{"gene":"DDX50","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2022,"finding":"DDX50 promotes activation of the IRF3 signalling pathway following stimulation with viral RNA or infection with RNA and DNA viruses. Deletion of DDX50 in mouse and human cells impaired IRF3 phosphorylation and IRF3-dependent endogenous gene expression and cytokine/chemokine production in response to cytoplasmic dsRNA (polyIC transfection) and viral infection. DDX50 co-immunoprecipitated TRIF, indicating it acts through the TRIF pathway, but independently of the previously described TRIF-dependent RNA sensor DDX1.","method":"CRISPR/shRNA deletion in mouse and human cells, IRF3 phosphorylation assay, cytokine/chemokine production assay, Co-immunoprecipitation, viral replication/dissemination assay (vaccinia virus, HSV, Zika virus)","journal":"Viruses","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, KO in multiple cell types, multiple orthogonal functional readouts, viral restriction confirmed across multiple virus types","pmids":["35215908"],"is_preprint":false},{"year":2017,"finding":"DDX50 negatively regulates DENV-2 replication during the early stages of infection by inducing IFN-β production. DDX50 knockdown increased DENV-2 RNA levels, while DDX50 overexpression decreased them. DDX50 cooperated with RIG-I and MDA5 to upregulate IFN-β promoter activity through an additive effect, and DDX50 overexpression increased transcription of IFN-stimulated genes.","method":"DDX50 knockdown and overexpression in cell lines, qRT-PCR for viral RNA, IFN-β promoter reporter assay, IFN-stimulated gene expression analysis","journal":"Archives of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with defined molecular phenotype (IFN-β promoter activity, viral RNA levels), single lab, two orthogonal methods","pmids":["28181036"],"is_preprint":false},{"year":2017,"finding":"DDX50 probably promoted Hantaan virus (HTNV) replication, in contrast to DDX21 and DDX60 which reinforced IFN responses and exerted anti-hantaviral effects.","method":"In-cell Western (ICW) assay to assess viral protein expression after DDX50 modulation in HTNV-infected cells","journal":"Frontiers in cellular and infection microbiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (ICW assay), described as 'probably', limited mechanistic follow-up","pmids":["28676847"],"is_preprint":false},{"year":2024,"finding":"DDX50 is a Pro/N-degron-containing RNA helicase that interacts with human GID4 (a substrate receptor of the CTLH ubiquitin ligase complex), identified as a GID4 interactor enriched among nucleolar proteins. The interaction is mediated through Pro/N-degron binding.","method":"Proximity-dependent biotinylation (BioID), quantitative proteomics using chemical probe PFI-7 to antagonize Pro/N-degron binding to GID4","journal":"Nature chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics with chemical probe antagonist and proximity biotinylation, single study","pmids":["38773330"],"is_preprint":false},{"year":2025,"finding":"DDX50 is essential for differentiation of diverse cell types. Glucose binding to conserved DDX50 ATP-binding sequences alters protein conformation and dissociates DDX50 dimers into monomers. DDX50 monomers bind STAU1 to redirect it from an RNA-decay-promoting complex with UPF1 to a DDX50-STAU1 ribonuclear complex that stabilizes pro-differentiation RNAs including JUN, OVOL1, CEBPB, PRDM1, and TINCR, and modifies their structures.","method":"Glucose-binding assay, protein conformation assay, co-immunoprecipitation (DDX50-STAU1, STAU1-UPF1), RNA-binding assay, RNA structure probing, DDX50 depletion with differentiation phenotype readout, RNA stability assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (biochemical glucose binding, Co-IP of complexes, RNA structure modification, KO with differentiation phenotype, RNA stability), mechanistic pathway placement established in single rigorous study","pmids":["39764852"],"is_preprint":false},{"year":2025,"finding":"DDX50 is required for resolving RNA-DNA hybrids (R-loops) that form during transcription. Depletion of DDX50 promotes DNA damage (H2AX phosphorylation, increased comet tail length), decreases DNA replication track length, causes RPA focus formation (replication stress), and increases RNA-DNA hybrids. The increased RNA-DNA hybrid formation and DNA damage upon DDX50 depletion can be reverted by RNase H1 overexpression or by inhibition of transcription.","method":"DDX50 knockdown, H2AX phosphorylation assay, comet assay, DNA fiber assay (replication track length), RPA focus formation assay, RNA-DNA hybrid detection, RNase H1 rescue experiment, transcription inhibition rescue","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays (comet, fiber, immunofluorescence, RNase H rescue, transcription inhibitor rescue) in single study establishing mechanistic pathway","pmids":["40043837"],"is_preprint":false}],"current_model":"DDX50 is a DExD/H-box RNA helicase that functions in at least three mechanistic contexts: (1) it promotes IRF3-dependent innate immune signaling by interacting with TRIF (independently of DDX1) to restrict RNA and DNA viral replication; (2) it resolves transcription-coupled R-loops (RNA-DNA hybrids) to prevent replication stress and maintain genome stability; and (3) upon glucose binding, DDX50 undergoes conformational change and monomerization, then binds STAU1 to redirect it away from UPF1-mediated mRNA decay toward stabilization of pro-differentiation RNAs, thereby enabling cellular differentiation."},"narrative":{"mechanistic_narrative":"DDX50 is a DExD/H-box RNA helicase that operates across innate antiviral signaling, genome maintenance, and cell differentiation [PMID:35215908, PMID:39764852, PMID:40043837]. In the immune context, DDX50 promotes IRF3-dependent antiviral responses: its loss impairs IRF3 phosphorylation and downstream cytokine/chemokine production after cytoplasmic dsRNA stimulation or viral infection, and it acts through the adaptor TRIF independently of the related sensor DDX1 to restrict both RNA and DNA viruses [PMID:35215908]. Independently, DDX50 safeguards genome stability by resolving transcription-coupled R-loops; its depletion increases RNA-DNA hybrids, provokes DNA damage and replication stress, and these phenotypes are reversed by RNase H1 overexpression or transcription inhibition, establishing the helicase as a hybrid-resolution factor at the transcription-replication interface [PMID:40043837]. In differentiation, glucose binding to conserved ATP-binding sequences in DDX50 triggers a conformational change that monomerizes the protein, allowing it to bind STAU1 and divert it from a UPF1 RNA-decay complex into a DDX50-STAU1 ribonuclear complex that stabilizes and remodels pro-differentiation transcripts including JUN, OVOL1, CEBPB, PRDM1, and TINCR [PMID:39764852].","teleology":[{"year":2017,"claim":"Established the first functional link between DDX50 and antiviral immunity by showing it restricts flavivirus replication via interferon induction, rather than being a passive RNA-binding protein.","evidence":"DDX50 knockdown/overexpression with DENV-2 RNA quantitation and IFN-β promoter reporter assays in cell lines","pmids":["28181036"],"confidence":"Medium","gaps":["Direct adaptor or sensor partner not identified","Cooperation with RIG-I/MDA5 shown only as additive promoter activity, not as physical mechanism"]},{"year":2017,"claim":"Tested whether DDX50 behaves like antiviral paralogs and instead found it may favor viral replication in a different infection context, hinting at virus-specific roles.","evidence":"In-cell Western assay of viral protein after DDX50 modulation in Hantaan virus-infected cells","pmids":["28676847"],"confidence":"Low","gaps":["Single method (ICW) and described as 'probably' — effect not confirmed","No mechanistic basis for the contrast with antiviral activity in other contexts","No reciprocal validation or genetic perturbation"]},{"year":2022,"claim":"Resolved how DDX50 feeds into innate signaling by placing it on the TRIF-IRF3 axis, distinguishing it from the related sensor DDX1 and demonstrating broad viral restriction.","evidence":"CRISPR/shRNA deletion in mouse and human cells, IRF3 phosphorylation and cytokine assays, TRIF Co-IP, and viral restriction across vaccinia, HSV, and Zika","pmids":["35215908"],"confidence":"High","gaps":["Whether DDX50 directly senses viral nucleic acid or acts downstream of a sensor is unresolved","Structural basis of the DDX50-TRIF interaction not defined","Catalytic (helicase) requirement for IRF3 activation not tested"]},{"year":2024,"claim":"Identified a post-translational regulatory input by showing DDX50 carries a Pro/N-degron recognized by the CTLH ubiquitin ligase substrate receptor GID4, linking its abundance to targeted degradation.","evidence":"BioID proximity proteomics and quantitative proteomics using the PFI-7 chemical antagonist of GID4 Pro/N-degron binding","pmids":["38773330"],"confidence":"Medium","gaps":["Ubiquitination and degradation of DDX50 not directly demonstrated","Functional consequence of GID4-mediated turnover for any DDX50 activity unknown","Single study"]},{"year":2025,"claim":"Defined a genome-protective function by showing DDX50 resolves transcription-generated R-loops to prevent replication stress and DNA damage.","evidence":"DDX50 knockdown with H2AX phosphorylation, comet, DNA fiber, RPA focus, and RNA-DNA hybrid assays, rescued by RNase H1 overexpression and transcription inhibition","pmids":["40043837"],"confidence":"High","gaps":["Direct in vitro hybrid-unwinding activity on R-loops not shown","Genomic sites of action and recruitment mechanism unknown","Relationship between this role and its immune/differentiation functions undefined"]},{"year":2025,"claim":"Uncovered a glucose-sensing, conformation-switched mechanism by which DDX50 controls mRNA fate to drive differentiation, redirecting STAU1 from decay to stabilization of pro-differentiation transcripts.","evidence":"Glucose-binding and conformation assays, DDX50-STAU1 and STAU1-UPF1 Co-IP, RNA-binding and structure probing, RNA stability assays, and depletion with differentiation phenotype readouts","pmids":["39764852"],"confidence":"High","gaps":["How glucose binding at ATP-binding sequences mechanistically links to monomerization at atomic resolution is not defined","Whether the same conformational switch governs its immune or R-loop functions is untested","Generality of target RNA set beyond the listed transcripts"]},{"year":null,"claim":"It remains unknown whether DDX50's three documented roles — IRF3/TRIF antiviral signaling, R-loop resolution, and STAU1-mediated mRNA stabilization — represent a single biochemical activity deployed in different contexts or distinct functions, and how its GID4-mediated turnover integrates with them.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying biochemical assay connects the helicase activity to all three roles","Direct catalytic substrate(s) of the helicase not defined in any context"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,5]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[5]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[5]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4]}],"complexes":["DDX50-STAU1 ribonuclear complex"],"partners":["TRIF","STAU1","GID4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BQ39","full_name":"ATP-dependent RNA helicase DDX50","aliases":["DEAD box protein 50","Gu-beta","Nucleolar protein Gu2"],"length_aa":737,"mass_kda":82.6,"function":"ATP-dependent RNA helicase that may play a role in various aspects of RNA metabolism including pre-mRNA splicing or ribosomal RNA production (PubMed:12027455). Also acts as a viral restriction factor and promotes the activation of the NF-kappa-B and IRF3 signaling pathways following its stimulation with viral RNA or infection with RNA and DNA viruses (PubMed:35215908). For instance, decreases vaccinia virus, herpes simplex virus, Zika virus or dengue virus replication during the early stage of infection (PubMed:28181036, PubMed:35215908). Mechanistically, acts via the adapter TICAM1 and independently of the DDX1-DDX21-DHX36 helicase complex to induce the production of interferon-beta (PubMed:35215908)","subcellular_location":"Nucleus, nucleolus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9BQ39/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DDX50","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DDX50","total_profiled":1310},"omim":[{"mim_id":"610373","title":"DExD-BOX HELICASE 50; DDX50","url":"https://www.omim.org/entry/610373"},{"mim_id":"606357","title":"DExD-BOX HELICASE 21; DDX21","url":"https://www.omim.org/entry/606357"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DDX50"},"hgnc":{"alias_symbol":["GU2","MGC3199","GUB","RH-II/GuB"],"prev_symbol":[]},"alphafold":{"accession":"Q9BQ39","domains":[{"cath_id":"3.40.50.300","chopping":"132-348","consensus_level":"high","plddt":89.809,"start":132,"end":348},{"cath_id":"3.40.50.300","chopping":"361-517","consensus_level":"high","plddt":87.204,"start":361,"end":517},{"cath_id":"-","chopping":"521-535_543-569","consensus_level":"high","plddt":88.5379,"start":521,"end":569},{"cath_id":"3.30.70.2280","chopping":"586-655","consensus_level":"high","plddt":82.919,"start":586,"end":655}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BQ39","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BQ39-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BQ39-F1-predicted_aligned_error_v6.png","plddt_mean":72.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDX50","jax_strain_url":"https://www.jax.org/strain/search?query=DDX50"},"sequence":{"accession":"Q9BQ39","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BQ39.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BQ39/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BQ39"}},"corpus_meta":[{"pmid":"10233949","id":"PMC_10233949","title":"Characterization 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Deletion of DDX50 in mouse and human cells impaired IRF3 phosphorylation and IRF3-dependent endogenous gene expression and cytokine/chemokine production in response to cytoplasmic dsRNA (polyIC transfection) and viral infection. DDX50 co-immunoprecipitated TRIF, indicating it acts through the TRIF pathway, but independently of the previously described TRIF-dependent RNA sensor DDX1.\",\n      \"method\": \"CRISPR/shRNA deletion in mouse and human cells, IRF3 phosphorylation assay, cytokine/chemokine production assay, Co-immunoprecipitation, viral replication/dissemination assay (vaccinia virus, HSV, Zika virus)\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, KO in multiple cell types, multiple orthogonal functional readouts, viral restriction confirmed across multiple virus types\",\n      \"pmids\": [\"35215908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDX50 negatively regulates DENV-2 replication during the early stages of infection by inducing IFN-β production. DDX50 knockdown increased DENV-2 RNA levels, while DDX50 overexpression decreased them. DDX50 cooperated with RIG-I and MDA5 to upregulate IFN-β promoter activity through an additive effect, and DDX50 overexpression increased transcription of IFN-stimulated genes.\",\n      \"method\": \"DDX50 knockdown and overexpression in cell lines, qRT-PCR for viral RNA, IFN-β promoter reporter assay, IFN-stimulated gene expression analysis\",\n      \"journal\": \"Archives of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with defined molecular phenotype (IFN-β promoter activity, viral RNA levels), single lab, two orthogonal methods\",\n      \"pmids\": [\"28181036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDX50 probably promoted Hantaan virus (HTNV) replication, in contrast to DDX21 and DDX60 which reinforced IFN responses and exerted anti-hantaviral effects.\",\n      \"method\": \"In-cell Western (ICW) assay to assess viral protein expression after DDX50 modulation in HTNV-infected cells\",\n      \"journal\": \"Frontiers in cellular and infection microbiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (ICW assay), described as 'probably', limited mechanistic follow-up\",\n      \"pmids\": [\"28676847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX50 is a Pro/N-degron-containing RNA helicase that interacts with human GID4 (a substrate receptor of the CTLH ubiquitin ligase complex), identified as a GID4 interactor enriched among nucleolar proteins. The interaction is mediated through Pro/N-degron binding.\",\n      \"method\": \"Proximity-dependent biotinylation (BioID), quantitative proteomics using chemical probe PFI-7 to antagonize Pro/N-degron binding to GID4\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics with chemical probe antagonist and proximity biotinylation, single study\",\n      \"pmids\": [\"38773330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX50 is essential for differentiation of diverse cell types. Glucose binding to conserved DDX50 ATP-binding sequences alters protein conformation and dissociates DDX50 dimers into monomers. DDX50 monomers bind STAU1 to redirect it from an RNA-decay-promoting complex with UPF1 to a DDX50-STAU1 ribonuclear complex that stabilizes pro-differentiation RNAs including JUN, OVOL1, CEBPB, PRDM1, and TINCR, and modifies their structures.\",\n      \"method\": \"Glucose-binding assay, protein conformation assay, co-immunoprecipitation (DDX50-STAU1, STAU1-UPF1), RNA-binding assay, RNA structure probing, DDX50 depletion with differentiation phenotype readout, RNA stability assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (biochemical glucose binding, Co-IP of complexes, RNA structure modification, KO with differentiation phenotype, RNA stability), mechanistic pathway placement established in single rigorous study\",\n      \"pmids\": [\"39764852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX50 is required for resolving RNA-DNA hybrids (R-loops) that form during transcription. Depletion of DDX50 promotes DNA damage (H2AX phosphorylation, increased comet tail length), decreases DNA replication track length, causes RPA focus formation (replication stress), and increases RNA-DNA hybrids. The increased RNA-DNA hybrid formation and DNA damage upon DDX50 depletion can be reverted by RNase H1 overexpression or by inhibition of transcription.\",\n      \"method\": \"DDX50 knockdown, H2AX phosphorylation assay, comet assay, DNA fiber assay (replication track length), RPA focus formation assay, RNA-DNA hybrid detection, RNase H1 rescue experiment, transcription inhibition rescue\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays (comet, fiber, immunofluorescence, RNase H rescue, transcription inhibitor rescue) in single study establishing mechanistic pathway\",\n      \"pmids\": [\"40043837\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DDX50 is a DExD/H-box RNA helicase that functions in at least three mechanistic contexts: (1) it promotes IRF3-dependent innate immune signaling by interacting with TRIF (independently of DDX1) to restrict RNA and DNA viral replication; (2) it resolves transcription-coupled R-loops (RNA-DNA hybrids) to prevent replication stress and maintain genome stability; and (3) upon glucose binding, DDX50 undergoes conformational change and monomerization, then binds STAU1 to redirect it away from UPF1-mediated mRNA decay toward stabilization of pro-differentiation RNAs, thereby enabling cellular differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDX50 is a DExD/H-box RNA helicase that operates across innate antiviral signaling, genome maintenance, and cell differentiation [#0, #4, #5]. In the immune context, DDX50 promotes IRF3-dependent antiviral responses: its loss impairs IRF3 phosphorylation and downstream cytokine/chemokine production after cytoplasmic dsRNA stimulation or viral infection, and it acts through the adaptor TRIF independently of the related sensor DDX1 to restrict both RNA and DNA viruses [#0]. Independently, DDX50 safeguards genome stability by resolving transcription-coupled R-loops; its depletion increases RNA-DNA hybrids, provokes DNA damage and replication stress, and these phenotypes are reversed by RNase H1 overexpression or transcription inhibition, establishing the helicase as a hybrid-resolution factor at the transcription-replication interface [#5]. In differentiation, glucose binding to conserved ATP-binding sequences in DDX50 triggers a conformational change that monomerizes the protein, allowing it to bind STAU1 and divert it from a UPF1 RNA-decay complex into a DDX50-STAU1 ribonuclear complex that stabilizes and remodels pro-differentiation transcripts including JUN, OVOL1, CEBPB, PRDM1, and TINCR [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the first functional link between DDX50 and antiviral immunity by showing it restricts flavivirus replication via interferon induction, rather than being a passive RNA-binding protein.\",\n      \"evidence\": \"DDX50 knockdown/overexpression with DENV-2 RNA quantitation and IFN-\\u03b2 promoter reporter assays in cell lines\",\n      \"pmids\": [\"28181036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct adaptor or sensor partner not identified\",\n        \"Cooperation with RIG-I/MDA5 shown only as additive promoter activity, not as physical mechanism\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Tested whether DDX50 behaves like antiviral paralogs and instead found it may favor viral replication in a different infection context, hinting at virus-specific roles.\",\n      \"evidence\": \"In-cell Western assay of viral protein after DDX50 modulation in Hantaan virus-infected cells\",\n      \"pmids\": [\"28676847\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single method (ICW) and described as 'probably' \\u2014 effect not confirmed\",\n        \"No mechanistic basis for the contrast with antiviral activity in other contexts\",\n        \"No reciprocal validation or genetic perturbation\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved how DDX50 feeds into innate signaling by placing it on the TRIF-IRF3 axis, distinguishing it from the related sensor DDX1 and demonstrating broad viral restriction.\",\n      \"evidence\": \"CRISPR/shRNA deletion in mouse and human cells, IRF3 phosphorylation and cytokine assays, TRIF Co-IP, and viral restriction across vaccinia, HSV, and Zika\",\n      \"pmids\": [\"35215908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DDX50 directly senses viral nucleic acid or acts downstream of a sensor is unresolved\",\n        \"Structural basis of the DDX50-TRIF interaction not defined\",\n        \"Catalytic (helicase) requirement for IRF3 activation not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a post-translational regulatory input by showing DDX50 carries a Pro/N-degron recognized by the CTLH ubiquitin ligase substrate receptor GID4, linking its abundance to targeted degradation.\",\n      \"evidence\": \"BioID proximity proteomics and quantitative proteomics using the PFI-7 chemical antagonist of GID4 Pro/N-degron binding\",\n      \"pmids\": [\"38773330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Ubiquitination and degradation of DDX50 not directly demonstrated\",\n        \"Functional consequence of GID4-mediated turnover for any DDX50 activity unknown\",\n        \"Single study\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a genome-protective function by showing DDX50 resolves transcription-generated R-loops to prevent replication stress and DNA damage.\",\n      \"evidence\": \"DDX50 knockdown with H2AX phosphorylation, comet, DNA fiber, RPA focus, and RNA-DNA hybrid assays, rescued by RNase H1 overexpression and transcription inhibition\",\n      \"pmids\": [\"40043837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct in vitro hybrid-unwinding activity on R-loops not shown\",\n        \"Genomic sites of action and recruitment mechanism unknown\",\n        \"Relationship between this role and its immune/differentiation functions undefined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a glucose-sensing, conformation-switched mechanism by which DDX50 controls mRNA fate to drive differentiation, redirecting STAU1 from decay to stabilization of pro-differentiation transcripts.\",\n      \"evidence\": \"Glucose-binding and conformation assays, DDX50-STAU1 and STAU1-UPF1 Co-IP, RNA-binding and structure probing, RNA stability assays, and depletion with differentiation phenotype readouts\",\n      \"pmids\": [\"39764852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How glucose binding at ATP-binding sequences mechanistically links to monomerization at atomic resolution is not defined\",\n        \"Whether the same conformational switch governs its immune or R-loop functions is untested\",\n        \"Generality of target RNA set beyond the listed transcripts\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether DDX50's three documented roles \\u2014 IRF3/TRIF antiviral signaling, R-loop resolution, and STAU1-mediated mRNA stabilization \\u2014 represent a single biochemical activity deployed in different contexts or distinct functions, and how its GID4-mediated turnover integrates with them.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unifying biochemical assay connects the helicase activity to all three roles\",\n        \"Direct catalytic substrate(s) of the helicase not defined in any context\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"DDX50-STAU1 ribonuclear complex\"\n    ],\n    \"partners\": [\n      \"TRIF\",\n      \"STAU1\",\n      \"GID4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}