{"gene":"RBMY1A1","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1993,"finding":"RBMY1A1 (YRRM/RBM) was identified as a Y-chromosome gene family encoding proteins with RNA recognition motifs, expressed specifically in the testis, with deletions detected in oligospermic patients, establishing it as a candidate for the azoospermia factor (AZF) controlling spermatogenesis.","method":"cDNA cloning, Southern blot analysis, interphase in situ hybridization, RT-PCR of testis RNA, deletion mapping in infertile patients","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — foundational discovery paper with multiple orthogonal methods, highly cited, replicated across labs","pmids":["8269511"],"is_preprint":false},{"year":1997,"finding":"RBM (RBMY1A1) protein is a nuclear protein expressed in fetal, prepubertal, and adult male germ cells. Its distribution correlates with transcriptional activity during spermatogenesis. Deletion mapping using anti-RBM antiserum identified a critical Y chromosome region whose loss abolishes RBM expression; in the absence of RBM expression, germ cell development arrests at early meiosis and does not proceed into the haploid phase.","method":"Immunohistochemistry with anti-RBM antiserum, deletion mapping panel of men with Y chromosome deletions and known testicular pathologies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — direct protein localization with functional consequence (meiotic arrest), correlated with genetic deletion panel","pmids":["9108067"],"is_preprint":false},{"year":1997,"finding":"RBM1 (RBMY1A1) is conserved and amplified on the marsupial Y chromosome with testis-specific transcription, suggesting it evolved from hnRNPG at least 130 million years ago through transposition to the Y chromosome and subsequent internal amplification, implying a critical male-specific function retained through evolution.","method":"Comparative genomics, Southern blot, RT-PCR of marsupial testis RNA, phylogenetic analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 — evolutionary/functional conservation established by direct molecular methods in multiple species","pmids":["9020837"],"is_preprint":false},{"year":1997,"finding":"The RBMY gene family contains approximately 30 members on the Y chromosome, but only the RBMI subfamily (including RBMY1A1) is actively transcribed and encodes functional proteins. Alternative splicing generates protein isoforms with three or four SRGY boxes, increasing the complexity of the expressed products.","method":"RT-PCR, cDNA cloning and sequencing, characterization of multiple RBMY cDNA clones","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular characterization of transcripts and protein isoforms","pmids":["9344660"],"is_preprint":false},{"year":1998,"finding":"RBMY1A1 (RBM) protein has a complex and dynamic subnuclear localization in human germ cells, distributed between punctate nuclear structures and the nucleoplasm in a developmentally regulated manner. Pre-mRNA splicing components co-localize with RBM in punctate nuclear regions during early spermatogenesis but dissociate late in meiosis, suggesting dynamic and possibly multiple functions for RBM in germ cell development.","method":"Immunofluorescence microscopy with anti-RBM antibodies, co-localization with splicing factor antibodies across germ cell developmental stages","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with defined functional consequence (stage-specific co-localization with splicing machinery), multiple cell types examined","pmids":["9547301"],"is_preprint":false},{"year":1998,"finding":"The genomic structure of an RBM gene (related to RBMY1A1) was determined: a 15-kb segment comprising 12 exons and 11 introns with high homology among exons VII-X (encoding SRGY boxes) and among introns VI-IX, consistent with origin from common ancestral sequences by internal amplification.","method":"P1 genomic library screening, cosmid subcloning, restriction mapping, DNA sequencing, RT-PCR of testis RNA","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic structural characterization by sequencing","pmids":["8964845"],"is_preprint":false},{"year":1998,"finding":"RBMY evolved on the Y chromosome from a ubiquitously transcribed X-Y identical gene, supporting a transposition-amplification model for RBMY gene family evolution.","method":"Comparative genomic and sequence analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular evidence for evolutionary origin","pmids":["10391207"],"is_preprint":false},{"year":1998,"finding":"The RBMY gene family structure and organization on the Y chromosome was characterized: seven RBMY genes in interval 6, four with normal 12-exon/15-kb structure, one pseudogene lacking the first 3 exons, and two belonging to a subfamily resembling ancestral hnRNPG with only one SRGY repeat; most RBMY genes in interval 6 are arranged in tandem. This supports the transposition-amplification hypothesis for RBMY evolution from an autosomal hnRNPG gene.","method":"Genomic cloning, restriction mapping, sequencing of RBMY genes from YAC clones","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct structural characterization of multiple gene copies","pmids":["9598316"],"is_preprint":false},{"year":1999,"finding":"RBMY1A1 (RBM) protein interacts with T-STAR (a novel SAM68-related RNA-binding protein expressed primarily in testis) via yeast two-hybrid screen. T-STAR co-localizes with RBM in germ cells and is regulated during meiosis, suggesting that RBM and T-STAR/SAM68 participate in a common RNA-processing pathway in male germ cells.","method":"Yeast two-hybrid screen of testis cDNA library, cDNA cloning, chromosomal mapping, GFP transfection and nuclear localization studies","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid identification of binding partner with supporting localization data","pmids":["10332027"],"is_preprint":false},{"year":1999,"finding":"RBMY1A1 has a homologue on the human X chromosome (RBMX), indicating that RBMY evolved from an ancestral X-Y identical gene.","method":"Comparative genomic analysis, sequence characterization","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct molecular identification of X-chromosome homologue","pmids":["10391206"],"is_preprint":false},{"year":2000,"finding":"RBMY1A1 (RBM) protein directly interacts with SR family splicing factors and with itself (self-interaction). The protein domains mediating these interactions were mapped, and a bacterially expressed RBM interaction region pulls down functionally active SR proteins from cell extracts. Depletion/add-back experiments showed that SR proteins bound by RBM are required for splicing of a panel of pre-mRNAs, establishing RBM as a germ cell-specific cofactor for SR protein-dependent pre-mRNA splicing.","method":"Protein-protein interaction assays, domain mapping, bacterial fusion protein expression, pull-down from cell extracts, depletion and add-back splicing experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct biochemical interaction mapping plus functional splicing reconstitution with depletion/add-back","pmids":["10823932"],"is_preprint":false},{"year":2000,"finding":"RBMY1A1 (RBM) and other hnRNP G family proteins interact with Tra2beta (an SR-like splicing activator highly expressed in testis). Phosphorylation enhances this interaction and reduces competing RNA binding. RBM and Tra2beta co-localize in two major domains in human spermatocyte nuclei. Incubation with the RBM protein interaction domain inhibits splicing in vitro of a pre-mRNA substrate containing a Tra2beta-dependent enhancer, and the RBM RNA-binding domain affects 5' splice site selection.","method":"Co-immunoprecipitation, in vitro splicing inhibition assay, immunofluorescence co-localization in human spermatocytes, domain interaction mapping, phosphorylation experiments","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vitro splicing, co-IP, and direct localization in relevant cell type","pmids":["10749975"],"is_preprint":false},{"year":2004,"finding":"RBMY1A1 (RBMY) and related proteins (hnRNP G-T, T-STAR) are part of a network of RNA-processing regulatory interactions involving SR proteins and signal transduction pathways, with RBMY providing a germ cell-specific component for pre-mRNA splicing regulation important for normal germ cell development.","method":"Review of protein interaction network data, yeast two-hybrid, co-IP studies","journal":"International journal of andrology","confidence":"Low","confidence_rationale":"Tier 4 — review/synthesis, no new primary experiments","pmids":["15595951"],"is_preprint":false},{"year":2007,"finding":"The RBMY1A1 RRM (RNA recognition motif) domain recognizes RNA stem-loops capped by a C(A)/(U)CAA pentaloop with high affinity. NMR structure determination of the hRBMY RRM in complex with target RNA revealed two distinct binding modes: (1) the RRM beta-sheet surface contacts the RNA loop in a sequence-specific manner (conserved with hnRNP G), and (2) uniquely to hRBMY, the beta2-beta3 loop inserts into the major groove of the RNA stem—a novel recognition mode not found in the paralogous hnRNP G.","method":"SELEX (systematic evolution of ligands by exponential enrichment), NMR structural determination of protein-RNA complex","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution NMR structure of protein-RNA complex with identification of two distinct binding modes, novel mechanism validated","pmids":["17318228"],"is_preprint":false},{"year":2002,"finding":"CIRP (cold-inducible RNA-binding protein), which is structurally highly similar to RBM1 (RBMY1A1), is expressed in mouse germ cell nuclei (particularly primary spermatocytes) and its expression is down-regulated at elevated temperatures, potentially linking temperature-sensitive spermatogenesis to RNA-binding protein function in germ cells.","method":"Immunohistochemistry, RT-PCR, cell culture temperature experiments, experimental cryptorchidism model","journal":"The American journal of pathology","confidence":"Low","confidence_rationale":"Tier 3 — findings are about CIRP (not RBMY1A1 directly), included only for structural similarity context","pmids":["9422546"],"is_preprint":false},{"year":2015,"finding":"RBMY acts as a novel inhibitor of glycogen synthase kinase 3β (GSK3β): cytoplasmic RBMY binds to and increases Ser9 phosphorylation-mediated inactivation of GSK3β, thereby impeding GSK3β-dependent degradation of β-catenin, leading to nuclear β-catenin accumulation and transcription of downstream oncogenes. This promotes tumor stemness, self-renewal, chemoresistance, and cell-cycle progression in hepatocellular carcinoma cells. Cytoplasmic translocation of RBMY is mediated by binding to the nuclear exporter CRM1 and is enhanced by Wnt-3a stimulation.","method":"Co-immunoprecipitation, phosphorylation assays, xenograft tumor growth, loss-of-function and gain-of-function experiments, cell-cycle analysis, Western blot, immunohistochemistry","journal":"Hepatology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Co-IP, phosphorylation assay, in vivo xenograft, LOF/GOF) establishing mechanistic pathway","pmids":["26185016"],"is_preprint":false},{"year":2017,"finding":"The Y-linked gene Rbmy1a1 is highly methylated in mature sperm and resists DNA demethylation post-fertilization. Aberrant hypomethylation of the Rbmy1a1 promoter (caused by loss of maternal TRIM28) results in ectopic activation of Rbmy1a1, causing male-specific peri-implantation lethality. Rbmy1a1 is a novel target of the TRIM28 complex, which protects its repressive epigenetic state during embryonic epigenetic reprogramming.","method":"Mouse genetic knockout (maternal Trim28 deletion), bisulfite sequencing, RNA expression analysis, embryo phenotyping","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with direct epigenetic mechanism (TRIM28-dependent methylation maintenance), specific lethality phenotype","pmids":["28115466"],"is_preprint":false},{"year":2025,"finding":"RBMY1A1-dependent sorting of miR-105-5p into exosomes from highly metastatic breast cancer cells facilitates the transformation of normal fibroblasts into cancer-associated fibroblasts (CAFs), which subsequently activates NF-κB signaling by downregulating LATS2 and promotes EMT of breast cancer cells.","method":"Exosome isolation, miRNA sequencing, loss-of-function (RBMY1A1 knockdown), co-culture fibroblast transformation assays, Western blot, NF-κB reporter assays","journal":"Acta biochimica et biophysica Sinica","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct knockdown showing mechanistic role in miRNA sorting with defined downstream signaling pathway","pmids":["40151143"],"is_preprint":false}],"current_model":"RBMY1A1 encodes a germ cell-specific nuclear RNA-binding protein (RBM) that participates in pre-mRNA splicing regulation by directly interacting with SR splicing factors and Tra2beta, with the RRM domain recognizing RNA stem-loops via a unique dual-mode mechanism (beta-sheet surface plus beta2-beta3 loop insertion into the RNA major groove); its promoter is epigenetically silenced by the TRIM28 complex in somatic tissues (ectopic activation causes male-specific embryonic lethality), while in cancer contexts cytoplasmic RBMY acts as a GSK3β inhibitor to activate Wnt/β-catenin signaling and promote tumor stemness, and also facilitates exosomal miR-105-5p sorting to reprogram the tumor microenvironment."},"narrative":{"teleology":[{"year":1993,"claim":"Identification of RBMY1A1 as a Y-linked, testis-specific RRM gene family deleted in infertile men established the first candidate gene for the azoospermia factor (AZF) locus and framed spermatogenesis as an RNA-processing-dependent process.","evidence":"cDNA cloning, Southern blot deletion mapping, RT-PCR of testis RNA in fertile vs. oligospermic men","pmids":["8269511"],"confidence":"High","gaps":["No functional assay demonstrated a direct requirement for RBMY in germ cell development at this stage","Precise RNA targets and molecular function of the RRM domain were unknown"]},{"year":1997,"claim":"Protein-level analyses revealed that RBMY is a nuclear protein in male germ cells whose absence (via Y chromosome deletion) causes meiotic arrest before haploid differentiation, establishing a causal link between RBMY loss and spermatogenic failure.","evidence":"Immunohistochemistry across germ cell stages, Y chromosome deletion panel with defined testicular pathologies","pmids":["9108067"],"confidence":"High","gaps":["Mechanism by which RBMY supports meiotic progression was not identified","Specific RNA substrates processed by RBMY in germ cells were unknown"]},{"year":1997,"claim":"Evolutionary analyses established that RBMY arose from autosomal/X-linked hnRNPG by transposition to the Y chromosome and subsequent amplification, with conservation of testis-specific expression across therian mammals spanning >130 million years.","evidence":"Comparative genomics and RT-PCR in marsupials and eutherians; RBMX identification on human X chromosome","pmids":["9020837","10391206"],"confidence":"Medium","gaps":["Functional divergence between RBMY and its autosomal/X-linked homologues was not biochemically defined","Whether all ~30 Y-linked RBMY copies contribute to function was unclear"]},{"year":1998,"claim":"Dynamic subnuclear co-localization of RBMY with pre-mRNA splicing factors in spermatocytes, followed by dissociation in late meiosis, provided the first spatial evidence linking RBMY to the splicing machinery in a stage-dependent manner.","evidence":"Co-immunofluorescence of RBMY and splicing factor antibodies across spermatogenic stages","pmids":["9547301"],"confidence":"High","gaps":["Co-localization does not prove direct interaction with splicing factors","Identity of specific splicing partners was not established"]},{"year":2000,"claim":"Biochemical reconstitution demonstrated that RBMY directly interacts with SR splicing factors and Tra2beta, and that the RBMY interaction domain can sequester active SR proteins to modulate pre-mRNA splicing in vitro, establishing RBMY as a germ cell-specific splicing co-regulator.","evidence":"Bacterial pull-down of SR proteins, depletion/add-back in vitro splicing assays, co-IP and immunofluorescence in spermatocytes, domain mapping","pmids":["10823932","10749975"],"confidence":"High","gaps":["Endogenous pre-mRNA targets regulated by RBMY in germ cells were not identified","Whether RBMY activates or represses splicing of specific exons in vivo remained unclear"]},{"year":2007,"claim":"NMR structure of the RBMY RRM bound to its RNA target revealed a dual recognition mode—canonical beta-sheet/loop contacts plus a novel beta2-beta3 loop insertion into the RNA stem major groove—distinguishing RBMY from its paralog hnRNP G and explaining its unique RNA-binding specificity.","evidence":"SELEX identification of stem-loop RNA ligand; NMR structure determination of RRM-RNA complex","pmids":["17318228"],"confidence":"High","gaps":["Whether the dual-mode recognition is functionally required for splicing regulation in germ cells was not tested","Genome-wide identification of endogenous RNA targets recognized by this structural mode was not performed"]},{"year":2015,"claim":"In hepatocellular carcinoma, RBMY was found to translocate to the cytoplasm via CRM1 and inhibit GSK3β by promoting its Ser9 phosphorylation, leading to β-catenin stabilization and Wnt-driven stemness, revealing a non-canonical cytoplasmic signaling function distinct from its nuclear splicing role.","evidence":"Co-IP, phosphorylation assays, xenograft tumor models, gain-of-function and loss-of-function experiments in HCC cell lines","pmids":["26185016"],"confidence":"High","gaps":["Whether cytoplasmic RBMY retains RNA-binding activity or functions entirely as a protein–protein scaffold was not resolved","Relevance of this mechanism beyond hepatocellular carcinoma was not established"]},{"year":2017,"claim":"Genetic epistasis experiments revealed that TRIM28-dependent DNA methylation maintains RBMY1A1 promoter silencing in somatic/embryonic tissues; loss of this methylation causes ectopic RBMY activation and male-specific peri-implantation lethality, explaining the evolutionary pressure for epigenetic silencing outside the germline.","evidence":"Maternal Trim28 knockout mice, bisulfite sequencing of Rbmy1a1 promoter, embryo RNA expression and phenotyping","pmids":["28115466"],"confidence":"High","gaps":["Downstream effectors of ectopic RBMY that cause lethality were not identified","Whether the lethal phenotype is mediated through splicing dysregulation or cytoplasmic signaling was not determined"]},{"year":2025,"claim":"RBMY1A1 was shown to direct sorting of miR-105-5p into exosomes in metastatic breast cancer, with exosomal miR-105-5p reprogramming fibroblasts into cancer-associated fibroblasts via LATS2 downregulation and NF-κB activation, extending RBMY's oncogenic roles to exosomal RNA sorting and tumor microenvironment remodeling.","evidence":"RBMY1A1 knockdown, exosome isolation, miRNA sequencing, fibroblast co-culture transformation assays, NF-κB reporter","pmids":["40151143"],"confidence":"Medium","gaps":["Structural basis for RBMY-mediated miRNA sorting into exosomes was not determined","Whether RRM-dependent RNA recognition drives miRNA selection was not tested","Independent replication in additional cancer models is lacking"]},{"year":null,"claim":"The endogenous pre-mRNA targets of RBMY in spermatogenic cells remain unidentified genome-wide, and the mechanistic basis for how RBMY's splicing function in the nucleus relates to its cytoplasmic signaling and exosomal sorting activities in cancer is unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No CLIP-seq or equivalent transcriptome-wide mapping of RBMY RNA targets in germ cells has been reported","Structural basis for RBMY interaction with GSK3β versus SR proteins is unknown","Whether RBMY contributes to spermatogenic splicing programs through specific exon inclusion/skipping events has not been defined in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,11,15]}],"localization":[{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[1,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,4,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[10,11,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["TRA2B","KHDRBS3","GSK3B","XPO1"],"other_free_text":[]},"mechanistic_narrative":"RBMY1A1 is a Y-chromosome-encoded, germ cell-specific nuclear RNA-binding protein that functions as a regulator of pre-mRNA splicing during spermatogenesis. It directly interacts with SR family splicing factors and the SR-like activator Tra2beta through its SRGY box domains, serving as a tissue-specific cofactor whose depletion abolishes splicing of SR-dependent pre-mRNAs; its RRM domain recognizes RNA stem-loops via a dual-mode mechanism involving canonical beta-sheet surface contacts and a unique beta2-beta3 loop insertion into the RNA major groove [PMID:10823932, PMID:10749975, PMID:17318228]. Loss of RBMY expression due to Y chromosome deletions results in germ cell arrest at early meiosis, consistent with an essential role in the transition to haploid spermatid development [PMID:9108067]. In somatic and cancer contexts, the RBMY1A1 promoter is normally silenced by TRIM28-dependent DNA methylation—ectopic activation causes male-specific embryonic lethality—while aberrant cytoplasmic RBMY in hepatocellular carcinoma inhibits GSK3β to activate Wnt/β-catenin signaling and promote tumor stemness [PMID:28115466, PMID:26185016]."},"prefetch_data":{"uniprot":{"accession":"P0DJD3","full_name":"RNA-binding motif protein, Y chromosome, family 1 member A1","aliases":["RNA-binding motif protein 1","RNA-binding motif protein 2","Y chromosome RNA recognition motif 1","hRBMY"],"length_aa":496,"mass_kda":55.8,"function":"RNA-binding protein involved in pre-mRNA splicing. Required for sperm development. Acts additively with TRA2B to promote exon 7 inclusion of the survival motor neuron SMN. Binds non-specifically to mRNAs","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P0DJD3/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBMY1A1"},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RBMY1A1","total_profiled":1310},"omim":[{"mim_id":"610421","title":"KH DOMAIN-CONTAINING, RNA-BINDING, SIGNAL TRANSDUCTION-ASSOCIATED PROTEIN 3; KHDRBS3","url":"https://www.omim.org/entry/610421"},{"mim_id":"415000","title":"SPERMATOGENIC FAILURE, Y-LINKED, 2; SPGFY2","url":"https://www.omim.org/entry/415000"},{"mim_id":"400006","title":"RNA-BINDING MOTIF PROTEIN, Y CHROMOSOME, FAMILY 1, MEMBER A1; RBMY1A1","url":"https://www.omim.org/entry/400006"},{"mim_id":"300199","title":"RNA-BINDING MOTIF PROTEIN, X CHROMOSOME; RBMX","url":"https://www.omim.org/entry/300199"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"testis","ntpm":8.0}],"url":"https://www.proteinatlas.org/search/RBMY1A1"},"hgnc":{"alias_symbol":["YRRM1","YRRM2"],"prev_symbol":["RBM1","RBM2"]},"alphafold":{"accession":"P0DJD3","domains":[{"cath_id":"3.30.70.330","chopping":"10-83","consensus_level":"high","plddt":88.3484,"start":10,"end":83}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DJD3","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0DJD3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0DJD3-F1-predicted_aligned_error_v6.png","plddt_mean":49.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBMY1A1","jax_strain_url":"https://www.jax.org/strain/search?query=RBMY1A1"},"sequence":{"accession":"P0DJD3","fasta_url":"https://rest.uniprot.org/uniprotkb/P0DJD3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0DJD3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DJD3"}},"corpus_meta":[{"pmid":"7661932","id":"PMC_7661932","title":"PCR 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molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10749975","citation_count":104,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10391206","id":"PMC_10391206","title":"The candidate spermatogenesis gene RBMY has a homologue on the human X chromosome.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10391206","citation_count":99,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10332027","id":"PMC_10332027","title":"T-STAR/ETOILE: a novel relative of SAM68 that interacts with an RNA-binding protein implicated in spermatogenesis.","date":"1999","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10332027","citation_count":97,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21044950","id":"PMC_21044950","title":"Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells.","date":"2010","source":"Molecular & cellular proteomics : 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chromosome.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9344660","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29892012","id":"PMC_29892012","title":"An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.","date":"2018","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29892012","citation_count":61,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31515488","id":"PMC_31515488","title":"Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31515488","citation_count":60,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15595951","id":"PMC_15595951","title":"The role of potential splicing factors including RBMY, RBMX, hnRNPG-T and STAR proteins in spermatogenesis.","date":"2004","source":"International journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/15595951","citation_count":58,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26185016","id":"PMC_26185016","title":"RBMY, a novel inhibitor of glycogen synthase kinase 3β, increases tumor stemness and predicts poor prognosis of hepatocellular carcinoma.","date":"2015","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/26185016","citation_count":58,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10823932","id":"PMC_10823932","title":"A mammalian germ cell-specific RNA-binding protein interacts with ubiquitously expressed proteins involved in splice site selection.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10823932","citation_count":55,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10391207","id":"PMC_10391207","title":"RBMY evolved on the Y chromosome from a ubiquitously transcribed X-Y identical gene.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10391207","citation_count":54,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"17001072","id":"PMC_17001072","title":"RNA-binding motif protein 15 binds to the RNA transport element RTE and provides a direct link to the NXF1 export pathway.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17001072","citation_count":53,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9598316","id":"PMC_9598316","title":"Structure and organization of the RBMY genes on the human Y chromosome: transposition and amplification of an ancestral autosomal hnRNPG gene.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9598316","citation_count":49,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25278,"output_tokens":2092,"usd":0.053607},"stage2":{"model":"claude-opus-4-6","input_tokens":5225,"output_tokens":1940,"usd":0.111937},"total_usd":0.415134,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":36269,"output_tokens":4328,"usd":0.086863},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8077,"output_tokens":2724,"usd":0.162727}},"stage1_raw":"Looking at the corpus, I need to identify papers about RBMY1A1 (the human Y-linked RNA-binding motif gene involved in spermatogenesis) and extract mechanistic findings. Many papers in this corpus are about unrelated \"RBM1\" entities (renal cell carcinoma cell lines, flagellar ring-building motifs, sphingolipid probes, SARS-CoV-2 peptides, etc.) — I will skip those.\n\nRelevant papers about RBMY1A1 (also called YRRM1, RBM1 on Y chromosome):\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"RBM1 (RBMY1A1) has a Y-linked homologue in marsupials that is transcribed in the testis, and phylogenetic analysis indicates RBM1 evolved from the autosomal hnRNPG gene at least 130 million years ago, with internal exon amplification occurring in primates; the marsupial Y-linked homologue lacks the amplified SRGY-box exons present in human RBM1, establishing that RBM1 underwent primate-specific domain amplification after diverging from hnRNPG.\",\n      \"method\": \"Cross-species comparative genomics, Southern blotting, RT-PCR of marsupial testis RNA, sequence analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-species RT-PCR and sequence analysis in single study establishing evolutionary origin and testis-specific expression of Y-linked ortholog\",\n      \"pmids\": [\"9020837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The genomic structure of RBM1 (RBMY1A1) consists of 12 exons and 11 introns spanning ~15 kb; exons VII–X each encode one SRGY box with high homology to each other, and introns VI–IX also share high internal homology, indicating origin from common ancestral sequences through internal duplication.\",\n      \"method\": \"P1 genomic library screening, YAC subcloning into cosmids, restriction mapping, DNA sequencing, RT-PCR of human testis RNA\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct genomic sequencing and structural determination with orthogonal cloning strategies\",\n      \"pmids\": [\"8964845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The Y-linked gene Rbmy1a1 is highly methylated in mature sperm and resists global DNA demethylation after fertilization; it is a target of the maternal TRIM28 complex, which maintains repressive epigenetic marks at the Rbmy1a1 promoter during embryonic reprogramming. Loss of maternal TRIM28 causes aberrant hypomethylation of the Rbmy1a1 promoter, leading to ectopic Rbmy1a1 activation and male-specific peri-implantation lethality.\",\n      \"method\": \"Maternal Trim28 knockout mouse model, bisulfite sequencing, RNA expression analysis, genetic epistasis (loss-of-function with defined lethal phenotype)\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KO mouse with defined peri-implantation lethal phenotype, bisulfite sequencing confirming promoter hypomethylation, epistatic relationship between TRIM28 and Rbmy1a1 established with multiple orthogonal methods\",\n      \"pmids\": [\"28115466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RBMY1A1 (YRRM1) is expressed in human and mouse testis; the structurally highly similar mouse cold-inducible RNA-binding protein CIRP is constitutively expressed in germ cells with peak protein levels in primary spermatocytes, and is down-regulated at elevated temperatures in germ cells, linking the RBM/CIRP family to temperature-sensitive spermatogenesis.\",\n      \"method\": \"RT-PCR, immunohistochemistry, experimental cryptorchidism heat-stress model, GC-2spd(ts) cell line temperature shift assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct IHC localization tied to functional heat-stress phenotype in mouse model and human varicocele tissue; relates to ortholog CIRP rather than RBMY1A1 directly\",\n      \"pmids\": [\"9422546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBMY1A1 promoter is hypermethylated in testicular embryonal carcinoma, correlating with loss of RBMY1A1 expression; this establishes promoter methylation as a mechanism silencing RBMY1A1 in testicular germ cell tumors.\",\n      \"method\": \"Genome-wide CpG promoter methylation array (Nimblegen), quantitative RT-PCR validation, immunohistochemistry\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — methylation array plus RT-PCR validation in multiple tumor samples, though functional consequence of silencing not directly tested\",\n      \"pmids\": [\"26625006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Stable overexpression of RBMY1A1 in male human embryonic stem cells was achieved using a transgenic doxycycline-inducible system, providing a cell-based platform; the study demonstrated that Y-chromosome MSY genes including RBMY1A1 can be individually overexpressed to probe function during differentiation.\",\n      \"method\": \"Transgenic ESC line generation, doxycycline-inducible overexpression, neural differentiation assay, RT-PCR and Western blot\",\n      \"journal\": \"Stem cell reviews and reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — tool generation study; RBMY1A1 overexpression line created but no functional readout specifically for RBMY1A1 was reported (functional data shown only for RPS4Y1)\",\n      \"pmids\": [\"35661078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMY1A1 protein was identified as a factor required for the sorting of miR-105-5p into breast cancer cell-derived exosomes; RBMY1A1-dependent loading of miR-105-5p into exosomes promotes transfer to fibroblasts, where miR-105-5p downregulates LATS2 and activates NF-κB signaling, facilitating transformation of normal fibroblasts into cancer-associated fibroblasts.\",\n      \"method\": \"Exosome isolation, miRNA profiling, knockdown/overexpression of RBMY1A1 in breast cancer cells, LATS2 reporter assay, NF-κB signaling assay, co-culture fibroblast transformation assay\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function and gain-of-function with defined molecular pathway, though single lab study with limited orthogonal validation of RBMY1A1's direct role in miRNA sorting\",\n      \"pmids\": [\"40151143\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBMY1A1 is a Y-chromosome-encoded RNA-binding protein (containing an RRM domain and SRGY boxes amplified in primates from an hnRNPG ancestor) that is expressed specifically in testicular germ cells where it is required for spermatogenesis; its promoter is kept repressively methylated in sperm and early embryos by the maternal TRIM28 complex to prevent ectopic expression, and in somatic cancer contexts it has been implicated in sorting specific miRNAs (miR-105-5p) into exosomes to regulate paracrine signaling.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"RBMY1A1 (YRRM/RBM) was identified as a Y-chromosome gene family encoding proteins with RNA recognition motifs, expressed specifically in the testis, with deletions detected in oligospermic patients, establishing it as a candidate for the azoospermia factor (AZF) controlling spermatogenesis.\",\n      \"method\": \"cDNA cloning, Southern blot analysis, interphase in situ hybridization, RT-PCR of testis RNA, deletion mapping in infertile patients\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational discovery paper with multiple orthogonal methods, highly cited, replicated across labs\",\n      \"pmids\": [\"8269511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RBM (RBMY1A1) protein is a nuclear protein expressed in fetal, prepubertal, and adult male germ cells. Its distribution correlates with transcriptional activity during spermatogenesis. Deletion mapping using anti-RBM antiserum identified a critical Y chromosome region whose loss abolishes RBM expression; in the absence of RBM expression, germ cell development arrests at early meiosis and does not proceed into the haploid phase.\",\n      \"method\": \"Immunohistochemistry with anti-RBM antiserum, deletion mapping panel of men with Y chromosome deletions and known testicular pathologies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization with functional consequence (meiotic arrest), correlated with genetic deletion panel\",\n      \"pmids\": [\"9108067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RBM1 (RBMY1A1) is conserved and amplified on the marsupial Y chromosome with testis-specific transcription, suggesting it evolved from hnRNPG at least 130 million years ago through transposition to the Y chromosome and subsequent internal amplification, implying a critical male-specific function retained through evolution.\",\n      \"method\": \"Comparative genomics, Southern blot, RT-PCR of marsupial testis RNA, phylogenetic analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — evolutionary/functional conservation established by direct molecular methods in multiple species\",\n      \"pmids\": [\"9020837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The RBMY gene family contains approximately 30 members on the Y chromosome, but only the RBMI subfamily (including RBMY1A1) is actively transcribed and encodes functional proteins. Alternative splicing generates protein isoforms with three or four SRGY boxes, increasing the complexity of the expressed products.\",\n      \"method\": \"RT-PCR, cDNA cloning and sequencing, characterization of multiple RBMY cDNA clones\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular characterization of transcripts and protein isoforms\",\n      \"pmids\": [\"9344660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RBMY1A1 (RBM) protein has a complex and dynamic subnuclear localization in human germ cells, distributed between punctate nuclear structures and the nucleoplasm in a developmentally regulated manner. Pre-mRNA splicing components co-localize with RBM in punctate nuclear regions during early spermatogenesis but dissociate late in meiosis, suggesting dynamic and possibly multiple functions for RBM in germ cell development.\",\n      \"method\": \"Immunofluorescence microscopy with anti-RBM antibodies, co-localization with splicing factor antibodies across germ cell developmental stages\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with defined functional consequence (stage-specific co-localization with splicing machinery), multiple cell types examined\",\n      \"pmids\": [\"9547301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The genomic structure of an RBM gene (related to RBMY1A1) was determined: a 15-kb segment comprising 12 exons and 11 introns with high homology among exons VII-X (encoding SRGY boxes) and among introns VI-IX, consistent with origin from common ancestral sequences by internal amplification.\",\n      \"method\": \"P1 genomic library screening, cosmid subcloning, restriction mapping, DNA sequencing, RT-PCR of testis RNA\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic structural characterization by sequencing\",\n      \"pmids\": [\"8964845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"RBMY evolved on the Y chromosome from a ubiquitously transcribed X-Y identical gene, supporting a transposition-amplification model for RBMY gene family evolution.\",\n      \"method\": \"Comparative genomic and sequence analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular evidence for evolutionary origin\",\n      \"pmids\": [\"10391207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The RBMY gene family structure and organization on the Y chromosome was characterized: seven RBMY genes in interval 6, four with normal 12-exon/15-kb structure, one pseudogene lacking the first 3 exons, and two belonging to a subfamily resembling ancestral hnRNPG with only one SRGY repeat; most RBMY genes in interval 6 are arranged in tandem. This supports the transposition-amplification hypothesis for RBMY evolution from an autosomal hnRNPG gene.\",\n      \"method\": \"Genomic cloning, restriction mapping, sequencing of RBMY genes from YAC clones\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct structural characterization of multiple gene copies\",\n      \"pmids\": [\"9598316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RBMY1A1 (RBM) protein interacts with T-STAR (a novel SAM68-related RNA-binding protein expressed primarily in testis) via yeast two-hybrid screen. T-STAR co-localizes with RBM in germ cells and is regulated during meiosis, suggesting that RBM and T-STAR/SAM68 participate in a common RNA-processing pathway in male germ cells.\",\n      \"method\": \"Yeast two-hybrid screen of testis cDNA library, cDNA cloning, chromosomal mapping, GFP transfection and nuclear localization studies\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid identification of binding partner with supporting localization data\",\n      \"pmids\": [\"10332027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RBMY1A1 has a homologue on the human X chromosome (RBMX), indicating that RBMY evolved from an ancestral X-Y identical gene.\",\n      \"method\": \"Comparative genomic analysis, sequence characterization\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct molecular identification of X-chromosome homologue\",\n      \"pmids\": [\"10391206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"RBMY1A1 (RBM) protein directly interacts with SR family splicing factors and with itself (self-interaction). The protein domains mediating these interactions were mapped, and a bacterially expressed RBM interaction region pulls down functionally active SR proteins from cell extracts. Depletion/add-back experiments showed that SR proteins bound by RBM are required for splicing of a panel of pre-mRNAs, establishing RBM as a germ cell-specific cofactor for SR protein-dependent pre-mRNA splicing.\",\n      \"method\": \"Protein-protein interaction assays, domain mapping, bacterial fusion protein expression, pull-down from cell extracts, depletion and add-back splicing experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical interaction mapping plus functional splicing reconstitution with depletion/add-back\",\n      \"pmids\": [\"10823932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"RBMY1A1 (RBM) and other hnRNP G family proteins interact with Tra2beta (an SR-like splicing activator highly expressed in testis). Phosphorylation enhances this interaction and reduces competing RNA binding. RBM and Tra2beta co-localize in two major domains in human spermatocyte nuclei. Incubation with the RBM protein interaction domain inhibits splicing in vitro of a pre-mRNA substrate containing a Tra2beta-dependent enhancer, and the RBM RNA-binding domain affects 5' splice site selection.\",\n      \"method\": \"Co-immunoprecipitation, in vitro splicing inhibition assay, immunofluorescence co-localization in human spermatocytes, domain interaction mapping, phosphorylation experiments\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro splicing, co-IP, and direct localization in relevant cell type\",\n      \"pmids\": [\"10749975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"RBMY1A1 (RBMY) and related proteins (hnRNP G-T, T-STAR) are part of a network of RNA-processing regulatory interactions involving SR proteins and signal transduction pathways, with RBMY providing a germ cell-specific component for pre-mRNA splicing regulation important for normal germ cell development.\",\n      \"method\": \"Review of protein interaction network data, yeast two-hybrid, co-IP studies\",\n      \"journal\": \"International journal of andrology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — review/synthesis, no new primary experiments\",\n      \"pmids\": [\"15595951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The RBMY1A1 RRM (RNA recognition motif) domain recognizes RNA stem-loops capped by a C(A)/(U)CAA pentaloop with high affinity. NMR structure determination of the hRBMY RRM in complex with target RNA revealed two distinct binding modes: (1) the RRM beta-sheet surface contacts the RNA loop in a sequence-specific manner (conserved with hnRNP G), and (2) uniquely to hRBMY, the beta2-beta3 loop inserts into the major groove of the RNA stem—a novel recognition mode not found in the paralogous hnRNP G.\",\n      \"method\": \"SELEX (systematic evolution of ligands by exponential enrichment), NMR structural determination of protein-RNA complex\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution NMR structure of protein-RNA complex with identification of two distinct binding modes, novel mechanism validated\",\n      \"pmids\": [\"17318228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CIRP (cold-inducible RNA-binding protein), which is structurally highly similar to RBM1 (RBMY1A1), is expressed in mouse germ cell nuclei (particularly primary spermatocytes) and its expression is down-regulated at elevated temperatures, potentially linking temperature-sensitive spermatogenesis to RNA-binding protein function in germ cells.\",\n      \"method\": \"Immunohistochemistry, RT-PCR, cell culture temperature experiments, experimental cryptorchidism model\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — findings are about CIRP (not RBMY1A1 directly), included only for structural similarity context\",\n      \"pmids\": [\"9422546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RBMY acts as a novel inhibitor of glycogen synthase kinase 3β (GSK3β): cytoplasmic RBMY binds to and increases Ser9 phosphorylation-mediated inactivation of GSK3β, thereby impeding GSK3β-dependent degradation of β-catenin, leading to nuclear β-catenin accumulation and transcription of downstream oncogenes. This promotes tumor stemness, self-renewal, chemoresistance, and cell-cycle progression in hepatocellular carcinoma cells. Cytoplasmic translocation of RBMY is mediated by binding to the nuclear exporter CRM1 and is enhanced by Wnt-3a stimulation.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, xenograft tumor growth, loss-of-function and gain-of-function experiments, cell-cycle analysis, Western blot, immunohistochemistry\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, phosphorylation assay, in vivo xenograft, LOF/GOF) establishing mechanistic pathway\",\n      \"pmids\": [\"26185016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The Y-linked gene Rbmy1a1 is highly methylated in mature sperm and resists DNA demethylation post-fertilization. Aberrant hypomethylation of the Rbmy1a1 promoter (caused by loss of maternal TRIM28) results in ectopic activation of Rbmy1a1, causing male-specific peri-implantation lethality. Rbmy1a1 is a novel target of the TRIM28 complex, which protects its repressive epigenetic state during embryonic epigenetic reprogramming.\",\n      \"method\": \"Mouse genetic knockout (maternal Trim28 deletion), bisulfite sequencing, RNA expression analysis, embryo phenotyping\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with direct epigenetic mechanism (TRIM28-dependent methylation maintenance), specific lethality phenotype\",\n      \"pmids\": [\"28115466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBMY1A1-dependent sorting of miR-105-5p into exosomes from highly metastatic breast cancer cells facilitates the transformation of normal fibroblasts into cancer-associated fibroblasts (CAFs), which subsequently activates NF-κB signaling by downregulating LATS2 and promotes EMT of breast cancer cells.\",\n      \"method\": \"Exosome isolation, miRNA sequencing, loss-of-function (RBMY1A1 knockdown), co-culture fibroblast transformation assays, Western blot, NF-κB reporter assays\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct knockdown showing mechanistic role in miRNA sorting with defined downstream signaling pathway\",\n      \"pmids\": [\"40151143\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBMY1A1 encodes a germ cell-specific nuclear RNA-binding protein (RBM) that participates in pre-mRNA splicing regulation by directly interacting with SR splicing factors and Tra2beta, with the RRM domain recognizing RNA stem-loops via a unique dual-mode mechanism (beta-sheet surface plus beta2-beta3 loop insertion into the RNA major groove); its promoter is epigenetically silenced by the TRIM28 complex in somatic tissues (ectopic activation causes male-specific embryonic lethality), while in cancer contexts cytoplasmic RBMY acts as a GSK3β inhibitor to activate Wnt/β-catenin signaling and promote tumor stemness, and also facilitates exosomal miR-105-5p sorting to reprogram the tumor microenvironment.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RBMY1A1 is a Y-chromosome-encoded RNA-binding protein that evolved from the autosomal hnRNPG gene at least 130 million years ago and underwent primate-specific internal exon amplification generating repeated SRGY-box domains [PMID:9020837, PMID:8964845]. Its expression is restricted to testicular germ cells, where the promoter is maintained in a hypermethylated, repressed state in sperm and early embryos by the maternal TRIM28 complex; loss of maternal TRIM28 causes ectopic Rbmy1a1 activation and male-specific peri-implantation lethality [PMID:28115466]. Promoter hypermethylation also silences RBMY1A1 in testicular embryonal carcinoma [PMID:26625006]. In breast cancer cells, RBMY1A1 directs sorting of miR-105-5p into exosomes, enabling paracrine activation of NF-κB signaling in recipient fibroblasts [PMID:40151143].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Determining the genomic architecture of RBMY1A1 revealed a 12-exon gene with four tandemly repeated SRGY-box exons arising from internal duplication, establishing the structural basis for its protein domain organization.\",\n      \"evidence\": \"P1 library screening, cosmid subcloning, restriction mapping, and full genomic sequencing of the RBMY1A1 locus\",\n      \"pmids\": [\"8964845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No functional role assigned to the SRGY-box repeats\",\n        \"RNA targets of the RRM domain unknown\",\n        \"No loss-of-function data for RBMY1A1 in spermatogenesis\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Cross-species analysis showed RBMY1A1 diverged from autosomal hnRNPG ≥130 Mya and that SRGY-box amplification is primate-specific, explaining how the gene acquired unique domain architecture relative to its autosomal ancestor.\",\n      \"evidence\": \"Southern blotting, RT-PCR of marsupial testis RNA, and phylogenetic sequence analysis across mammals\",\n      \"pmids\": [\"9020837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of SRGY-box expansion not tested\",\n        \"Only a single marsupial species examined\",\n        \"Whether primate-specific amplification alters RNA-binding specificity is unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Localization of RBM-family expression to primary spermatocytes and its temperature sensitivity linked the RBMY1A1 gene family to temperature-dependent regulation of spermatogenesis.\",\n      \"evidence\": \"Immunohistochemistry in mouse and human testis sections and heat-stress cryptorchidism model, though data primarily concern the related cold-inducible RNA-binding protein CIRP\",\n      \"pmids\": [\"9422546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Data are for CIRP rather than RBMY1A1 directly; relevance to RBMY1A1 is inferred from family membership\",\n        \"No direct RBMY1A1 protein expression data under heat stress\",\n        \"No RNA targets identified\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery that RBMY1A1 promoter hypermethylation silences its expression in testicular embryonal carcinoma established epigenetic regulation as a mechanism controlling RBMY1A1 in germ cell tumors.\",\n      \"evidence\": \"Genome-wide CpG methylation array (Nimblegen) with quantitative RT-PCR and immunohistochemistry validation in human tumor samples\",\n      \"pmids\": [\"26625006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of RBMY1A1 silencing in tumor biology not tested\",\n        \"No demethylation rescue experiment to confirm causality\",\n        \"Correlation-based; no mechanistic link to tumorigenesis\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstration that the maternal TRIM28 complex maintains repressive DNA methylation at the Rbmy1a1 promoter during embryonic reprogramming, and that its loss causes ectopic Rbmy1a1 expression and male-specific peri-implantation lethality, revealed a critical epigenetic safeguard preventing inappropriate Y-gene activation.\",\n      \"evidence\": \"Maternal Trim28 conditional knockout mouse, bisulfite sequencing of Rbmy1a1 promoter, RNA expression analysis, and genetic epistasis with lethal phenotype\",\n      \"pmids\": [\"28115466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether ectopic RBMY1A1 protein is directly toxic or acts through RNA targets is unresolved\",\n        \"Rescue by Rbmy1a1 deletion in the TRIM28-null background not shown\",\n        \"Mechanism by which RBMY1A1 causes lethality is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of RBMY1A1 as a factor that sorts miR-105-5p into breast cancer exosomes, thereby activating NF-κB via LATS2 downregulation in recipient fibroblasts, revealed a somatic cancer context for this germ-cell protein's RNA-binding activity.\",\n      \"evidence\": \"Knockdown and overexpression of RBMY1A1 in breast cancer cells, exosome miRNA profiling, LATS2 reporter assay, NF-κB signaling assay, and fibroblast co-culture transformation assay\",\n      \"pmids\": [\"40151143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-laboratory study without independent replication\",\n        \"Direct physical interaction between RBMY1A1 and miR-105-5p not demonstrated (e.g., CLIP)\",\n        \"Mechanism by which RBMY1A1 is aberrantly expressed in breast cancer cells not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct RNA targets of RBMY1A1 in germ cells, the molecular mechanism by which its ectopic expression causes embryonic lethality, and whether the SRGY-box domains confer specificity for particular RNA substrates all remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No genome-wide RNA target identification (e.g., CLIP-seq) for RBMY1A1\",\n        \"No structural model of RRM or SRGY boxes bound to RNA\",\n        \"Role in normal spermatogenesis not established by direct loss-of-function in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0003723\",\n        \"supporting_discovery_ids\": [0, 1, 6]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005634\",\n        \"supporting_discovery_ids\": [2, 3]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-8953854\",\n        \"supporting_discovery_ids\": [0, 1, 6]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TRIM28\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"RBMY1A1 is a Y-chromosome-encoded, germ cell-specific nuclear RNA-binding protein that functions as a regulator of pre-mRNA splicing during spermatogenesis. It directly interacts with SR family splicing factors and the SR-like activator Tra2beta through its SRGY box domains, serving as a tissue-specific cofactor whose depletion abolishes splicing of SR-dependent pre-mRNAs; its RRM domain recognizes RNA stem-loops via a dual-mode mechanism involving canonical beta-sheet surface contacts and a unique beta2-beta3 loop insertion into the RNA major groove [PMID:10823932, PMID:10749975, PMID:17318228]. Loss of RBMY expression due to Y chromosome deletions results in germ cell arrest at early meiosis, consistent with an essential role in the transition to haploid spermatid development [PMID:9108067]. In somatic and cancer contexts, the RBMY1A1 promoter is normally silenced by TRIM28-dependent DNA methylation—ectopic activation causes male-specific embryonic lethality—while aberrant cytoplasmic RBMY in hepatocellular carcinoma inhibits GSK3β to activate Wnt/β-catenin signaling and promote tumor stemness [PMID:28115466, PMID:26185016].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of RBMY1A1 as a Y-linked, testis-specific RRM gene family deleted in infertile men established the first candidate gene for the azoospermia factor (AZF) locus and framed spermatogenesis as an RNA-processing-dependent process.\",\n      \"evidence\": \"cDNA cloning, Southern blot deletion mapping, RT-PCR of testis RNA in fertile vs. oligospermic men\",\n      \"pmids\": [\"8269511\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No functional assay demonstrated a direct requirement for RBMY in germ cell development at this stage\",\n        \"Precise RNA targets and molecular function of the RRM domain were unknown\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Protein-level analyses revealed that RBMY is a nuclear protein in male germ cells whose absence (via Y chromosome deletion) causes meiotic arrest before haploid differentiation, establishing a causal link between RBMY loss and spermatogenic failure.\",\n      \"evidence\": \"Immunohistochemistry across germ cell stages, Y chromosome deletion panel with defined testicular pathologies\",\n      \"pmids\": [\"9108067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which RBMY supports meiotic progression was not identified\",\n        \"Specific RNA substrates processed by RBMY in germ cells were unknown\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Evolutionary analyses established that RBMY arose from autosomal/X-linked hnRNPG by transposition to the Y chromosome and subsequent amplification, with conservation of testis-specific expression across therian mammals spanning >130 million years.\",\n      \"evidence\": \"Comparative genomics and RT-PCR in marsupials and eutherians; RBMX identification on human X chromosome\",\n      \"pmids\": [\"9020837\", \"10391206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional divergence between RBMY and its autosomal/X-linked homologues was not biochemically defined\",\n        \"Whether all ~30 Y-linked RBMY copies contribute to function was unclear\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Dynamic subnuclear co-localization of RBMY with pre-mRNA splicing factors in spermatocytes, followed by dissociation in late meiosis, provided the first spatial evidence linking RBMY to the splicing machinery in a stage-dependent manner.\",\n      \"evidence\": \"Co-immunofluorescence of RBMY and splicing factor antibodies across spermatogenic stages\",\n      \"pmids\": [\"9547301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Co-localization does not prove direct interaction with splicing factors\",\n        \"Identity of specific splicing partners was not established\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Biochemical reconstitution demonstrated that RBMY directly interacts with SR splicing factors and Tra2beta, and that the RBMY interaction domain can sequester active SR proteins to modulate pre-mRNA splicing in vitro, establishing RBMY as a germ cell-specific splicing co-regulator.\",\n      \"evidence\": \"Bacterial pull-down of SR proteins, depletion/add-back in vitro splicing assays, co-IP and immunofluorescence in spermatocytes, domain mapping\",\n      \"pmids\": [\"10823932\", \"10749975\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous pre-mRNA targets regulated by RBMY in germ cells were not identified\",\n        \"Whether RBMY activates or represses splicing of specific exons in vivo remained unclear\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"NMR structure of the RBMY RRM bound to its RNA target revealed a dual recognition mode—canonical beta-sheet/loop contacts plus a novel beta2-beta3 loop insertion into the RNA stem major groove—distinguishing RBMY from its paralog hnRNP G and explaining its unique RNA-binding specificity.\",\n      \"evidence\": \"SELEX identification of stem-loop RNA ligand; NMR structure determination of RRM-RNA complex\",\n      \"pmids\": [\"17318228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the dual-mode recognition is functionally required for splicing regulation in germ cells was not tested\",\n        \"Genome-wide identification of endogenous RNA targets recognized by this structural mode was not performed\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"In hepatocellular carcinoma, RBMY was found to translocate to the cytoplasm via CRM1 and inhibit GSK3β by promoting its Ser9 phosphorylation, leading to β-catenin stabilization and Wnt-driven stemness, revealing a non-canonical cytoplasmic signaling function distinct from its nuclear splicing role.\",\n      \"evidence\": \"Co-IP, phosphorylation assays, xenograft tumor models, gain-of-function and loss-of-function experiments in HCC cell lines\",\n      \"pmids\": [\"26185016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether cytoplasmic RBMY retains RNA-binding activity or functions entirely as a protein–protein scaffold was not resolved\",\n        \"Relevance of this mechanism beyond hepatocellular carcinoma was not established\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic epistasis experiments revealed that TRIM28-dependent DNA methylation maintains RBMY1A1 promoter silencing in somatic/embryonic tissues; loss of this methylation causes ectopic RBMY activation and male-specific peri-implantation lethality, explaining the evolutionary pressure for epigenetic silencing outside the germline.\",\n      \"evidence\": \"Maternal Trim28 knockout mice, bisulfite sequencing of Rbmy1a1 promoter, embryo RNA expression and phenotyping\",\n      \"pmids\": [\"28115466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream effectors of ectopic RBMY that cause lethality were not identified\",\n        \"Whether the lethal phenotype is mediated through splicing dysregulation or cytoplasmic signaling was not determined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"RBMY1A1 was shown to direct sorting of miR-105-5p into exosomes in metastatic breast cancer, with exosomal miR-105-5p reprogramming fibroblasts into cancer-associated fibroblasts via LATS2 downregulation and NF-κB activation, extending RBMY's oncogenic roles to exosomal RNA sorting and tumor microenvironment remodeling.\",\n      \"evidence\": \"RBMY1A1 knockdown, exosome isolation, miRNA sequencing, fibroblast co-culture transformation assays, NF-κB reporter\",\n      \"pmids\": [\"40151143\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for RBMY-mediated miRNA sorting into exosomes was not determined\",\n        \"Whether RRM-dependent RNA recognition drives miRNA selection was not tested\",\n        \"Independent replication in additional cancer models is lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous pre-mRNA targets of RBMY in spermatogenic cells remain unidentified genome-wide, and the mechanistic basis for how RBMY's splicing function in the nucleus relates to its cytoplasmic signaling and exosomal sorting activities in cancer is unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No CLIP-seq or equivalent transcriptome-wide mapping of RBMY RNA targets in germ cells has been reported\",\n        \"Structural basis for RBMY interaction with GSK3β versus SR proteins is unknown\",\n        \"Whether RBMY contributes to spermatogenic splicing programs through specific exon inclusion/skipping events has not been defined in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 11, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 4, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [10, 11, 13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TRA2B\",\n      \"KHDRBS3\",\n      \"GSK3B\",\n      \"XPO1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}