{"gene":"DDX43","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2017,"finding":"DDX43 is an ATP-dependent dual RNA and DNA helicase. It exhibits 5' to 3' polarity on RNA and 3' to 5' directionality on DNA. The N-terminal K-homology (KH) domain is required for nucleic acid binding and full unwinding activity; the C-terminal helicase domain alone has no RNA unwinding activity and significantly reduced DNA unwinding activity. DDX43 exists as a monomer in solution.","method":"Purified recombinant protein, in vitro helicase/ATPase assays, truncation mutations, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant protein, multiple orthogonal assays (helicase, ATPase, EMSA), truncation and point mutagenesis, replicated across independent labs","pmids":["28468824"],"is_preprint":false},{"year":2020,"finding":"The KH domain of DDX43 preferentially binds pyrimidine-rich ssDNA and ssRNA; the GXXG loop and an adjacent alanine residue are critical for pyrimidine binding. The optimal binding sequence is TTGT/UUGU. The KH domain facilitates substrate sequence specificity and unwinding processivity of the full-length DDX43 helicase.","method":"EMSA, NMR (15N-HSQC), SELEX, ChIP-seq, CLIP-seq, mutational analysis of GXXG loop","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including NMR, SELEX, ChIP-seq, CLIP-seq, and mutagenesis in a single rigorous study","pmids":["33199368"],"is_preprint":false},{"year":2019,"finding":"Full binding activity of DDX43 to single-stranded DNA or RNA (preferring substrates ≥12 nt and guanosine-rich sequences) requires physical connection of all protein domains; absence or disjunction of any domain reduces binding affinity approximately 10-fold. The unwinding activity of DDX43 in vitro was found to be neither efficient nor sustainable.","method":"Recombinant protein expression in E. coli, purification, EMSA, in vitro binding and unwinding assays with domain deletion and disconnection constructs","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with systematic domain analysis, but single lab and partially contradicts polarity findings from PMID 28468824 on substrate preference","pmids":["31623828"],"is_preprint":false},{"year":2012,"finding":"HAGE (DDX43) knockdown in ABCB5+ malignant melanoma-initiating cells reduces NRAS protein expression and decreases AKT and ERK pathway activation, inhibiting tumor growth in vivo. HAGE promotes NRAS mRNA unwinding in vitro, and NRAS expression silenced by siRNA can be rescued by re-introduction of HAGE, confirming dependence on helicase activity.","method":"siRNA knockdown, NRAS rescue experiment, in vitro unwinding assay, tumor transplantation in NOD/SCID mice","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (siRNA + rescue), in vitro mechanistic assay, and in vivo tumor model, single lab","pmids":["22393060"],"is_preprint":false},{"year":2014,"finding":"HAGE (DDX43) prevents PML tumor suppressor expression in ABCB5+ malignant melanoma-initiating cells by promoting SOCS1 expression, which inhibits JAK-STAT pathway activation. HAGE promotes SOCS1 mRNA unwinding in vitro. HAGE knockdown reduces SOCS1, activates JAK-STAT, and increases PML. SOCS1 silenced by siRNA can be rescued by re-introduction of HAGE, confirming helicase-activity dependence. HAGE promotes tumor initiation and growth by preventing anti-proliferative effects of IFN-α.","method":"siRNA knockdown, SOCS1 rescue experiment, in vitro mRNA unwinding assay, stem cell proliferation assay, tumor xenotransplantation in NOD/SCID mice","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (siRNA + rescue), in vitro mechanistic assay, and in vivo tumor model, single lab","pmids":["24525737"],"is_preprint":false},{"year":2014,"finding":"Overexpression of DDX43 in MEK inhibitor-resistant uveal melanoma cells mediates resistance by upregulating RAS (KRAS, HRAS, NRAS) protein levels and activating ERK and AKT pathways. Depletion of DDX43 decreases RAS proteins and inhibits downstream signaling. Ectopic expression of DDX43 in parental cells induces RAS protein levels and renders cells resistant to MEK inhibition.","method":"siRNA knockdown, ectopic overexpression, Western blotting for pathway activation, analysis of MEK inhibitor-resistant cell lines","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments in multiple cell line contexts, reciprocal validation, single lab","pmids":["24899684"],"is_preprint":false},{"year":2018,"finding":"DDX43 overexpression in CML cell lines enhances survival and colony formation and inhibits apoptosis. DDX43 regulates H19 lncRNA expression through demethylation. miR-186 directly targets DDX43 (overexpression of miR-186 increases apoptosis and decreases cell survival). Silencing H19 inhibits cell survival downstream of DDX43.","method":"DDX43 overexpression and siRNA knockdown, colony formation assay, apoptosis assay, miRNA-target validation, H19 expression analysis with methylation studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cellular assays with gain/loss-of-function and miRNA target validation, single lab","pmids":["29449695"],"is_preprint":false},{"year":2023,"finding":"DDX43 is an essential regulator of chromatin remodeling during spermiogenesis. Testis-specific Ddx43 knockout mice are male-infertile with defective histone-to-protamine replacement and post-meiotic chromatin condensation defects. Loss of ATP hydrolysis activity via a missense mutation replicates the infertility phenotype, demonstrating that ATPase/helicase activity is required. DDX43 regulates dynamic RNA regulatory processes in spermatids, and eCLIP-seq identified Elfn2 as a DDX43-targeted hub gene.","method":"Conditional and global knockout mice, ATPase-dead missense mutation knock-in, single-cell RNA-seq, eCLIP-seq, chromatin analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo knockout with specific phenotype, ATPase-dead mutant phenocopy confirming catalytic requirement, multiple orthogonal genomics methods (scRNA-seq, eCLIP-seq)","pmids":["37120627"],"is_preprint":false},{"year":2007,"finding":"HAGE (DDX43) promoter CpG island methylation status directly correlates with HAGE expression in CML cell lines and patient samples; demethylation of the promoter is associated with gene overexpression, establishing promoter methylation as the epigenetic mechanism controlling HAGE expression.","method":"Quantitative methylation-specific PCR, bisulfite sequencing, quantitative RT-PCR in cell lines and patient samples","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — correlation between methylation and expression confirmed across cell lines and large patient cohort, corroborated by independent studies (PMID 24656837, 23495895)","pmids":["17296563","24656837","23495895"],"is_preprint":false},{"year":2014,"finding":"Restoration of DDX43 expression in K562 cells by 5-aza-2'-deoxycytidine (DNA demethylating agent) treatment confirms that promoter methylation directly regulates DDX43 gene expression.","method":"5-aza-2'-deoxycytidine demethylation treatment, quantitative RT-PCR","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological demethylation restores expression, single experiment but mechanistically direct","pmids":["24656837"],"is_preprint":false},{"year":2022,"finding":"In Nile tilapia, OnDDX43 is localized to the cytoplasm and positively regulates IFN-β expression. Pull-down assays showed that OnDDX43 interacts with the antiviral adaptor proteins IPS-1 (MAVS) and TRIF, identifying these as binding partners in the innate immune signaling pathway.","method":"Subcellular localization, overexpression in 293T cells, IFN-β reporter assay, pull-down assay","journal":"Molecular immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pull-down in a non-mammalian fish ortholog, single lab, functional relevance to human DDX43 uncertain","pmids":["34990938"],"is_preprint":false},{"year":2025,"finding":"Human DDX43 overexpression inhibits HSV-2 replication, and knockdown of endogenous DDX43 enhances HSV-2 replication, in an interferon-independent manner.","method":"Overexpression and knockdown experiments in HeLa and ARPE-19 cells, viral replication assay, IFN independence confirmed experimentally","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function with specific phenotypic readout and mechanistic distinction (IFN-independent), single lab","pmids":["41157636"],"is_preprint":false}],"current_model":"DDX43 (HAGE) is an ATP-dependent DEAD-box RNA/DNA helicase whose N-terminal KH domain binds pyrimidine-rich sequences (preferring TTGT/UUGU) and is required for substrate specificity, processivity, and full unwinding activity; it is essential for spermiogenesis chromatin remodeling (histone-to-protamine exchange) via its ATPase activity, promotes oncogenic RAS (NRAS, KRAS, HRAS) protein expression by unwinding RAS mRNAs to activate AKT/ERK signaling and drive melanoma and uveal melanoma tumor growth, suppresses PML expression in melanoma stem cells through SOCS1-mediated JAK-STAT inhibition, and its expression is epigenetically controlled by promoter CpG methylation in hematological malignancies."},"narrative":{"mechanistic_narrative":"DDX43 (HAGE) is an ATP-dependent dual RNA/DNA helicase that couples nucleic-acid unwinding to chromatin remodeling, oncogenic signaling, and antiviral defense [PMID:28468824, PMID:37120627]. Biochemically it unwinds RNA with 5'-to-3' polarity and DNA with 3'-to-5' directionality, functioning as a monomer in which the N-terminal K-homology (KH) domain — not the helicase core alone — is required for nucleic-acid binding and full unwinding activity [PMID:28468824]. The KH domain preferentially recognizes pyrimidine-rich single-stranded substrates (optimal TTGT/UUGU) through its GXXG loop, thereby imposing sequence specificity and processivity on the full-length enzyme [PMID:33199368]. In vivo, DDX43 ATPase/helicase activity is essential for chromatin remodeling during spermiogenesis: testis-specific knockout or an ATPase-dead knock-in mutation causes male infertility through defective histone-to-protamine exchange and post-meiotic condensation, with eCLIP-seq linking DDX43 to RNA regulatory programs in spermatids (Elfn2 hub target) [PMID:37120627]. In malignant melanoma-initiating cells, DDX43 promotes oncogenic RAS protein expression (NRAS, KRAS, HRAS) by unwinding RAS mRNAs to drive AKT/ERK signaling and tumor growth and to confer MEK-inhibitor resistance [PMID:22393060, PMID:24899684], and it represses the PML tumor suppressor by promoting SOCS1 expression to inhibit JAK-STAT signaling [PMID:24525737]. DDX43 expression is epigenetically controlled by promoter CpG methylation, with demethylation restoring expression in hematological malignancies [PMID:17296563, PMID:24656837, PMID:23495895]. DDX43 additionally restricts HSV-2 replication in an interferon-independent manner [PMID:41157636].","teleology":[{"year":2007,"claim":"Established the regulatory layer controlling DDX43 abundance, showing its expression is set epigenetically rather than constitutively.","evidence":"methylation-specific PCR and bisulfite sequencing in CML cell lines and patient samples","pmids":["17296563","24656837","23495895"],"confidence":"Medium","gaps":["Does not address DDX43 molecular activity or downstream targets","Correlative for expression control; trans-acting factors driving methylation not defined"]},{"year":2012,"claim":"Connected DDX43 helicase activity to a concrete oncogenic output by showing it unwinds NRAS mRNA to sustain AKT/ERK signaling.","evidence":"siRNA knockdown with helicase-dependent NRAS rescue, in vitro unwinding, and NOD/SCID tumor model in melanoma-initiating cells","pmids":["22393060"],"confidence":"Medium","gaps":["Direct binding of DDX43 to NRAS mRNA not mapped to specific sequence elements","Single lab; in vitro unwinding does not establish cellular target selectivity"]},{"year":2014,"claim":"Extended the oncogenic mechanism to immune evasion, showing DDX43 represses PML via SOCS1-mediated JAK-STAT inhibition, and broadened the RAS axis to MEK-inhibitor resistance.","evidence":"siRNA knockdown with helicase-dependent SOCS1 rescue and xenografts; ectopic DDX43 expression inducing RAS and conferring MEK-inhibitor resistance in uveal melanoma","pmids":["24525737","24899684"],"confidence":"Medium","gaps":["Whether RAS and SOCS1 effects share a common mRNA-unwinding mechanism not resolved","Single-lab studies; structural basis of mRNA target recognition unaddressed"]},{"year":2017,"claim":"Defined the core enzymology, establishing DDX43 as a monomeric dual RNA/DNA helicase with opposite polarities on RNA versus DNA and a KH domain required for activity.","evidence":"purified recombinant protein with helicase/ATPase assays, truncations, and point mutagenesis","pmids":["28468824"],"confidence":"High","gaps":["Physiological DNA versus RNA substrates not defined","No high-resolution structure of the full-length enzyme"]},{"year":2019,"claim":"Tested how the multidomain architecture contributes to binding, finding that all domains must be physically connected for full single-stranded substrate affinity.","evidence":"domain-deletion and domain-disconnection constructs with EMSA and in vitro unwinding","pmids":["31623828"],"confidence":"Medium","gaps":["Reported guanosine-rich substrate preference and weak unwinding partially conflict with other in vitro studies","Single lab; physiological relevance of disconnected-domain behavior unclear"]},{"year":2020,"claim":"Resolved the basis of substrate specificity, showing the KH domain reads pyrimidine-rich TTGT/UUGU motifs via its GXXG loop to direct full-length unwinding.","evidence":"EMSA, NMR (15N-HSQC), SELEX, ChIP-seq, CLIP-seq, and GXXG-loop mutagenesis","pmids":["33199368"],"confidence":"High","gaps":["How motif recognition couples to processive unwinding mechanistically not detailed","Genome-wide functional targets bearing this motif not validated"]},{"year":2023,"claim":"Provided in vivo proof of an essential physiological role, demonstrating that DDX43 ATPase/helicase activity drives chromatin remodeling during spermiogenesis.","evidence":"conditional and global knockout mice, ATPase-dead knock-in phenocopy, scRNA-seq, and eCLIP-seq","pmids":["37120627"],"confidence":"High","gaps":["Mechanism linking RNA targets (e.g. Elfn2) to histone-to-protamine exchange not defined","Whether the same RNA-unwinding activity underlies its oncogenic roles untested"]},{"year":2025,"claim":"Identified an antiviral function, showing human DDX43 restricts HSV-2 replication independently of interferon.","evidence":"reciprocal overexpression and knockdown in HeLa and ARPE-19 cells with viral replication readouts and confirmed IFN independence","pmids":["41157636"],"confidence":"Medium","gaps":["Molecular mechanism of restriction (target, step inhibited) unknown","Single lab; relationship to the fish-ortholog innate-immune adaptor interactions unestablished"]},{"year":null,"claim":"It remains unknown whether the in vitro RNA/DNA helicase activity and KH-domain motif recognition mechanistically unify DDX43's distinct roles in spermatid chromatin remodeling, RAS/SOCS1 mRNA regulation in cancer, and antiviral restriction.","evidence":"no single study connects the defined enzymology to validated cellular RNA targets across these contexts","pmids":[],"confidence":"Low","gaps":["No structural model of substrate-engaged full-length DDX43","Cellular target spectrum and recruitment determinants not mapped across tissues"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,3]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[11]}],"complexes":[],"partners":["SOCS1","MAVS","TRIF"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NXZ2","full_name":"Probable ATP-dependent RNA helicase DDX43","aliases":["Cancer/testis antigen 13","CT13","DEAD box protein 43","DEAD box protein HAGE","Helical antigen"],"length_aa":648,"mass_kda":72.8,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9NXZ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DDX43","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DDX43","total_profiled":1310},"omim":[{"mim_id":"606286","title":"DEAD-BOX HELICASE 43; DDX43","url":"https://www.omim.org/entry/606286"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":4.6},{"tissue":"testis","ntpm":18.3}],"url":"https://www.proteinatlas.org/search/DDX43"},"hgnc":{"alias_symbol":["HAGE","DKFZp434H2114","CT13"],"prev_symbol":[]},"alphafold":{"accession":"Q9NXZ2","domains":[{"cath_id":"3.30.1370.10","chopping":"71-132","consensus_level":"high","plddt":86.8187,"start":71,"end":132},{"cath_id":"3.40.50.300","chopping":"221-308_319-451","consensus_level":"medium","plddt":92.0247,"start":221,"end":451},{"cath_id":"3.40.50.300","chopping":"462-634","consensus_level":"high","plddt":89.0299,"start":462,"end":634}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NXZ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NXZ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NXZ2-F1-predicted_aligned_error_v6.png","plddt_mean":79.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDX43","jax_strain_url":"https://www.jax.org/strain/search?query=DDX43"},"sequence":{"accession":"Q9NXZ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NXZ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NXZ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NXZ2"}},"corpus_meta":[{"pmid":"12399967","id":"PMC_12399967","title":"Frequent expression of HAGE in presentation chronic myeloid leukaemias.","date":"2002","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/12399967","citation_count":68,"is_preprint":false},{"pmid":"17296563","id":"PMC_17296563","title":"Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia.","date":"2007","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/17296563","citation_count":44,"is_preprint":false},{"pmid":"37120627","id":"PMC_37120627","title":"Single-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37120627","citation_count":37,"is_preprint":false},{"pmid":"20058853","id":"PMC_20058853","title":"HAGE, a cancer/testis antigen expressed at the protein level in a variety of cancers.","date":"2010","source":"Cancer immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20058853","citation_count":36,"is_preprint":false},{"pmid":"28468824","id":"PMC_28468824","title":"The DEAD-box protein DDX43 (HAGE) is a dual RNA-DNA helicase and has a K-homology domain required for full nucleic acid unwinding activity.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28468824","citation_count":33,"is_preprint":false},{"pmid":"22393060","id":"PMC_22393060","title":"The helicase HAGE expressed by malignant melanoma-initiating cells is required for tumor cell proliferation in vivo.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22393060","citation_count":32,"is_preprint":false},{"pmid":"22527039","id":"PMC_22527039","title":"Hydroxybutyrate prevents protein aggregation in the halotolerant bacterium Pseudomonas sp. 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It exhibits 5' to 3' polarity on RNA and 3' to 5' directionality on DNA. The N-terminal K-homology (KH) domain is required for nucleic acid binding and full unwinding activity; the C-terminal helicase domain alone has no RNA unwinding activity and significantly reduced DNA unwinding activity. DDX43 exists as a monomer in solution.\",\n      \"method\": \"Purified recombinant protein, in vitro helicase/ATPase assays, truncation mutations, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant protein, multiple orthogonal assays (helicase, ATPase, EMSA), truncation and point mutagenesis, replicated across independent labs\",\n      \"pmids\": [\"28468824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The KH domain of DDX43 preferentially binds pyrimidine-rich ssDNA and ssRNA; the GXXG loop and an adjacent alanine residue are critical for pyrimidine binding. The optimal binding sequence is TTGT/UUGU. The KH domain facilitates substrate sequence specificity and unwinding processivity of the full-length DDX43 helicase.\",\n      \"method\": \"EMSA, NMR (15N-HSQC), SELEX, ChIP-seq, CLIP-seq, mutational analysis of GXXG loop\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including NMR, SELEX, ChIP-seq, CLIP-seq, and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"33199368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Full binding activity of DDX43 to single-stranded DNA or RNA (preferring substrates ≥12 nt and guanosine-rich sequences) requires physical connection of all protein domains; absence or disjunction of any domain reduces binding affinity approximately 10-fold. The unwinding activity of DDX43 in vitro was found to be neither efficient nor sustainable.\",\n      \"method\": \"Recombinant protein expression in E. coli, purification, EMSA, in vitro binding and unwinding assays with domain deletion and disconnection constructs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with systematic domain analysis, but single lab and partially contradicts polarity findings from PMID 28468824 on substrate preference\",\n      \"pmids\": [\"31623828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HAGE (DDX43) knockdown in ABCB5+ malignant melanoma-initiating cells reduces NRAS protein expression and decreases AKT and ERK pathway activation, inhibiting tumor growth in vivo. HAGE promotes NRAS mRNA unwinding in vitro, and NRAS expression silenced by siRNA can be rescued by re-introduction of HAGE, confirming dependence on helicase activity.\",\n      \"method\": \"siRNA knockdown, NRAS rescue experiment, in vitro unwinding assay, tumor transplantation in NOD/SCID mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (siRNA + rescue), in vitro mechanistic assay, and in vivo tumor model, single lab\",\n      \"pmids\": [\"22393060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HAGE (DDX43) prevents PML tumor suppressor expression in ABCB5+ malignant melanoma-initiating cells by promoting SOCS1 expression, which inhibits JAK-STAT pathway activation. HAGE promotes SOCS1 mRNA unwinding in vitro. HAGE knockdown reduces SOCS1, activates JAK-STAT, and increases PML. SOCS1 silenced by siRNA can be rescued by re-introduction of HAGE, confirming helicase-activity dependence. HAGE promotes tumor initiation and growth by preventing anti-proliferative effects of IFN-α.\",\n      \"method\": \"siRNA knockdown, SOCS1 rescue experiment, in vitro mRNA unwinding assay, stem cell proliferation assay, tumor xenotransplantation in NOD/SCID mice\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (siRNA + rescue), in vitro mechanistic assay, and in vivo tumor model, single lab\",\n      \"pmids\": [\"24525737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Overexpression of DDX43 in MEK inhibitor-resistant uveal melanoma cells mediates resistance by upregulating RAS (KRAS, HRAS, NRAS) protein levels and activating ERK and AKT pathways. Depletion of DDX43 decreases RAS proteins and inhibits downstream signaling. Ectopic expression of DDX43 in parental cells induces RAS protein levels and renders cells resistant to MEK inhibition.\",\n      \"method\": \"siRNA knockdown, ectopic overexpression, Western blotting for pathway activation, analysis of MEK inhibitor-resistant cell lines\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments in multiple cell line contexts, reciprocal validation, single lab\",\n      \"pmids\": [\"24899684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX43 overexpression in CML cell lines enhances survival and colony formation and inhibits apoptosis. DDX43 regulates H19 lncRNA expression through demethylation. miR-186 directly targets DDX43 (overexpression of miR-186 increases apoptosis and decreases cell survival). Silencing H19 inhibits cell survival downstream of DDX43.\",\n      \"method\": \"DDX43 overexpression and siRNA knockdown, colony formation assay, apoptosis assay, miRNA-target validation, H19 expression analysis with methylation studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cellular assays with gain/loss-of-function and miRNA target validation, single lab\",\n      \"pmids\": [\"29449695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DDX43 is an essential regulator of chromatin remodeling during spermiogenesis. Testis-specific Ddx43 knockout mice are male-infertile with defective histone-to-protamine replacement and post-meiotic chromatin condensation defects. Loss of ATP hydrolysis activity via a missense mutation replicates the infertility phenotype, demonstrating that ATPase/helicase activity is required. DDX43 regulates dynamic RNA regulatory processes in spermatids, and eCLIP-seq identified Elfn2 as a DDX43-targeted hub gene.\",\n      \"method\": \"Conditional and global knockout mice, ATPase-dead missense mutation knock-in, single-cell RNA-seq, eCLIP-seq, chromatin analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo knockout with specific phenotype, ATPase-dead mutant phenocopy confirming catalytic requirement, multiple orthogonal genomics methods (scRNA-seq, eCLIP-seq)\",\n      \"pmids\": [\"37120627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HAGE (DDX43) promoter CpG island methylation status directly correlates with HAGE expression in CML cell lines and patient samples; demethylation of the promoter is associated with gene overexpression, establishing promoter methylation as the epigenetic mechanism controlling HAGE expression.\",\n      \"method\": \"Quantitative methylation-specific PCR, bisulfite sequencing, quantitative RT-PCR in cell lines and patient samples\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — correlation between methylation and expression confirmed across cell lines and large patient cohort, corroborated by independent studies (PMID 24656837, 23495895)\",\n      \"pmids\": [\"17296563\", \"24656837\", \"23495895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Restoration of DDX43 expression in K562 cells by 5-aza-2'-deoxycytidine (DNA demethylating agent) treatment confirms that promoter methylation directly regulates DDX43 gene expression.\",\n      \"method\": \"5-aza-2'-deoxycytidine demethylation treatment, quantitative RT-PCR\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological demethylation restores expression, single experiment but mechanistically direct\",\n      \"pmids\": [\"24656837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Nile tilapia, OnDDX43 is localized to the cytoplasm and positively regulates IFN-β expression. Pull-down assays showed that OnDDX43 interacts with the antiviral adaptor proteins IPS-1 (MAVS) and TRIF, identifying these as binding partners in the innate immune signaling pathway.\",\n      \"method\": \"Subcellular localization, overexpression in 293T cells, IFN-β reporter assay, pull-down assay\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pull-down in a non-mammalian fish ortholog, single lab, functional relevance to human DDX43 uncertain\",\n      \"pmids\": [\"34990938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human DDX43 overexpression inhibits HSV-2 replication, and knockdown of endogenous DDX43 enhances HSV-2 replication, in an interferon-independent manner.\",\n      \"method\": \"Overexpression and knockdown experiments in HeLa and ARPE-19 cells, viral replication assay, IFN independence confirmed experimentally\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function with specific phenotypic readout and mechanistic distinction (IFN-independent), single lab\",\n      \"pmids\": [\"41157636\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DDX43 (HAGE) is an ATP-dependent DEAD-box RNA/DNA helicase whose N-terminal KH domain binds pyrimidine-rich sequences (preferring TTGT/UUGU) and is required for substrate specificity, processivity, and full unwinding activity; it is essential for spermiogenesis chromatin remodeling (histone-to-protamine exchange) via its ATPase activity, promotes oncogenic RAS (NRAS, KRAS, HRAS) protein expression by unwinding RAS mRNAs to activate AKT/ERK signaling and drive melanoma and uveal melanoma tumor growth, suppresses PML expression in melanoma stem cells through SOCS1-mediated JAK-STAT inhibition, and its expression is epigenetically controlled by promoter CpG methylation in hematological malignancies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDX43 (HAGE) is an ATP-dependent dual RNA/DNA helicase that couples nucleic-acid unwinding to chromatin remodeling, oncogenic signaling, and antiviral defense [#0, #7]. Biochemically it unwinds RNA with 5'-to-3' polarity and DNA with 3'-to-5' directionality, functioning as a monomer in which the N-terminal K-homology (KH) domain — not the helicase core alone — is required for nucleic-acid binding and full unwinding activity [#0]. The KH domain preferentially recognizes pyrimidine-rich single-stranded substrates (optimal TTGT/UUGU) through its GXXG loop, thereby imposing sequence specificity and processivity on the full-length enzyme [#1]. In vivo, DDX43 ATPase/helicase activity is essential for chromatin remodeling during spermiogenesis: testis-specific knockout or an ATPase-dead knock-in mutation causes male infertility through defective histone-to-protamine exchange and post-meiotic condensation, with eCLIP-seq linking DDX43 to RNA regulatory programs in spermatids (Elfn2 hub target) [#7]. In malignant melanoma-initiating cells, DDX43 promotes oncogenic RAS protein expression (NRAS, KRAS, HRAS) by unwinding RAS mRNAs to drive AKT/ERK signaling and tumor growth and to confer MEK-inhibitor resistance [#3, #5], and it represses the PML tumor suppressor by promoting SOCS1 expression to inhibit JAK-STAT signaling [#4]. DDX43 expression is epigenetically controlled by promoter CpG methylation, with demethylation restoring expression in hematological malignancies [#8, #9]. DDX43 additionally restricts HSV-2 replication in an interferon-independent manner [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established the regulatory layer controlling DDX43 abundance, showing its expression is set epigenetically rather than constitutively.\",\n      \"evidence\": \"methylation-specific PCR and bisulfite sequencing in CML cell lines and patient samples\",\n      \"pmids\": [\"17296563\", \"24656837\", \"23495895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address DDX43 molecular activity or downstream targets\", \"Correlative for expression control; trans-acting factors driving methylation not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected DDX43 helicase activity to a concrete oncogenic output by showing it unwinds NRAS mRNA to sustain AKT/ERK signaling.\",\n      \"evidence\": \"siRNA knockdown with helicase-dependent NRAS rescue, in vitro unwinding, and NOD/SCID tumor model in melanoma-initiating cells\",\n      \"pmids\": [\"22393060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding of DDX43 to NRAS mRNA not mapped to specific sequence elements\", \"Single lab; in vitro unwinding does not establish cellular target selectivity\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the oncogenic mechanism to immune evasion, showing DDX43 represses PML via SOCS1-mediated JAK-STAT inhibition, and broadened the RAS axis to MEK-inhibitor resistance.\",\n      \"evidence\": \"siRNA knockdown with helicase-dependent SOCS1 rescue and xenografts; ectopic DDX43 expression inducing RAS and conferring MEK-inhibitor resistance in uveal melanoma\",\n      \"pmids\": [\"24525737\", \"24899684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether RAS and SOCS1 effects share a common mRNA-unwinding mechanism not resolved\", \"Single-lab studies; structural basis of mRNA target recognition unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the core enzymology, establishing DDX43 as a monomeric dual RNA/DNA helicase with opposite polarities on RNA versus DNA and a KH domain required for activity.\",\n      \"evidence\": \"purified recombinant protein with helicase/ATPase assays, truncations, and point mutagenesis\",\n      \"pmids\": [\"28468824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological DNA versus RNA substrates not defined\", \"No high-resolution structure of the full-length enzyme\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Tested how the multidomain architecture contributes to binding, finding that all domains must be physically connected for full single-stranded substrate affinity.\",\n      \"evidence\": \"domain-deletion and domain-disconnection constructs with EMSA and in vitro unwinding\",\n      \"pmids\": [\"31623828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reported guanosine-rich substrate preference and weak unwinding partially conflict with other in vitro studies\", \"Single lab; physiological relevance of disconnected-domain behavior unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the basis of substrate specificity, showing the KH domain reads pyrimidine-rich TTGT/UUGU motifs via its GXXG loop to direct full-length unwinding.\",\n      \"evidence\": \"EMSA, NMR (15N-HSQC), SELEX, ChIP-seq, CLIP-seq, and GXXG-loop mutagenesis\",\n      \"pmids\": [\"33199368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How motif recognition couples to processive unwinding mechanistically not detailed\", \"Genome-wide functional targets bearing this motif not validated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided in vivo proof of an essential physiological role, demonstrating that DDX43 ATPase/helicase activity drives chromatin remodeling during spermiogenesis.\",\n      \"evidence\": \"conditional and global knockout mice, ATPase-dead knock-in phenocopy, scRNA-seq, and eCLIP-seq\",\n      \"pmids\": [\"37120627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking RNA targets (e.g. Elfn2) to histone-to-protamine exchange not defined\", \"Whether the same RNA-unwinding activity underlies its oncogenic roles untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an antiviral function, showing human DDX43 restricts HSV-2 replication independently of interferon.\",\n      \"evidence\": \"reciprocal overexpression and knockdown in HeLa and ARPE-19 cells with viral replication readouts and confirmed IFN independence\",\n      \"pmids\": [\"41157636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of restriction (target, step inhibited) unknown\", \"Single lab; relationship to the fish-ortholog innate-immune adaptor interactions unestablished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the in vitro RNA/DNA helicase activity and KH-domain motif recognition mechanistically unify DDX43's distinct roles in spermatid chromatin remodeling, RAS/SOCS1 mRNA regulation in cancer, and antiviral restriction.\",\n      \"evidence\": \"no single study connects the defined enzymology to validated cellular RNA targets across these contexts\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of substrate-engaged full-length DDX43\", \"Cellular target spectrum and recruitment determinants not mapped across tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SOCS1\", \"MAVS\", \"TRIF\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":7,"faith_total":7,"faith_pct":100.0}}