{"gene":"RBM26","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2020,"finding":"RBM26 (along with RBM27, ZC3H3, and PABPN1) is a component of the PAXT (Poly(A) Tail eXosome Targeting) connection required for nuclear RNA exosome-mediated degradation of polyadenylated RNA. Loss of RBM26 results in accumulation of PAXT substrates, establishing it as a limiting factor for PAXT activity.","method":"Characterization of nuclear pA+-RNA bound proteomes, MTR4-ZFC3H1 co-complex purification, knockdown/loss-of-function with substrate accumulation readout","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal complex purification, loss-of-function with defined molecular phenotype (substrate accumulation), multiple orthogonal methods in a focused study","pmids":["31950173"],"is_preprint":false},{"year":2024,"finding":"ZFC3H1 (core PAXT component) adopts a 'closed' conformation when initially loaded co-transcriptionally, blocking exosome recruitment. Short RNAs with fewer exons preferentially recruit transient PAXT components ZC3H3 and RBM26/27 to the 3' end, which triggers ZFC3H1 'opening' and subsequent exosomal degradation, thereby determining RNA fate between export and decay.","method":"Functional dissection of ZFC3H1 conformational states, depletion of RBM26/27 and ZC3H3 with RNA fate readouts, co-transcriptional loading assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic model supported by multiple functional experiments in a single rigorous study with defined molecular phenotypes","pmids":["39461342"],"is_preprint":false},{"year":2023,"finding":"PABPN1 recruits RBM26 and RBM27 to promote splicing of last introns with weak 3' splice sites; this interaction involves the coiled-coil and RRM domain of RBM27 (and by extension RBM26), and tethering PABPN1 to non-polyadenylated transcripts is sufficient to promote splicing, indicating a direct role.","method":"PABPN1 depletion with intron retention readout, TurboID-MS interactome, tethering assay, domain interaction mapping","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TurboID-MS interactome plus functional tethering assay, single lab, domain-level interaction characterization","pmids":["37661812"],"is_preprint":false},{"year":2024,"finding":"In C. elegans, rbm-26 (ortholog of human RBM26/RBM27) encodes an RNA-binding protein that negatively regulates expression of the MALS-1 (MALSU1) mitoribosomal assembly factor by binding its mRNA. Loss of rbm-26 causes dramatic overexpression of mals-1 mRNA and MALS-1 protein, leading to mitochondrial dysfunction and axon degeneration during larval neurodevelopment; genetic epistasis shows MALS-1 overexpression is responsible for these defects.","method":"Biochemical mRNA-binding screen, C. elegans loss-of-function genetics, genetic epistasis (double mutant rescue), protein and mRNA quantification","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical binding assay identifying mRNA substrate, genetic epistasis confirming pathway position, multiple orthogonal methods in a focused study","pmids":["39480871"],"is_preprint":false},{"year":2024,"finding":"Autism-associated missense variants in C. elegans rbm-26 (RBM26/27 ortholog) cause a sharp decrease in RBM-26 protein expression and produce axon overlap and axon degeneration phenotypes during larval development, mechanistically linking disease-associated variants to loss of RBM-26 protein stability and downstream MALS-1 dysregulation.","method":"Missense variant introduction in C. elegans, protein expression quantification, axon morphology phenotyping","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo variant analysis with protein quantification and defined cellular phenotype, single lab","pmids":["39480871"],"is_preprint":false},{"year":2024,"finding":"Preprint version confirms rbm-26 (C. elegans RBM26/27 ortholog) binds mals-1 mRNA and negatively regulates its expression; loss of rbm-26 overexpresses MALS-1 and causes mitochondrial and axon degeneration defects reversed by reducing mals-1, consistent with the published peer-reviewed findings.","method":"Biochemical screen, genetics, mRNA/protein quantification in C. elegans","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint with same evidence as published study; included for completeness but superseded by peer-reviewed paper","pmids":["37873356"],"is_preprint":true},{"year":2025,"finding":"In fission yeast S. japonicus, the RBM26/27 ortholog Rmn1 interacts with Pab2/PABPN1 and participates in constitutive heterochromatin formation at centromeres; Rmn1 can also interact with the H3K9 methyltransferase Clr4, placing it in a complex required for heterochromatin assembly.","method":"Co-immunoprecipitation, genetic deletion analysis (Pab2 N-terminal deletion disrupting interaction), chromatin/histone methylation assays at centromeres","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and deletion genetics in a model organism ortholog, single lab, multiple methods but indirect relevance to human RBM26","pmids":["40163528"],"is_preprint":false},{"year":2017,"finding":"RBM26 was identified as a mono-methylated arginine (MMA)-containing protein in EBV-transformed B-cells, co-immunoprecipitated using an MMA-RG-repeat-specific antibody and confirmed by immunoprecipitation and/or Western blot, indicating RBM26 harbors MMA post-translational modifications on its RG repeat sequences.","method":"Immunoprecipitation with MMA-specific monoclonal antibody, mass spectrometry, Western blot confirmation","journal":"The Journal of general virology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS identification confirmed by WB, no functional follow-up on RBM26 specifically","pmids":["28758620"],"is_preprint":false}],"current_model":"RBM26 is a nuclear RNA-binding protein (containing RG repeats subject to arginine methylation) that functions as a transient/limiting component of the PAXT complex, where it is recruited to the 3' ends of short nuclear polyadenylated RNAs to trigger ZFC3H1 'opening' and exosome-mediated RNA degradation; it also interacts with PABPN1 to promote splicing of terminal introns with weak 3' splice sites, and its C. elegans ortholog rbm-26 directly binds mals-1 mRNA to repress expression of the MALSU1 mitoribosomal assembly factor, thereby protecting neurons from mitochondrial dysfunction and axon degeneration."},"narrative":{"mechanistic_narrative":"RBM26 is a nuclear RNA-binding protein that governs the fate of nuclear polyadenylated RNAs by coupling transcript features to exosome-mediated decay and to splicing of terminal introns [PMID:31950173, PMID:37661812]. As a limiting, transient component of the PAXT connection (with RBM27, ZC3H3, and PABPN1), RBM26 is recruited to the 3' ends of short, exon-poor polyadenylated RNAs, where it cooperates with ZC3H3 to trigger 'opening' of the core PAXT factor ZFC3H1 from its co-transcriptionally loaded closed conformation, thereby licensing exosomal degradation and steering transcripts away from export [PMID:31950173, PMID:39461342]. In a distinct branch, RBM26 is recruited by PABPN1 to promote splicing of last introns bearing weak 3' splice sites [PMID:37661812]. Studies of the C. elegans ortholog rbm-26 establish a direct post-transcriptional repressor role: it binds mals-1 (MALSU1) mRNA to limit expression of this mitoribosomal assembly factor, protecting developing neurons from mitochondrial dysfunction and axon degeneration; autism-associated missense variants destabilize the protein and recapitulate these axonal defects [PMID:39480871].","teleology":[{"year":2017,"claim":"Established that RBM26 carries arginine methylation, raising the question of whether its RG repeats are post-translationally regulated.","evidence":"Immunoprecipitation with an MMA-RG-repeat-specific antibody and mass spectrometry in EBV-transformed B-cells","pmids":["28758620"],"confidence":"Low","gaps":["Single Co-IP/MS identification with no functional follow-up on RBM26 specifically","Methyltransferase responsible and functional consequence of methylation unknown"]},{"year":2020,"claim":"Placed RBM26 in the nuclear RNA decay machinery by identifying it as a limiting component of the PAXT connection required for exosomal degradation of polyadenylated RNA.","evidence":"Nuclear pA+-RNA proteome characterization, MTR4-ZFC3H1 co-complex purification, and loss-of-function with substrate accumulation readout","pmids":["31950173"],"confidence":"High","gaps":["Direct RNA target spectrum of RBM26 within PAXT not defined","Whether RBM26 and RBM27 act redundantly or distinctly unresolved"]},{"year":2023,"claim":"Revealed a non-decay function: PABPN1 recruits RBM26/27 to promote splicing of terminal introns with weak 3' splice sites, expanding its role beyond degradation.","evidence":"PABPN1 depletion with intron retention readout, TurboID-MS interactome, tethering assay, and domain mapping","pmids":["37661812"],"confidence":"Medium","gaps":["RBM26-specific (vs RBM27) contribution to splicing not separated","Mechanism by which weak 3' splice sites are selected is unclear"]},{"year":2024,"claim":"Defined how RBM26 acts mechanistically within PAXT, showing it (with ZC3H3) is recruited to 3' ends of short RNAs to trigger ZFC3H1 conformational opening that commits transcripts to decay.","evidence":"Functional dissection of ZFC3H1 closed/open states with RBM26/27 and ZC3H3 depletion and co-transcriptional loading assays","pmids":["39461342"],"confidence":"High","gaps":["Structural basis of RBM26-induced ZFC3H1 opening not resolved","Features beyond exon number that mark a transcript for RBM26 recruitment undefined"]},{"year":2024,"claim":"Demonstrated a direct, conserved post-transcriptional repressor activity: the ortholog rbm-26 binds mals-1 mRNA to limit MALSU1 expression and protect neurons from mitochondrial dysfunction and axon degeneration, and disease-associated variants destabilize the protein to recapitulate defects.","evidence":"Biochemical mRNA-binding screen, C. elegans loss-of-function and missense-variant genetics, epistasis, and protein/mRNA quantification (peer-reviewed plus corresponding preprint)","pmids":["39480871","37873356"],"confidence":"High","gaps":["Whether human RBM26 represses MALSU1 mRNA equivalently not shown","Connection between mRNA repression and the PAXT/splicing functions unestablished"]},{"year":null,"claim":"How RBM26's three reported activities—PAXT-mediated decay, terminal-intron splicing, and direct mRNA target repression—are integrated within one protein, and whether they share an RNA-binding determinant, remains open.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking decay, splicing, and target-specific repression","Human RBM26 RNA target set not directly mapped","Functional role of RG-repeat arginine methylation in any of these activities unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2]}],"complexes":["PAXT connection"],"partners":["RBM27","ZC3H3","PABPN1","ZFC3H1","MTR4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T8P6","full_name":"RNA-binding protein 26","aliases":["CTCL tumor antigen se70-2","RNA-binding motif protein 26"],"length_aa":1007,"mass_kda":113.6,"function":"May be involved in the turnover of nuclear polyadenylated (pA+) RNA","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q5T8P6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM26","classification":"Not Classified","n_dependent_lines":9,"n_total_lines":1208,"dependency_fraction":0.0074503311258278145},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"SRPK2","stoichiometry":0.2},{"gene":"TNPO3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RBM26","total_profiled":1310},"omim":[{"mim_id":"620082","title":"RNA-BINDING MOTIF PROTEIN 27; RBM27","url":"https://www.omim.org/entry/620082"},{"mim_id":"620081","title":"RNA-BINDING MOTIF PROTEIN 26; RBM26","url":"https://www.omim.org/entry/620081"},{"mim_id":"618640","title":"ZINC FINGER CCCH DOMAIN-CONTAINING PROTEIN 3; ZC3H3","url":"https://www.omim.org/entry/618640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM26"},"hgnc":{"alias_symbol":["PRO1777","SE70-2","FLJ20957","ZC3H17","ARRS2","PPP1R132"],"prev_symbol":["C13orf10"]},"alphafold":{"accession":"Q5T8P6","domains":[{"cath_id":"3.30.70.330","chopping":"532-602","consensus_level":"high","plddt":90.0668,"start":532,"end":602},{"cath_id":"3.30.70.330","chopping":"889-967","consensus_level":"medium","plddt":81.8232,"start":889,"end":967},{"cath_id":"1.20.1390","chopping":"9-77","consensus_level":"high","plddt":85.1557,"start":9,"end":77},{"cath_id":"1.20.58","chopping":"736-791","consensus_level":"medium","plddt":91.1916,"start":736,"end":791}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T8P6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T8P6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T8P6-F1-predicted_aligned_error_v6.png","plddt_mean":57.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM26","jax_strain_url":"https://www.jax.org/strain/search?query=RBM26"},"sequence":{"accession":"Q5T8P6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T8P6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T8P6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T8P6"}},"corpus_meta":[{"pmid":"15161670","id":"PMC_15161670","title":"Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/15161670","citation_count":87,"is_preprint":false},{"pmid":"31950173","id":"PMC_31950173","title":"The human ZC3H3 and RBM26/27 proteins are critical for PAXT-mediated nuclear RNA decay.","date":"2020","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/31950173","citation_count":62,"is_preprint":false},{"pmid":"26387816","id":"PMC_26387816","title":"Molecular and Biochemical Characterization of a Novel Xylanase from Massilia sp. RBM26 Isolated from the Feces of Rhinopithecus bieti.","date":"2016","source":"Journal of microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26387816","citation_count":33,"is_preprint":false},{"pmid":"37661812","id":"PMC_37661812","title":"The polyA tail facilitates splicing of last introns with weak 3' splice sites via PABPN1.","date":"2023","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/37661812","citation_count":23,"is_preprint":false},{"pmid":"22737227","id":"PMC_22737227","title":"Genome-wide profiling of pluripotent cells reveals a unique molecular signature of human embryonic germ cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22737227","citation_count":17,"is_preprint":false},{"pmid":"31109875","id":"PMC_31109875","title":"Characterization of a novel salt-, xylose- and alkali-tolerant GH43 bifunctional β-xylosidase/α-l-arabinofuranosidase from the gut bacterial genome.","date":"2019","source":"Journal of 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the PAXT (Poly(A) Tail eXosome Targeting) connection required for nuclear RNA exosome-mediated degradation of polyadenylated RNA. Loss of RBM26 results in accumulation of PAXT substrates, establishing it as a limiting factor for PAXT activity.\",\n      \"method\": \"Characterization of nuclear pA+-RNA bound proteomes, MTR4-ZFC3H1 co-complex purification, knockdown/loss-of-function with substrate accumulation readout\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal complex purification, loss-of-function with defined molecular phenotype (substrate accumulation), multiple orthogonal methods in a focused study\",\n      \"pmids\": [\"31950173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZFC3H1 (core PAXT component) adopts a 'closed' conformation when initially loaded co-transcriptionally, blocking exosome recruitment. Short RNAs with fewer exons preferentially recruit transient PAXT components ZC3H3 and RBM26/27 to the 3' end, which triggers ZFC3H1 'opening' and subsequent exosomal degradation, thereby determining RNA fate between export and decay.\",\n      \"method\": \"Functional dissection of ZFC3H1 conformational states, depletion of RBM26/27 and ZC3H3 with RNA fate readouts, co-transcriptional loading assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic model supported by multiple functional experiments in a single rigorous study with defined molecular phenotypes\",\n      \"pmids\": [\"39461342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PABPN1 recruits RBM26 and RBM27 to promote splicing of last introns with weak 3' splice sites; this interaction involves the coiled-coil and RRM domain of RBM27 (and by extension RBM26), and tethering PABPN1 to non-polyadenylated transcripts is sufficient to promote splicing, indicating a direct role.\",\n      \"method\": \"PABPN1 depletion with intron retention readout, TurboID-MS interactome, tethering assay, domain interaction mapping\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TurboID-MS interactome plus functional tethering assay, single lab, domain-level interaction characterization\",\n      \"pmids\": [\"37661812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In C. elegans, rbm-26 (ortholog of human RBM26/RBM27) encodes an RNA-binding protein that negatively regulates expression of the MALS-1 (MALSU1) mitoribosomal assembly factor by binding its mRNA. Loss of rbm-26 causes dramatic overexpression of mals-1 mRNA and MALS-1 protein, leading to mitochondrial dysfunction and axon degeneration during larval neurodevelopment; genetic epistasis shows MALS-1 overexpression is responsible for these defects.\",\n      \"method\": \"Biochemical mRNA-binding screen, C. elegans loss-of-function genetics, genetic epistasis (double mutant rescue), protein and mRNA quantification\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical binding assay identifying mRNA substrate, genetic epistasis confirming pathway position, multiple orthogonal methods in a focused study\",\n      \"pmids\": [\"39480871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Autism-associated missense variants in C. elegans rbm-26 (RBM26/27 ortholog) cause a sharp decrease in RBM-26 protein expression and produce axon overlap and axon degeneration phenotypes during larval development, mechanistically linking disease-associated variants to loss of RBM-26 protein stability and downstream MALS-1 dysregulation.\",\n      \"method\": \"Missense variant introduction in C. elegans, protein expression quantification, axon morphology phenotyping\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo variant analysis with protein quantification and defined cellular phenotype, single lab\",\n      \"pmids\": [\"39480871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Preprint version confirms rbm-26 (C. elegans RBM26/27 ortholog) binds mals-1 mRNA and negatively regulates its expression; loss of rbm-26 overexpresses MALS-1 and causes mitochondrial and axon degeneration defects reversed by reducing mals-1, consistent with the published peer-reviewed findings.\",\n      \"method\": \"Biochemical screen, genetics, mRNA/protein quantification in C. elegans\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint with same evidence as published study; included for completeness but superseded by peer-reviewed paper\",\n      \"pmids\": [\"37873356\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In fission yeast S. japonicus, the RBM26/27 ortholog Rmn1 interacts with Pab2/PABPN1 and participates in constitutive heterochromatin formation at centromeres; Rmn1 can also interact with the H3K9 methyltransferase Clr4, placing it in a complex required for heterochromatin assembly.\",\n      \"method\": \"Co-immunoprecipitation, genetic deletion analysis (Pab2 N-terminal deletion disrupting interaction), chromatin/histone methylation assays at centromeres\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and deletion genetics in a model organism ortholog, single lab, multiple methods but indirect relevance to human RBM26\",\n      \"pmids\": [\"40163528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RBM26 was identified as a mono-methylated arginine (MMA)-containing protein in EBV-transformed B-cells, co-immunoprecipitated using an MMA-RG-repeat-specific antibody and confirmed by immunoprecipitation and/or Western blot, indicating RBM26 harbors MMA post-translational modifications on its RG repeat sequences.\",\n      \"method\": \"Immunoprecipitation with MMA-specific monoclonal antibody, mass spectrometry, Western blot confirmation\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS identification confirmed by WB, no functional follow-up on RBM26 specifically\",\n      \"pmids\": [\"28758620\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM26 is a nuclear RNA-binding protein (containing RG repeats subject to arginine methylation) that functions as a transient/limiting component of the PAXT complex, where it is recruited to the 3' ends of short nuclear polyadenylated RNAs to trigger ZFC3H1 'opening' and exosome-mediated RNA degradation; it also interacts with PABPN1 to promote splicing of terminal introns with weak 3' splice sites, and its C. elegans ortholog rbm-26 directly binds mals-1 mRNA to repress expression of the MALSU1 mitoribosomal assembly factor, thereby protecting neurons from mitochondrial dysfunction and axon degeneration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM26 is a nuclear RNA-binding protein that governs the fate of nuclear polyadenylated RNAs by coupling transcript features to exosome-mediated decay and to splicing of terminal introns [#0, #2]. As a limiting, transient component of the PAXT connection (with RBM27, ZC3H3, and PABPN1), RBM26 is recruited to the 3' ends of short, exon-poor polyadenylated RNAs, where it cooperates with ZC3H3 to trigger 'opening' of the core PAXT factor ZFC3H1 from its co-transcriptionally loaded closed conformation, thereby licensing exosomal degradation and steering transcripts away from export [#0, #1]. In a distinct branch, RBM26 is recruited by PABPN1 to promote splicing of last introns bearing weak 3' splice sites [#2]. Studies of the C. elegans ortholog rbm-26 establish a direct post-transcriptional repressor role: it binds mals-1 (MALSU1) mRNA to limit expression of this mitoribosomal assembly factor, protecting developing neurons from mitochondrial dysfunction and axon degeneration; autism-associated missense variants destabilize the protein and recapitulate these axonal defects [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that RBM26 carries arginine methylation, raising the question of whether its RG repeats are post-translationally regulated.\",\n      \"evidence\": \"Immunoprecipitation with an MMA-RG-repeat-specific antibody and mass spectrometry in EBV-transformed B-cells\",\n      \"pmids\": [\"28758620\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP/MS identification with no functional follow-up on RBM26 specifically\", \"Methyltransferase responsible and functional consequence of methylation unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed RBM26 in the nuclear RNA decay machinery by identifying it as a limiting component of the PAXT connection required for exosomal degradation of polyadenylated RNA.\",\n      \"evidence\": \"Nuclear pA+-RNA proteome characterization, MTR4-ZFC3H1 co-complex purification, and loss-of-function with substrate accumulation readout\",\n      \"pmids\": [\"31950173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA target spectrum of RBM26 within PAXT not defined\", \"Whether RBM26 and RBM27 act redundantly or distinctly unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a non-decay function: PABPN1 recruits RBM26/27 to promote splicing of terminal introns with weak 3' splice sites, expanding its role beyond degradation.\",\n      \"evidence\": \"PABPN1 depletion with intron retention readout, TurboID-MS interactome, tethering assay, and domain mapping\",\n      \"pmids\": [\"37661812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RBM26-specific (vs RBM27) contribution to splicing not separated\", \"Mechanism by which weak 3' splice sites are selected is unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined how RBM26 acts mechanistically within PAXT, showing it (with ZC3H3) is recruited to 3' ends of short RNAs to trigger ZFC3H1 conformational opening that commits transcripts to decay.\",\n      \"evidence\": \"Functional dissection of ZFC3H1 closed/open states with RBM26/27 and ZC3H3 depletion and co-transcriptional loading assays\",\n      \"pmids\": [\"39461342\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RBM26-induced ZFC3H1 opening not resolved\", \"Features beyond exon number that mark a transcript for RBM26 recruitment undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a direct, conserved post-transcriptional repressor activity: the ortholog rbm-26 binds mals-1 mRNA to limit MALSU1 expression and protect neurons from mitochondrial dysfunction and axon degeneration, and disease-associated variants destabilize the protein to recapitulate defects.\",\n      \"evidence\": \"Biochemical mRNA-binding screen, C. elegans loss-of-function and missense-variant genetics, epistasis, and protein/mRNA quantification (peer-reviewed plus corresponding preprint)\",\n      \"pmids\": [\"39480871\", \"37873356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether human RBM26 represses MALSU1 mRNA equivalently not shown\", \"Connection between mRNA repression and the PAXT/splicing functions unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBM26's three reported activities—PAXT-mediated decay, terminal-intron splicing, and direct mRNA target repression—are integrated within one protein, and whether they share an RNA-binding determinant, remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking decay, splicing, and target-specific repression\", \"Human RBM26 RNA target set not directly mapped\", \"Functional role of RG-repeat arginine methylation in any of these activities unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [\"PAXT connection\"],\n    \"partners\": [\"RBM27\", \"ZC3H3\", \"PABPN1\", \"ZFC3H1\", \"MTR4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}