{"gene":"RBM42","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2008,"finding":"RBM42 directly binds hnRNP K both in vivo and in vitro, co-localizes with hnRNP K in the nucleus, and both proteins relocalize to stress granules upon treatment with puromycin, sorbitol, or arsenite. RBM42 also directly binds the 3' UTR of p21 mRNA. Simultaneous depletion of RBM42 and hnRNP K enhances the ATP depletion phenotype seen with hnRNP K knockdown alone, indicating a cooperative role in maintaining cellular ATP levels under stress.","method":"Co-immunoprecipitation, in vitro binding assay, RNA immunoprecipitation, RNAi knockdown, immunofluorescence/co-localization, ATP level measurement","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal in vivo/in vitro binding assays, co-localization, and functional knockdown phenotype, single lab with multiple orthogonal methods","pmids":["19170760"],"is_preprint":false},{"year":2013,"finding":"The Toxoplasma gondii ortholog TgRRM1 (containing a single RNA-recognition motif) is required for G1 cell cycle progression; loss-of-function causes a splicing defect affecting cell cycle and constitutively expressed mRNAs. TgRRM1 interacts with components of the tri-snRNP complex (U4/U6 & U5 snRNPs), indicating a role in assembling an active spliceosome. Human RBM42 can functionally replace TgRRM1 in vivo, establishing RBM42 as a conserved splicing regulator.","method":"Temperature-sensitive mutant analysis, transcriptome profiling, co-immunoprecipitation with spliceosome components, functional complementation with human RBM42","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation and interaction with spliceosome components established, single lab but multiple orthogonal methods","pmids":["23437009"],"is_preprint":false},{"year":2017,"finding":"m6A modification disrupts RNA binding by RBM42 (and stress granule proteins G3BP1/2, USP10, CAPRIN1), as identified by photo-cross-linking with diazirine-containing RNA probes and quantitative proteomics. This indicates RBM42 is a reader/sensor of m6A that is negatively regulated by this modification.","method":"Photo-cross-linking chemical proteomics with diazirine-containing m6A RNA probes, quantitative mass spectrometry","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro chemical proteomics reconstitution with synthetic probes, single lab, single method","pmids":["29140688"],"is_preprint":false},{"year":2019,"finding":"MYC-sensitive RNA-binding proteins SRSF1 and RBM42 interact with 5'UTR sequence motifs to mediate MYC-driven changes in mRNA translation efficiency, including translation of electron transport chain components in lymphoma cells.","method":"Polysome profiling, ribosome profiling, RNA-binding protein interaction analysis with 5'UTR motifs in lymphoma cells","journal":"The Journal of experimental medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic association described but molecular details of RBM42's specific contribution are not deeply resolved in the abstract; single study","pmids":["31142587"],"is_preprint":false},{"year":2021,"finding":"The Fusarium ortholog FgRbp1 (rescued by human RBM42) binds the motif CAAGR in target mRNAs and interacts with splicing factor FgU2AF23 (a U2AF small subunit involved in 3' splice site recognition), enhancing recruitment of FgU2AF23 to target mRNAs and promoting their splicing. This defines a sequence-dependent splicing regulatory mechanism conserved in human RBM42.","method":"Deletion mutant analysis, RNA immunoprecipitation (motif binding), co-immunoprecipitation (FgRbp1–FgU2AF23), functional complementation with human RBM42, RNA-seq splicing analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ortholog functional complementation plus Co-IP and RNA binding motif identification, single lab with multiple orthogonal methods","pmids":["33976182"],"is_preprint":false},{"year":2023,"finding":"RBM42 facilitates CDKN1A (p21) pre-mRNA splicing by counteracting the splicing-inhibitory effect of RBM4. RBM42 also promotes translation of CDKN1A and other splicing targets. Genome-wide eCLIP mapping confirms direct RBM42–RNA interactions at both splicing and translation targets, demonstrating a dual role coupling splicing and translation machineries during DNA damage response.","method":"eCLIP (transcriptome-wide RNA interaction mapping), ribosome profiling/polysome analysis, siRNA knockdown, RNA-seq, interactome analysis, co-depletion of RBM4 and RBM42","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — eCLIP plus ribosome profiling plus genetic epistasis (RBM4 counteraction) plus loss-of-function phenotype, multiple orthogonal methods in one rigorous study","pmids":["37993446"],"is_preprint":false},{"year":2024,"finding":"The RBM42 p.A438T variant (in the RRM domain) impairs RBM42 protein stability in vivo and disrupts its interaction with hnRNP K. Biallelic loss-of-function in RBM42 causes a neurodevelopmental syndrome in humans. Mouse compound heterozygous Rbm42 mutants die by E13.5 with gross developmental defects, and RNA-seq confirms RBM42 is required for normal alternative splicing in neurological and myocardial development.","method":"Whole-exome sequencing, in vivo protein stability assay, co-immunoprecipitation (RBM42–hnRNP K interaction), functional complementation in Fusarium ΔFgRbp1, mouse compound heterozygous model, RNA-seq alternative splicing analysis","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vivo stability, mouse model, RNA-seq, complementation), replicated across human patient, mouse, and fungal systems","pmids":["37294900"],"is_preprint":false},{"year":2025,"finding":"RBM42 selectively binds and remodels the MYC 5'UTR RNA structure, facilitating formation of the translation pre-initiation complex and driving selective translation of MYC, JUN, and EGFR mRNAs. RBM42 is a ribosome-associated protein (RAP) identified by IP-mass spectrometry, and is necessary for PDAC tumorigenesis in a Myc-dependent manner in vivo.","method":"CRISPRi genome-wide screen, CLIP-seq, polysome sequencing, IP-mass spectrometry, DMS-Seq RNA structure probing, mutagenesis, xenograft mouse models","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPRi screen validation, CLIP-seq, RNA structure probing with mutagenesis, IP-MS, and in vivo xenograft, multiple orthogonal methods in one rigorous study","pmids":["39905246"],"is_preprint":false},{"year":2025,"finding":"In C. elegans, upon dendrite injury, IDR-1 (insulin-degrading enzyme ortholog) promotes nuclear export of RBM-42, enabling its localization to dendrites. RBM-42 then promotes translation of ced-7 (a phagocytosis pathway component) and facilitates microtubule assembly to drive dendrite regeneration. IDR-1 functions upstream of RBM-42, and RBM-42 functions upstream of CED-7 in this pathway.","method":"Forward genetic screen in C. elegans, genetic epistasis (idr-1, rbm-42, ced-7 double/single mutants), subcellular localization (nuclear export assay), translation reporter assay, dendrite regeneration imaging","journal":"bioRxiv : the preprint server for biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis and localization with functional consequence established in C. elegans, preprint, single lab","pmids":["41332648"],"is_preprint":true},{"year":2025,"finding":"Sensitivity to CMP76 (a compound that induces hnRNPK-dependent stress granule formation and MYC mRNA translational silencing) is significantly associated with RBM42 dependency across cancer cell lines, linking RBM42 functionally to the hnRNPK–MYC translation axis.","method":"High-throughput chemical screen, ribosome profiling, CETSA, subcellular localization studies, cancer cell line dependency correlation","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — associative dependency correlation rather than direct mechanistic experiment on RBM42; single study","pmids":["40943063"],"is_preprint":false}],"current_model":"RBM42 is a conserved RNA-binding protein with dual roles in pre-mRNA splicing and translation: it facilitates spliceosome assembly (interacting with U2AF/tri-snRNP components and counteracting RBM4-mediated splicing inhibition), while also acting as a ribosome-associated protein that remodels 5'UTR RNA structures (notably of MYC) to promote translation pre-initiation complex formation; it binds hnRNP K in the nucleus and at stress granules, is negatively regulated by m6A modification of its RNA targets, is required for DNA damage-induced p21 induction, and plays essential roles in embryonic development and cell cycle progression."},"narrative":{"mechanistic_narrative":"RBM42 is a conserved RNA-recognition-motif protein that couples pre-mRNA splicing to selective translation, acting as a node that links RNA processing to cellular stress responses, cell cycle progression, and development [PMID:37993446, PMID:37294900]. In splicing, it engages spliceosome assembly machinery — its orthologs bind sequence motifs in target mRNAs and recruit the U2AF small subunit involved in 3' splice site recognition and interact with tri-snRNP components, a function conserved through human RBM42 by complementation [PMID:23437009, PMID:33976182]. During the DNA damage response RBM42 promotes CDKN1A (p21) maturation by counteracting the splicing-inhibitory activity of RBM4, while genome-wide eCLIP shows it binds RNA at both splicing and translation targets, establishing a dual splicing-translation role [PMID:37993446]. As a ribosome-associated protein, RBM42 selectively binds and remodels the MYC 5'UTR RNA structure to promote translation pre-initiation complex formation, driving selective translation of MYC, JUN, and EGFR and supporting MYC-dependent tumorigenesis [PMID:31142587, PMID:39905246]. RBM42 directly binds hnRNP K and co-relocalizes with it to stress granules under stress, and this interaction is disrupted by a disease-associated RRM variant [PMID:19170760, PMID:37294900]. Biallelic loss-of-function in RBM42 causes a human neurodevelopmental syndrome, and Rbm42 mutant mice die in mid-embryogenesis with developmental defects and aberrant alternative splicing [PMID:37294900].","teleology":[{"year":2008,"claim":"Established RBM42 as a physical and functional partner of hnRNP K and a stress-responsive RNA-binding protein, the first mechanistic anchor for the protein.","evidence":"Co-IP, in vitro binding, RNA-IP, RNAi, and co-localization in human cells under stress","pmids":["19170760"],"confidence":"Medium","gaps":["Did not resolve which RNA-processing step RBM42 acts in","Functional consequence of p21 3'UTR binding not defined","Stress granule recruitment mechanism unknown"]},{"year":2013,"claim":"Identified RBM42's conserved role in spliceosome assembly and cell cycle progression by showing its Toxoplasma ortholog interacts with tri-snRNP components and is functionally replaceable by human RBM42.","evidence":"Temperature-sensitive mutant, transcriptome profiling, Co-IP with spliceosome components, and complementation with human RBM42","pmids":["23437009"],"confidence":"Medium","gaps":["Did not define the RNA sequence specificity of RBM42","Direct human substrates not mapped","Mechanism of spliceosome assembly contribution unresolved"]},{"year":2017,"claim":"Defined RBM42 as an m6A-sensitive RNA binder whose RNA association is disrupted by the modification, placing it among m6A-regulated stress granule factors.","evidence":"Photo-cross-linking chemical proteomics with diazirine m6A RNA probes and quantitative mass spectrometry in vitro","pmids":["29140688"],"confidence":"Medium","gaps":["In vitro probe binding not validated on endogenous transcripts","Cellular consequence of m6A regulation of RBM42 not shown","No specific target context defined"]},{"year":2019,"claim":"Linked RBM42 to MYC-driven translational control by associating it with 5'UTR motifs governing translation efficiency in lymphoma.","evidence":"Polysome/ribosome profiling and 5'UTR motif RNA-binding analysis in lymphoma cells","pmids":["31142587"],"confidence":"Low","gaps":["RBM42's specific molecular contribution not resolved in this study","Direct 5'UTR binding not demonstrated structurally","Distinct from its splicing role not yet integrated"]},{"year":2021,"claim":"Resolved a sequence-dependent splicing mechanism: the Fusarium ortholog binds a defined motif and recruits the U2AF small subunit to promote 3' splice site recognition, conserved through human RBM42.","evidence":"Deletion mutants, RNA-IP motif mapping, Co-IP with FgU2AF23, complementation with human RBM42, and RNA-seq splicing analysis","pmids":["33976182"],"confidence":"Medium","gaps":["Human RBM42 motif specificity not directly mapped here","Whether U2AF recruitment operates identically in human cells untested","No structural basis for motif recognition"]},{"year":2023,"claim":"Unified RBM42's splicing and translation activities by showing it counteracts RBM4 to promote CDKN1A splicing and translation during DNA damage, with transcriptome-wide direct RNA binding.","evidence":"eCLIP, ribosome profiling, siRNA knockdown, RNA-seq, and RBM4/RBM42 co-depletion epistasis in human cells","pmids":["37993446"],"confidence":"High","gaps":["Molecular basis of RBM4 antagonism not defined","How splicing and translation roles are partitioned per transcript unclear","Upstream DNA-damage signaling to RBM42 unknown"]},{"year":2024,"claim":"Established RBM42 as a disease gene: biallelic loss-of-function causes a human neurodevelopmental syndrome, with an RRM variant destabilizing the protein and disrupting hnRNP K binding, and mouse loss causing embryonic lethality with splicing defects.","evidence":"Whole-exome sequencing, in vivo stability assay, Co-IP, Fusarium complementation, mouse compound heterozygous model, and RNA-seq","pmids":["37294900"],"confidence":"High","gaps":["Tissue-specific splicing targets driving phenotype not fully cataloged","Genotype-phenotype relationship of variant severity unresolved","Whether hnRNP K loss alone explains the syndrome unknown"]},{"year":2025,"claim":"Mechanistically defined RBM42's translational role: as a ribosome-associated protein it binds and remodels the MYC 5'UTR structure to enable pre-initiation complex formation and selective translation, driving MYC-dependent PDAC tumorigenesis.","evidence":"CRISPRi screen, CLIP-seq, polysome sequencing, IP-MS, DMS-Seq structure probing, mutagenesis, and xenograft models","pmids":["39905246"],"confidence":"High","gaps":["Structural detail of the remodeled 5'UTR not solved","How RBM42 partitions between nuclear splicing and ribosomal pools unclear","Generality of structure remodeling beyond MYC/JUN/EGFR untested"]},{"year":2025,"claim":"Extended RBM42's translational function to neuronal regeneration, showing IDR-1-driven nuclear export enables dendritic RBM-42 to promote ced-7 translation and microtubule assembly in C. elegans.","evidence":"Forward genetic screen, epistasis, nuclear export and translation reporter assays, and dendrite regeneration imaging (preprint)","pmids":["41332648"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Conservation of the IDR-1/RBM-42 axis in mammals untested","Mechanism of regulated nuclear export not defined"]},{"year":null,"claim":"How RBM42 is partitioned and switched between its nuclear spliceosome-assembly role and its cytoplasmic ribosome-associated 5'UTR-remodeling role, and how upstream signals (stress, DNA damage, m6A, regulated export) toggle these activities, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of RBM42 RNA recognition","Regulatory logic coupling splicing and translation undefined","In vivo m6A regulation of endogenous targets not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,4,5,7]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0045182","term_label":"translation regulator activity","supporting_discovery_ids":[5,7]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,4,5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7]}],"complexes":["spliceosome (tri-snRNP)","stress granule"],"partners":["HNRNPK","RBM4","U2AF (SMALL SUBUNIT)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BTD8","full_name":"RNA-binding protein 42","aliases":["RNA-binding motif protein 42"],"length_aa":480,"mass_kda":50.4,"function":"Binds (via the RRM domain) to the 3'-untranslated region (UTR) of CDKN1A mRNA","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BTD8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RBM42","classification":"Common Essential","n_dependent_lines":963,"n_total_lines":1208,"dependency_fraction":0.7971854304635762},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000126254","cell_line_id":"CID001487","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"RPL38","stoichiometry":10.0},{"gene":"LSM6","stoichiometry":10.0},{"gene":"RPL36AL;RPL36A;RPL36A-HNRNPH2","stoichiometry":10.0},{"gene":"DDX23","stoichiometry":10.0},{"gene":"PRRC2C","stoichiometry":10.0},{"gene":"SAP18","stoichiometry":10.0},{"gene":"PRPF6","stoichiometry":10.0},{"gene":"MFAP1","stoichiometry":4.0},{"gene":"USP10","stoichiometry":4.0},{"gene":"PRPF4B","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001487","total_profiled":1310},"omim":[{"mim_id":"620823","title":"RNA, U4 SMALL NUCLEAR 2; RNU4-2","url":"https://www.omim.org/entry/620823"},{"mim_id":"613232","title":"RNA-BINDING MOTIF PROTEIN 42; RBM42","url":"https://www.omim.org/entry/613232"},{"mim_id":"600712","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN K; HNRNPK","url":"https://www.omim.org/entry/600712"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RBM42"},"hgnc":{"alias_symbol":["MGC10433"],"prev_symbol":[]},"alphafold":{"accession":"Q9BTD8","domains":[{"cath_id":"3.30.70.330","chopping":"378-465","consensus_level":"high","plddt":91.5547,"start":378,"end":465}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTD8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTD8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTD8-F1-predicted_aligned_error_v6.png","plddt_mean":62.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RBM42","jax_strain_url":"https://www.jax.org/strain/search?query=RBM42"},"sequence":{"accession":"Q9BTD8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BTD8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BTD8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTD8"}},"corpus_meta":[{"pmid":"29140688","id":"PMC_29140688","title":"RNA Chemical Proteomics Reveals the N6-Methyladenosine (m6A)-Regulated Protein-RNA Interactome.","date":"2017","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/29140688","citation_count":221,"is_preprint":false},{"pmid":"19170760","id":"PMC_19170760","title":"hnRNP K interacts with RNA binding motif protein 42 and functions in the maintenance of cellular ATP level during stress conditions.","date":"2008","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/19170760","citation_count":72,"is_preprint":false},{"pmid":"31142587","id":"PMC_31142587","title":"c-MYC regulates mRNA translation efficiency and start-site selection in lymphoma.","date":"2019","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31142587","citation_count":39,"is_preprint":false},{"pmid":"31952466","id":"PMC_31952466","title":"Identification of biomarkers in common chronic lung diseases by co-expression networks and drug-target interactions analysis.","date":"2020","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/31952466","citation_count":37,"is_preprint":false},{"pmid":"23437009","id":"PMC_23437009","title":"Discovery of a splicing regulator required for cell cycle progression.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23437009","citation_count":33,"is_preprint":false},{"pmid":"33976182","id":"PMC_33976182","title":"The RNA binding protein FgRbp1 regulates specific pre-mRNA splicing via interacting with U2AF23 in Fusarium.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33976182","citation_count":25,"is_preprint":false},{"pmid":"21107721","id":"PMC_21107721","title":"Analyses of porcine public SNPs in coding-gene regions by re-sequencing and phenotypic association studies.","date":"2010","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21107721","citation_count":22,"is_preprint":false},{"pmid":"37993446","id":"PMC_37993446","title":"A dual role of RBM42 in modulating splicing and translation of CDKN1A/p21 during DNA damage response.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37993446","citation_count":21,"is_preprint":false},{"pmid":"37221550","id":"PMC_37221550","title":"Extracellular vesicle-microRNAs mediated response of bovine ovaries to seasonal environmental changes.","date":"2023","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/37221550","citation_count":16,"is_preprint":false},{"pmid":"33261069","id":"PMC_33261069","title":"Proteomic and Transcriptomic Analysis Identify Spliceosome as a Significant Component of the Molecular Machinery in the Pituitary Tumors Derived from POU1F1- and NR5A1-Cell Lineages.","date":"2020","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33261069","citation_count":11,"is_preprint":false},{"pmid":"39905246","id":"PMC_39905246","title":"Functional screen identifies RBM42 as a mediator of oncogenic mRNA translation specificity.","date":"2025","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39905246","citation_count":8,"is_preprint":false},{"pmid":"37294900","id":"PMC_37294900","title":"Biallelic variants in RBM42 cause a multisystem disorder with neurological, facial, cardiac, and musculoskeletal involvement.","date":"2024","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/37294900","citation_count":5,"is_preprint":false},{"pmid":"31209069","id":"PMC_31209069","title":"c-Myc steers translation in lymphoma.","date":"2019","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31209069","citation_count":5,"is_preprint":false},{"pmid":"40943063","id":"PMC_40943063","title":"Discovery of Small Molecules That Inhibit MYC mRNA Translation Through hnRNPK and Induction of Stress Granule-Mediated mRNA Relocalization.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40943063","citation_count":1,"is_preprint":false},{"pmid":"39416102","id":"PMC_39416102","title":"Functional screen for mediators of onco-mRNA translation specificity.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39416102","citation_count":0,"is_preprint":false},{"pmid":"41332648","id":"PMC_41332648","title":"Injury-induced nuclear export of RNA-binding proteins drives mRNA stabilization and translation to promote dendrite regeneration.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41332648","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9798,"output_tokens":2856,"usd":0.036117,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10169,"output_tokens":3538,"usd":0.069648,"stage2_stop_reason":"end_turn"},"total_usd":0.105765,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"RBM42 directly binds hnRNP K both in vivo and in vitro, co-localizes with hnRNP K in the nucleus, and both proteins relocalize to stress granules upon treatment with puromycin, sorbitol, or arsenite. RBM42 also directly binds the 3' UTR of p21 mRNA. Simultaneous depletion of RBM42 and hnRNP K enhances the ATP depletion phenotype seen with hnRNP K knockdown alone, indicating a cooperative role in maintaining cellular ATP levels under stress.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, RNA immunoprecipitation, RNAi knockdown, immunofluorescence/co-localization, ATP level measurement\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal in vivo/in vitro binding assays, co-localization, and functional knockdown phenotype, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19170760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The Toxoplasma gondii ortholog TgRRM1 (containing a single RNA-recognition motif) is required for G1 cell cycle progression; loss-of-function causes a splicing defect affecting cell cycle and constitutively expressed mRNAs. TgRRM1 interacts with components of the tri-snRNP complex (U4/U6 & U5 snRNPs), indicating a role in assembling an active spliceosome. Human RBM42 can functionally replace TgRRM1 in vivo, establishing RBM42 as a conserved splicing regulator.\",\n      \"method\": \"Temperature-sensitive mutant analysis, transcriptome profiling, co-immunoprecipitation with spliceosome components, functional complementation with human RBM42\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation and interaction with spliceosome components established, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23437009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"m6A modification disrupts RNA binding by RBM42 (and stress granule proteins G3BP1/2, USP10, CAPRIN1), as identified by photo-cross-linking with diazirine-containing RNA probes and quantitative proteomics. This indicates RBM42 is a reader/sensor of m6A that is negatively regulated by this modification.\",\n      \"method\": \"Photo-cross-linking chemical proteomics with diazirine-containing m6A RNA probes, quantitative mass spectrometry\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro chemical proteomics reconstitution with synthetic probes, single lab, single method\",\n      \"pmids\": [\"29140688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYC-sensitive RNA-binding proteins SRSF1 and RBM42 interact with 5'UTR sequence motifs to mediate MYC-driven changes in mRNA translation efficiency, including translation of electron transport chain components in lymphoma cells.\",\n      \"method\": \"Polysome profiling, ribosome profiling, RNA-binding protein interaction analysis with 5'UTR motifs in lymphoma cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic association described but molecular details of RBM42's specific contribution are not deeply resolved in the abstract; single study\",\n      \"pmids\": [\"31142587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Fusarium ortholog FgRbp1 (rescued by human RBM42) binds the motif CAAGR in target mRNAs and interacts with splicing factor FgU2AF23 (a U2AF small subunit involved in 3' splice site recognition), enhancing recruitment of FgU2AF23 to target mRNAs and promoting their splicing. This defines a sequence-dependent splicing regulatory mechanism conserved in human RBM42.\",\n      \"method\": \"Deletion mutant analysis, RNA immunoprecipitation (motif binding), co-immunoprecipitation (FgRbp1–FgU2AF23), functional complementation with human RBM42, RNA-seq splicing analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ortholog functional complementation plus Co-IP and RNA binding motif identification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33976182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RBM42 facilitates CDKN1A (p21) pre-mRNA splicing by counteracting the splicing-inhibitory effect of RBM4. RBM42 also promotes translation of CDKN1A and other splicing targets. Genome-wide eCLIP mapping confirms direct RBM42–RNA interactions at both splicing and translation targets, demonstrating a dual role coupling splicing and translation machineries during DNA damage response.\",\n      \"method\": \"eCLIP (transcriptome-wide RNA interaction mapping), ribosome profiling/polysome analysis, siRNA knockdown, RNA-seq, interactome analysis, co-depletion of RBM4 and RBM42\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — eCLIP plus ribosome profiling plus genetic epistasis (RBM4 counteraction) plus loss-of-function phenotype, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"37993446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The RBM42 p.A438T variant (in the RRM domain) impairs RBM42 protein stability in vivo and disrupts its interaction with hnRNP K. Biallelic loss-of-function in RBM42 causes a neurodevelopmental syndrome in humans. Mouse compound heterozygous Rbm42 mutants die by E13.5 with gross developmental defects, and RNA-seq confirms RBM42 is required for normal alternative splicing in neurological and myocardial development.\",\n      \"method\": \"Whole-exome sequencing, in vivo protein stability assay, co-immunoprecipitation (RBM42–hnRNP K interaction), functional complementation in Fusarium ΔFgRbp1, mouse compound heterozygous model, RNA-seq alternative splicing analysis\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, in vivo stability, mouse model, RNA-seq, complementation), replicated across human patient, mouse, and fungal systems\",\n      \"pmids\": [\"37294900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RBM42 selectively binds and remodels the MYC 5'UTR RNA structure, facilitating formation of the translation pre-initiation complex and driving selective translation of MYC, JUN, and EGFR mRNAs. RBM42 is a ribosome-associated protein (RAP) identified by IP-mass spectrometry, and is necessary for PDAC tumorigenesis in a Myc-dependent manner in vivo.\",\n      \"method\": \"CRISPRi genome-wide screen, CLIP-seq, polysome sequencing, IP-mass spectrometry, DMS-Seq RNA structure probing, mutagenesis, xenograft mouse models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPRi screen validation, CLIP-seq, RNA structure probing with mutagenesis, IP-MS, and in vivo xenograft, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"39905246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans, upon dendrite injury, IDR-1 (insulin-degrading enzyme ortholog) promotes nuclear export of RBM-42, enabling its localization to dendrites. RBM-42 then promotes translation of ced-7 (a phagocytosis pathway component) and facilitates microtubule assembly to drive dendrite regeneration. IDR-1 functions upstream of RBM-42, and RBM-42 functions upstream of CED-7 in this pathway.\",\n      \"method\": \"Forward genetic screen in C. elegans, genetic epistasis (idr-1, rbm-42, ced-7 double/single mutants), subcellular localization (nuclear export assay), translation reporter assay, dendrite regeneration imaging\",\n      \"journal\": \"bioRxiv : the preprint server for biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis and localization with functional consequence established in C. elegans, preprint, single lab\",\n      \"pmids\": [\"41332648\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sensitivity to CMP76 (a compound that induces hnRNPK-dependent stress granule formation and MYC mRNA translational silencing) is significantly associated with RBM42 dependency across cancer cell lines, linking RBM42 functionally to the hnRNPK–MYC translation axis.\",\n      \"method\": \"High-throughput chemical screen, ribosome profiling, CETSA, subcellular localization studies, cancer cell line dependency correlation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — associative dependency correlation rather than direct mechanistic experiment on RBM42; single study\",\n      \"pmids\": [\"40943063\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RBM42 is a conserved RNA-binding protein with dual roles in pre-mRNA splicing and translation: it facilitates spliceosome assembly (interacting with U2AF/tri-snRNP components and counteracting RBM4-mediated splicing inhibition), while also acting as a ribosome-associated protein that remodels 5'UTR RNA structures (notably of MYC) to promote translation pre-initiation complex formation; it binds hnRNP K in the nucleus and at stress granules, is negatively regulated by m6A modification of its RNA targets, is required for DNA damage-induced p21 induction, and plays essential roles in embryonic development and cell cycle progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RBM42 is a conserved RNA-recognition-motif protein that couples pre-mRNA splicing to selective translation, acting as a node that links RNA processing to cellular stress responses, cell cycle progression, and development [#5, #6]. In splicing, it engages spliceosome assembly machinery — its orthologs bind sequence motifs in target mRNAs and recruit the U2AF small subunit involved in 3' splice site recognition and interact with tri-snRNP components, a function conserved through human RBM42 by complementation [#1, #4]. During the DNA damage response RBM42 promotes CDKN1A (p21) maturation by counteracting the splicing-inhibitory activity of RBM4, while genome-wide eCLIP shows it binds RNA at both splicing and translation targets, establishing a dual splicing-translation role [#5]. As a ribosome-associated protein, RBM42 selectively binds and remodels the MYC 5'UTR RNA structure to promote translation pre-initiation complex formation, driving selective translation of MYC, JUN, and EGFR and supporting MYC-dependent tumorigenesis [#3, #7]. RBM42 directly binds hnRNP K and co-relocalizes with it to stress granules under stress, and this interaction is disrupted by a disease-associated RRM variant [#0, #6]. Biallelic loss-of-function in RBM42 causes a human neurodevelopmental syndrome, and Rbm42 mutant mice die in mid-embryogenesis with developmental defects and aberrant alternative splicing [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established RBM42 as a physical and functional partner of hnRNP K and a stress-responsive RNA-binding protein, the first mechanistic anchor for the protein.\",\n      \"evidence\": \"Co-IP, in vitro binding, RNA-IP, RNAi, and co-localization in human cells under stress\",\n      \"pmids\": [\"19170760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve which RNA-processing step RBM42 acts in\", \"Functional consequence of p21 3'UTR binding not defined\", \"Stress granule recruitment mechanism unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified RBM42's conserved role in spliceosome assembly and cell cycle progression by showing its Toxoplasma ortholog interacts with tri-snRNP components and is functionally replaceable by human RBM42.\",\n      \"evidence\": \"Temperature-sensitive mutant, transcriptome profiling, Co-IP with spliceosome components, and complementation with human RBM42\",\n      \"pmids\": [\"23437009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the RNA sequence specificity of RBM42\", \"Direct human substrates not mapped\", \"Mechanism of spliceosome assembly contribution unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined RBM42 as an m6A-sensitive RNA binder whose RNA association is disrupted by the modification, placing it among m6A-regulated stress granule factors.\",\n      \"evidence\": \"Photo-cross-linking chemical proteomics with diazirine m6A RNA probes and quantitative mass spectrometry in vitro\",\n      \"pmids\": [\"29140688\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro probe binding not validated on endogenous transcripts\", \"Cellular consequence of m6A regulation of RBM42 not shown\", \"No specific target context defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked RBM42 to MYC-driven translational control by associating it with 5'UTR motifs governing translation efficiency in lymphoma.\",\n      \"evidence\": \"Polysome/ribosome profiling and 5'UTR motif RNA-binding analysis in lymphoma cells\",\n      \"pmids\": [\"31142587\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"RBM42's specific molecular contribution not resolved in this study\", \"Direct 5'UTR binding not demonstrated structurally\", \"Distinct from its splicing role not yet integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved a sequence-dependent splicing mechanism: the Fusarium ortholog binds a defined motif and recruits the U2AF small subunit to promote 3' splice site recognition, conserved through human RBM42.\",\n      \"evidence\": \"Deletion mutants, RNA-IP motif mapping, Co-IP with FgU2AF23, complementation with human RBM42, and RNA-seq splicing analysis\",\n      \"pmids\": [\"33976182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human RBM42 motif specificity not directly mapped here\", \"Whether U2AF recruitment operates identically in human cells untested\", \"No structural basis for motif recognition\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Unified RBM42's splicing and translation activities by showing it counteracts RBM4 to promote CDKN1A splicing and translation during DNA damage, with transcriptome-wide direct RNA binding.\",\n      \"evidence\": \"eCLIP, ribosome profiling, siRNA knockdown, RNA-seq, and RBM4/RBM42 co-depletion epistasis in human cells\",\n      \"pmids\": [\"37993446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of RBM4 antagonism not defined\", \"How splicing and translation roles are partitioned per transcript unclear\", \"Upstream DNA-damage signaling to RBM42 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established RBM42 as a disease gene: biallelic loss-of-function causes a human neurodevelopmental syndrome, with an RRM variant destabilizing the protein and disrupting hnRNP K binding, and mouse loss causing embryonic lethality with splicing defects.\",\n      \"evidence\": \"Whole-exome sequencing, in vivo stability assay, Co-IP, Fusarium complementation, mouse compound heterozygous model, and RNA-seq\",\n      \"pmids\": [\"37294900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific splicing targets driving phenotype not fully cataloged\", \"Genotype-phenotype relationship of variant severity unresolved\", \"Whether hnRNP K loss alone explains the syndrome unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mechanistically defined RBM42's translational role: as a ribosome-associated protein it binds and remodels the MYC 5'UTR structure to enable pre-initiation complex formation and selective translation, driving MYC-dependent PDAC tumorigenesis.\",\n      \"evidence\": \"CRISPRi screen, CLIP-seq, polysome sequencing, IP-MS, DMS-Seq structure probing, mutagenesis, and xenograft models\",\n      \"pmids\": [\"39905246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the remodeled 5'UTR not solved\", \"How RBM42 partitions between nuclear splicing and ribosomal pools unclear\", \"Generality of structure remodeling beyond MYC/JUN/EGFR untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended RBM42's translational function to neuronal regeneration, showing IDR-1-driven nuclear export enables dendritic RBM-42 to promote ced-7 translation and microtubule assembly in C. elegans.\",\n      \"evidence\": \"Forward genetic screen, epistasis, nuclear export and translation reporter assays, and dendrite regeneration imaging (preprint)\",\n      \"pmids\": [\"41332648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Conservation of the IDR-1/RBM-42 axis in mammals untested\", \"Mechanism of regulated nuclear export not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RBM42 is partitioned and switched between its nuclear spliceosome-assembly role and its cytoplasmic ribosome-associated 5'UTR-remodeling role, and how upstream signals (stress, DNA damage, m6A, regulated export) toggle these activities, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of RBM42 RNA recognition\", \"Regulatory logic coupling splicing and translation undefined\", \"In vivo m6A regulation of endogenous targets not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 4, 5, 7]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0045182\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\"spliceosome (tri-snRNP)\", \"stress granule\"],\n    \"partners\": [\"HNRNPK\", \"RBM4\", \"U2AF (small subunit)\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}