM8A promotes BBC3 mRNA degradation. Co-immunoprecipitation confirmed RBM8A-UPF3B interaction.\",\n      \"method\": \"RIP-seq, RIP-qPCR, RNA pull-down, FISH-immunofluorescence, actinomycin D mRNA stability assay, co-immunoprecipitation\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple RNA binding methods plus mRNA stability assay plus co-IP, single lab\",\n      \"pmids\": [\"40613240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM8A recruits eIF4A3 to stabilize EGFR mRNA, shielding it from exonucleolytic degradation, thereby sustaining EGFR protein levels and enabling nuclear EGFR-DNA-PKcs complex formation to drive NHEJ-mediated DNA repair and suppress oxaliplatin-induced apoptosis in gastric cancer cells.\",\n      \"method\": \"siRNA screen, RIP-seq, co-immunoprecipitation (RBM8A-eIF4A3), mRNA stability assay, nuclear EGFR-DNA-PKcs interaction, NHEJ reporter, xenograft model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus RIP-seq plus functional NHEJ and stability assays, single lab\",\n      \"pmids\": [\"41354714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PYM1 interaction with RBM8A/MAGOH heterodimer is required for translation-independent EJC destabilization but not for translation-dependent disassembly. EJCs lacking PYM1 interaction are enriched on non-canonical sites including intronless transcripts and transcripts with fewer and longer exons. Acute PYM1 depletion modestly inhibits NMD and stabilizes mRNAs localizing to ER-associated TIS granules.\",\n      \"method\": \"EJC occupancy mapping (iCLIP/eCLIP), acute PYM1 depletion, NMD reporter assay, RNA-seq, auxin degron system\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide occupancy mapping plus functional disassembly and NMD assays, single lab, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.03.13.643037\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish, rbm8a deficiency causes accumulation of mRNAs with retained introns including non-canonical Wnt/PCP pathway components. Genetic interaction experiments show reduced rbm8a function interacts with wnt5b, wnt11f2, fzd7a, and vangl2 mutations. Rbm8a deficiency impairs lateral plate mesoderm architecture and hematopoietic gene expression (runx1, gfi1aa), connecting rbm8a to Wnt/PCP-mediated hematopoietic development.\",\n      \"method\": \"Zebrafish hypomorphic mutants, RNA-seq (intron retention), genetic epistasis with Wnt/PCP pathway mutants, live imaging of lateral plate mesoderm, in situ hybridization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple pathway mutants plus transcriptomic evidence plus live imaging, peer-reviewed\",\n      \"pmids\": [\"40907933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of RBM8a in mouse hippocampal dentate gyrus leads to increased anxiety-like behavior and abnormal social interaction. RNA immunoprecipitation (RNA-IP) detected that RBM8a binds CaMK2, GluR1, and Egr1 mRNA in neurons, and RBM8a overexpression increases miniature excitatory postsynaptic current (mEPSC) frequency.\",\n      \"method\": \"Lentiviral overexpression in vivo, behavioral tests, RNA immunoprecipitation, electrophysiology (mEPSC)\",\n      \"journal\": \"Current molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA-IP for binding plus electrophysiology plus in vivo behavioral readout, single lab\",\n      \"pmids\": [\"23638902\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM8A (Y14) is a core component of the exon junction complex (EJC) that binds spliced mRNA immediately upstream of exon-exon junctions via protein-protein interaction with MAGOH (which occludes Y14's RRM RNA-binding surface), persists on mRNAs through nuclear export until displaced by translating ribosomes, and coordinates multiple downstream processes including nonsense-mediated mRNA decay (through direct interaction with UPF3b), translational enhancement (via mRNA cap binding at Trp-73), mRNA decapping inhibition (through direct inhibition of Dcp2), snRNP biogenesis (by promoting PRMT5-mediated Sm protein methylation), DNA double-strand break repair (through RNA-dependent recruitment of NHEJ factors via SRPK1-phosphorylation-driven phase condensates with Ku70/80), regulation of p53 splicing and the Y14-p53 circuit in megakaryocyte differentiation, and signaling modulation (STAT3 and NF-κB pathways) independent of EJC context.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM8A (Y14) is a core subunit of the exon junction complex (EJC) that controls the fate of spliced mRNAs from nuclear processing through cytoplasmic translation, and additionally serves EJC-independent roles in genome maintenance and signaling [#0, #2]. It binds spliced mRNA in a position-specific but RNA-sequence-independent manner by heterodimerizing with MAGOH, whose flat beta-sheet engages and masks the RNA-binding surface of the Y14 RRM, explaining why deposition is dictated by exon-exon junction position rather than sequence [#0, #5, #6]. Y14 persists on mRNAs through nuclear export and is removed in the cytoplasm by translating ribosomes; PYM caps the Mago-Y14 interface to drive disassembly [#2, #7]. From this platform Y14 coordinates downstream RNA fates: it activates nonsense-mediated mRNA decay through a direct interaction with UPF3B that is essential for NMD [#3, #4], enhances translation and protects mRNA via a conserved Trp-73 cap-binding residue [#21], and inhibits Dcp2-mediated decapping to stabilize transcripts and modulate P-body formation [#15]. Beyond canonical EJC functions, Y14 promotes PRMT5-mediated methylation of Sm proteins during snRNP biogenesis [#13], regulates p53 pre-mRNA splicing and protein levels [#22], and participates in DNA double-strand break repair, where SRPK1-driven phosphorylation promotes Mg2+-dependent liquid-liquid phase separation that recruits Ku70/80 and NHEJ factors to damage sites [#24, #30, #33]. Phosphorylation of its C-terminal RS dipeptides governs EJC/NMD-factor association, subcellular localization, and phase-separation capacity [#8, #23, #30]. EJC-independent activities include positive regulation of STAT3 and TNF-α-induced NF-κB signaling [#11, #19]. Developmentally, Y14 maintains neural progenitor proliferation and influences interneuron production and cortical GABAergic signaling [#20, #27], and operates in a Y14-p53 circuit required for megakaryocyte differentiation and platelet production [#28]. RBM8A insufficiency, through compound inheritance of a null allele with hypomorphic regulatory SNPs, causes thrombocytopenia-absent radius (TAR) syndrome [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that Y14 is deposited on spliced mRNA at a fixed position upstream of exon junctions and uniquely persists into the cytoplasm, defining it as a mark of splicing history rather than a sequence-specific binder.\",\n      \"evidence\": \"Xenopus oocyte microinjection with RNase mapping and cytoplasmic fractionation; in vivo Drosophila genetics showing Mago-nashi interaction and oskar mRNA localization\",\n      \"pmids\": [\"11296238\", \"11696323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how position-specific deposition is achieved mechanistically\", \"Cytoplasmic function of persistent Y14 not yet defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Answered how the cytoplasmic EJC mark is erased, showing translation displaces Y14 and links its removal to ribosome transit.\",\n      \"evidence\": \"Polysome profiling, coupled in vitro splicing/translation, and in vivo 5' UTR structural block\",\n      \"pmids\": [\"12121612\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the factor that physically strips Y14 from translated mRNA\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the molecular basis of EJC assembly and its coupling to NMD: MAGOH binds the Y14 RRM RNA surface, and the Y14-UPF3b axis is the essential NMD-activating interaction.\",\n      \"evidence\": \"Multiple independent crystal structures of Y14-Mago(h) and tethered-function/RNAi NMD assays with UPF3b\",\n      \"pmids\": [\"12730685\", \"12781131\", \"12704080\", \"12718880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain how the EJC signals decay across long distances on mRNA\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified PYM as the disassembly factor that caps the Mago-Y14 interface, providing a mechanism for cytoplasmic EJC recycling.\",\n      \"evidence\": \"Crystal structure of the PYM-Mago-Y14 ternary complex with binding and NMD tethering assays\",\n      \"pmids\": [\"14968132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate translation-dependent from translation-independent disassembly roles of PYM\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that RS-dipeptide phosphorylation and arginine methylation toggle Y14's ability to engage EJC and NMD factors, establishing post-translational control of complex assembly.\",\n      \"evidence\": \"Phosphorylation/methylation mapping, SR-kinase inhibition, and non-phosphorylatable mutants with polysome fractionation\",\n      \"pmids\": [\"16100109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific kinase identity not pinned down at this stage\", \"Physiological triggers of PTM switching unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected Y14 to nuclear mRNA export by demonstrating an NXF1 complex retained in an ATP-dependent manner near nuclear speckles.\",\n      \"evidence\": \"BiFC, RNA co-IP, and FRAP/FLIP with ATP depletion in permeabilized cells\",\n      \"pmids\": [\"16431928\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; molecular basis of ATP-dependent retention not defined\", \"Functional consequence of speckle retention for export not directly tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended Y14 beyond RNA metabolism, identifying it as a STAT3 cofactor required for IL-6-induced STAT3 activation.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and siRNA knockdown with STAT3 phosphorylation/transcription readouts\",\n      \"pmids\": [\"18503751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; mechanism of how Y14 promotes STAT3 phosphorylation unclear\", \"EJC dependence not resolved here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed MAGOH competes with STAT3 for Y14, integrating EJC assembly with signaling output.\",\n      \"evidence\": \"Endogenous co-IP and MAGOH siRNA knockdown with STAT3-dependent gene expression\",\n      \"pmids\": [\"19254694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; quantitative partitioning of Y14 between EJC and STAT3 pools not determined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked the Y14/MAGOH heterodimer to snRNP biogenesis by showing it stimulates PRMT5-mediated Sm protein methylation, and mapped a C-terminal element controlling import and mRNA association.\",\n      \"evidence\": \"Reciprocal co-IP with methylosome, Sm methylation assays, and domain-mapping localization assays\",\n      \"pmids\": [\"21209085\", \"22355610\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab methylosome data\", \"Magoh-independent import pathway not molecularly defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed Y14 as a direct inhibitor of decapping and stabilizer of mRNA, and established that RBM8A insufficiency causes TAR syndrome.\",\n      \"evidence\": \"In vitro Dcp2 decapping assays, cap-binding/mRNA half-life assays, P-body imaging; genetic and reporter analysis plus patient platelet Western blots\",\n      \"pmids\": [\"23115303\", \"22366785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How decapping inhibition relates to EJC versus free Y14 not separated\", \"Tissue specificity of TAR phenotype not explained mechanistically\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Documented mitotic and centrosomal roles for the RBM8A-MAGOH complex and an EJC-independent function promoting NF-κB and neuronal mRNA regulation.\",\n      \"evidence\": \"siRNA cell-cycle/apoptosis assays, centrosome proximity ligation with PLK1, NF-κB reporter with RIP1/TRADD co-IP, and neuronal RNA-IP with electrophysiology\",\n      \"pmids\": [\"23970407\", \"23949737\", \"23817415\", \"23638902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Centrosomal function molecularly unresolved\", \"Single-lab signaling and behavioral data\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established Y14 as a regulator of neural progenitor proliferation versus differentiation through control of alternative splicing and NMD targets.\",\n      \"evidence\": \"In utero electroporation gain/loss-of-function with BrdU and genome-wide RNA-seq\",\n      \"pmids\": [\"26094033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Key effector splicing/NMD targets driving proliferation not individually validated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Pinpointed Trp-73 as the cap-binding residue separating Y14's translation-enhancement and mRNA-protection functions from its NMD activity.\",\n      \"evidence\": \"Site-directed W73V mutagenesis with cap-binding, stability, and in vitro/in vivo translation assays\",\n      \"pmids\": [\"26887951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cap binding is coordinated with MAGOH-masked RRM not structurally resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected Y14 to genome-protective gene regulation by showing EJC-dependent suppression of aberrant p53 splicing and modulation of p21 and genotoxic sensitivity.\",\n      \"evidence\": \"siRNA/overexpression with RT-PCR splicing analysis, Western blot, and viability assays\",\n      \"pmids\": [\"28361991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; biphasic effect of depletion vs overexpression on p53 unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated a direct role for Y14 in DNA double-strand break repair via ATM-dependent interaction with Ku and chromatin recruitment of DDR factors.\",\n      \"evidence\": \"IP-mass spectrometry, chromatin fractionation, γH2AX foci imaging, and DNA end-joining assays with R-loop detection\",\n      \"pmids\": [\"30901577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-dependence of recruitment not yet mechanistically defined\", \"Did not yet implicate phase separation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established conserved developmental requirements for RBM8A in vertebrate neurogenesis, muscle, motor neuron, and hematopoietic development, placing it upstream of foxo3b in an NMD-controlled pathway.\",\n      \"evidence\": \"Zebrafish rbm8a mutants with epistasis (foxo3b rescue) and conditional KO mice with electrophysiology and RNA-seq\",\n      \"pmids\": [\"32502192\", \"33154347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous versus non-autonomous contributions not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a Y14-p53 regulatory circuit as the basis of RBM8A's requirement in platelet production, linking the molecular pathway to the TAR phenotype.\",\n      \"evidence\": \"Megakaryocyte-specific conditional KO with Trp53 KO epistasis and pharmacological p53 inhibition\",\n      \"pmids\": [\"34816104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular route from Y14 loss to p53 induction in megakaryocytes not detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified RBM8A as a global regulator of intronless and ribosomal protein transcript levels using acute depletion.\",\n      \"evidence\": \"CRISPR screen and auxin-degron acute depletion with genome-wide nascent transcription analysis\",\n      \"pmids\": [\"36187487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; mechanism of intronless transcript regulation not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked Y14's repair function to biophysics, showing recombinant Y14 undergoes phosphorylation-tunable, RNA-responsive liquid-liquid phase separation that correlates with DSB repair activity.\",\n      \"evidence\": \"In vitro phase-separation assays with domain/phosphomimetic mutants, RNA titration, and DSB repair assays\",\n      \"pmids\": [\"37001915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet identify the kinase or co-condensing repair factors in cells\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded RBM8A's cytoplasmic targeted-RNA regulation, identifying circRNA/Ipo13-mediated nuclear transport and an eIF4A3 partnership stabilizing growth-signaling mRNAs.\",\n      \"evidence\": \"RNA pull-down/MS with Ipo13 co-IP in trophoblasts; co-IP, RIP-seq, and ChIP linking RBM8A/EIF4A3 to IGF1R/IRS-2 and TEAD4 regulation in breast cancer\",\n      \"pmids\": [\"39413593\", \"39232805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; generality of eIF4A3-dependent mRNA stabilization across contexts untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the mechanism of Y14-dependent NHEJ, showing SRPK1 phosphorylation drives Mg2+-dependent condensates that partition Ku70/80, and extended targeted mRNA regulation to UPF3B-dependent BBC3 decay and eIF4A3-mediated EGFR stabilization supporting repair.\",\n      \"evidence\": \"Live-cell laser-damage imaging with SRPK1 inhibition and in vitro phospho-Y14 co-condensation with Ku70/80; RIP-seq, RNA pull-down, and stability assays for BBC3 and EGFR with NHEJ readouts\",\n      \"pmids\": [\"40727937\", \"40613240\", \"41354714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-lab cancer-context studies for BBC3/EGFR\", \"How condensate-based repair integrates with canonical EJC pool unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected RBM8A to non-canonical Wnt/PCP signaling and intron retention control in hematopoietic and developmental contexts, and refined PYM1's role in EJC disassembly site selectivity.\",\n      \"evidence\": \"Zebrafish hypomorphs with Wnt/PCP genetic epistasis and intron-retention RNA-seq; EJC occupancy mapping with acute PYM1 depletion (preprint)\",\n      \"pmids\": [\"40907933\", \"bio_10.1101_2025.03.13.643037\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct splicing targets mediating Wnt/PCP effects not validated\", \"PYM1 disassembly findings remain a preprint\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Y14 partitions between its EJC-bound pool and its many EJC-independent roles (signaling, snRNP methylation, condensate-based repair) within a single cell, and what determines target and pathway selection, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for context-dependent activity switching\", \"Quantitative pool partitioning not measured\", \"Structural basis of cap binding within the MAGOH-masked RRM unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 15, 21, 30, 34]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 19, 24]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13, 15]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [14, 23, 25, 31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [9, 23]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [24, 33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2, 3, 13, 15]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [24, 30, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [20, 26, 27, 37]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 19, 32]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [22, 29]}\n    ],\n    \"complexes\": [\"exon junction complex (EJC)\", \"methylosome (PRMT5)\"],\n    \"partners\": [\"MAGOH\", \"UPF3B\", \"PYM1\", \"EIF4A3\", \"NXF1\", \"STAT3\", \"KU70/80\", \"DCP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":9,"faith_total":9,"faith_pct":100.0}}