{"gene":"DDX18","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2022,"finding":"PARP-1 mediates the association of DDX18 with R-loops, and DDX18 depletion causes aberrant endogenous R-loop accumulation, DNA-replication defects, reduced RPA32 and RAD51 foci formation after irradiation, γH2AX accumulation, and genome instability; RNase H1 overexpression rescues all DNA-repair defects caused by DDX18 depletion, confirming R-loop as the causal intermediate.","method":"shRNA depletion, RNase H1 overexpression rescue, γH2AX immunofluorescence, RPA32/RAD51 foci assay, Co-IP (PARP-1/DDX18/R-loop association)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, foci assays, RNase H1 rescue) in a single focused study, RNase H1 rescue provides direct causal link to R-loops","pmids":["35858569"],"is_preprint":false},{"year":2024,"finding":"DDX18 is a nucleolus-resident protein that regulates nucleolus phase separation and nuclear organization by interacting with NPM1 in the granular nucleolar component, driven by specific nucleolar RNAs; loss of DDX18 disrupts nucleolar substructures, impairs centromere clustering, and disrupts perinucleolar heterochromatin (PNH) formation, leading to loss of pluripotency in human embryonic stem cells.","method":"Hi-C, DNA/RNA-FISH, biomolecular condensate analysis, Co-IP (DDX18–NPM1), NoCasDrop nucleolar targeting tool, DDX18 knockdown in hESCs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Hi-C, FISH, condensate analysis, Co-IP, functional rescue with NoCasDrop) in a single rigorous study","pmids":["39738032"],"is_preprint":false},{"year":2011,"finding":"In zebrafish, loss of Ddx18 causes p53-dependent G1 cell-cycle arrest and hematopoietic defects; loss of p53, but not Bcl-xl overexpression, rescues myeloid cells, placing Ddx18 upstream of p53-dependent G1 arrest; a human AML mutation DDX18-E76del acts as a dominant-negative allele, failing to rescue hematopoiesis in ddx18 mutant embryos.","method":"Zebrafish insertional mutagenesis, p53 loss-of-function epistasis, Bcl-xl overexpression epistasis, mRNA rescue experiments with wild-type and mutant DDX18","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (p53 rescue vs Bcl-xl non-rescue), dominant-negative rescue experiments, multiple alleles tested","pmids":["21653321"],"is_preprint":false},{"year":2007,"finding":"DDX18 (MrDb) is a nucleolar protein ubiquitously expressed in tumor cells; inhibition by dominant-negative mutant or shRNA reduces tumor cell proliferation without inducing cell-cycle arrest or apoptosis.","method":"Subcellular fractionation/immunofluorescence (nucleolar localization), dominant-negative mutant expression, shRNA knockdown, cell proliferation assay, cell-cycle analysis, apoptosis assay","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment plus functional knockdown with defined proliferation phenotype, single lab, two orthogonal inhibition approaches","pmids":["18351129"],"is_preprint":false},{"year":2017,"finding":"DDX18 interacts with PRRSV nsp2 (via nsp2 N-terminus) and nsp10 (via both N- and C-termini); expression of nsp2 or nsp10 redistributes DDX18 from the nucleus to the cytoplasm; DDX18 silencing down-regulates PRRSV replication.","method":"Co-immunoprecipitation, deletion-mapping of binding regions, immunofluorescence (subcellular redistribution), siRNA knockdown, viral replication assay","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP with binding-domain mapping, localization shift, and functional knockdown, single lab but multiple orthogonal methods","pmids":["28648849"],"is_preprint":false},{"year":2021,"finding":"DDX18 promotes maturation of microRNA-21 through direct interaction with Drosha; this reduces PTEN levels and upregulates AKT signaling in gastric cancer cells.","method":"Co-immunoprecipitation (DDX18–Drosha), small RNA sequencing, western blotting, xenograft and PDX models","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP showing direct DDX18–Drosha interaction plus functional readouts (miR-21 maturation, PTEN/AKT), single lab","pmids":["33489896"],"is_preprint":false},{"year":2023,"finding":"DDX18 deposits on the STAT1 promoter region and counteracts H3K27me3 deposition by modulating formation of the PRC2 complex, thereby transcriptionally upregulating STAT1, which in turn elevates PD-L1 expression and promotes immune evasion in pancreatic cancer.","method":"ChIP (DDX18 binding to STAT1 promoter), H3K27me3 ChIP, PRC2 complex co-IP, DDX18 knockdown with STAT1/PD-L1 expression readouts, anti-PD-L1 combination treatment in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and Co-IP data support direct promoter occupancy and PRC2 interaction, single lab, multiple complementary approaches","pmids":["37620449"],"is_preprint":false},{"year":2023,"finding":"ALKBH1 (DNA 6mA demethylase) regulates DDX18 expression by erasing DNA N6-methyladenine at the DDX18 promoter, thereby increasing DDX18 transcription; dual-luciferase reporter assay confirmed that 6mA levels modulate DDX18 promoter activity; exogenous DDX18 overexpression rescues proliferation arrested by ALKBH1 knockdown.","method":"MeDIP-seq, RNA sequencing, dual-luciferase reporter assay, Dot blotting, qRT-PCR, siRNA knockdown, overexpression rescue, patient-derived organoid assay","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (MeDIP-seq, reporter assay, rescue experiment) establishing epigenetic regulation of DDX18 promoter, single lab","pmids":["36976498"],"is_preprint":false},{"year":2024,"finding":"DDX18 directly transcriptionally activates CDK4 expression (identified by RNA-seq and ChIP); DDX18 depletion induces G1 cell-cycle arrest; c-Myc binds the DDX18 promoter but does not influence DDX18 expression (negative result for c-Myc as DDX18 transcriptional regulator).","method":"RNA sequencing, chromatin immunoprecipitation (DDX18 on CDK4 promoter; c-Myc on DDX18 promoter), siRNA knockdown, cell-cycle analysis, in vivo xenograft","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP identifies CDK4 as direct transcriptional target of DDX18, supported by RNA-seq and cell-cycle readout; c-Myc negative result by ChIP, single lab","pmids":["38732173"],"is_preprint":false},{"year":2025,"finding":"YY1 binds to and stimulates DDX18 transcription (confirmed by dual-luciferase reporter and ChIP assays); DDX18 promotes EMT and activates the AKT/mTOR signaling pathway in esophageal cancer; AKT inhibitors abrogate the oncogenic effects of DDX18.","method":"ChIP assay, dual-luciferase reporter assay, DDX18 knockdown/overexpression, AKT inhibitor treatment, rescue experiments, xenograft model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP + luciferase confirm direct YY1–DDX18 promoter interaction; AKT inhibitor rescue places DDX18 in pathway, single lab","pmids":["40394670"],"is_preprint":false},{"year":2024,"finding":"DDX18 expression positively correlates with R-loop accumulation in colorectal cancer; elevated DDX18 delays completion of DNA damage repair and increases double-strand DNA breaks, promoting genomic instability and enhancing sensitivity to DNA-damaging agents.","method":"Colon cancer tissue/cell lines/patient-derived organoids, R-loop detection, DSB assays (γH2AX), DDX18 knockdown, chemosensitivity assays","journal":"Experimental cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, primarily correlative with limited mechanistic resolution; no direct biochemical assay of DDX18 R-loop unwinding activity","pmids":["39577603"],"is_preprint":false},{"year":2025,"finding":"DDX18 interacts with REXO4 (confirmed by Co-IP and immunofluorescence colocalization); DDX18/REXO4 axis promotes HCC tumor growth and metastasis by regulating EMT and MAPK signaling; overexpression of REXO4 reverses the inhibitory effects of DDX18 knockdown.","method":"Co-immunoprecipitation, immunofluorescence colocalization, DDX18 knockdown/overexpression, REXO4 overexpression rescue, xenograft model, western blot for MAPK/EMT markers","journal":"Journal of gastrointestinal oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP establishes DDX18–REXO4 interaction but mechanism linking this interaction to MAPK/EMT is not biochemically resolved; single lab","pmids":["40950356"],"is_preprint":false},{"year":2026,"finding":"NOP58 directly interacts with DDX18 (confirmed by pull-down assay) and regulates DDX18 expression; DDX18 overexpression reverses the radiosensitizing effects of NOP58 knockdown, indicating that NOP58 promotes radioresistance through DDX18-mediated DNA damage repair.","method":"Pull-down assay, siRNA knockdown, DDX18 overexpression rescue, γH2AX immunofluorescence, comet assay, clonogenic survival assay","journal":"Journal of radiation research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pull-down confirms NOP58–DDX18 physical interaction, functional rescue supports pathway placement, but single lab with limited mechanistic resolution","pmids":["41834519"],"is_preprint":false},{"year":2025,"finding":"DDX18 (as a nucleolar-resident protein) interacts with SRSF1, which is recruited to the nucleolus under pH stress; this interaction is required for SRSF1 nucleolar localization and the restoration of nucleolar pH homeostasis and multiphase organization.","method":"Immunofluorescence (SRSF1 nuclear speckle-to-nucleolus shuttling), protein interaction assay (molecular interaction with DDX18 described), SRSF1 knockdown with nucleolar pH and phase readouts","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, interaction described but biochemical validation of DDX18–SRSF1 binding not fully detailed in abstract; single lab","pmids":["bio_10.1101_2025.04.12.648491"],"is_preprint":true}],"current_model":"DDX18 is a nucleolus-resident DEAD-box RNA helicase that maintains R-loop homeostasis (recruited to R-loops by PARP-1), regulates nucleolus phase separation and nuclear architecture by interacting with NPM1, transcriptionally controls target genes (including CDK4 and STAT1) partly through modulating PRC2/H3K27me3 deposition, promotes microRNA-21 maturation via Drosha interaction, and is required for normal cell-cycle progression and genome stability, with its own expression controlled by YY1 transcription and ALKBH1-mediated promoter demethylation."},"narrative":{"mechanistic_narrative":"DDX18 is a nucleolus-resident DEAD-box RNA helicase that maintains genome stability and nuclear architecture while serving as a transcriptional regulator of cell-cycle and immune-evasion programs [PMID:35858569, PMID:39738032, PMID:38732173]. Within the nucleolus, DDX18 organizes the granular component through an RNA-driven interaction with NPM1, sustaining nucleolar phase separation, perinucleolar heterochromatin formation, and centromere clustering; its loss disrupts these substructures and abolishes pluripotency in human embryonic stem cells [PMID:39738032]. DDX18 also governs R-loop homeostasis: PARP-1 recruits DDX18 to R-loops, and its depletion drives aberrant R-loop accumulation, replication defects, impaired RPA32/RAD51 focus formation, and genome instability that is reversed by RNase H1 overexpression, establishing R-loops as the causal intermediate [PMID:35858569]. Beyond RNA metabolism, DDX18 acts on chromatin as a transcriptional activator, directly occupying the CDK4 promoter to promote G1 progression [PMID:38732173] and binding the STAT1 promoter to counteract PRC2-mediated H3K27me3 deposition, thereby elevating STAT1 and downstream PD-L1 to drive immune evasion [PMID:37620449]. DDX18 additionally promotes microRNA-21 maturation through interaction with Drosha, lowering PTEN and activating AKT signaling [PMID:33489896]. Genetic studies place DDX18 upstream of p53-dependent G1 arrest, with a leukemia-associated E76del allele acting as a dominant negative [PMID:21653321]. Its own expression is controlled by YY1 transcriptional activation [PMID:40394670] and by ALKBH1-mediated erasure of promoter DNA N6-methyladenine [PMID:36976498].","teleology":[{"year":2007,"claim":"Established DDX18 as a nucleolar protein whose activity supports tumor cell proliferation, distinguishing a growth-promoting role from cell-cycle or apoptotic checkpoints.","evidence":"subcellular fractionation/immunofluorescence and dominant-negative/shRNA inhibition with proliferation, cell-cycle, and apoptosis readouts in tumor cells","pmids":["18351129"],"confidence":"Medium","gaps":["No molecular substrate or helicase target identified","Mechanism linking nucleolar residence to proliferation not resolved"]},{"year":2011,"claim":"Placed DDX18 genetically upstream of p53-dependent G1 arrest and showed an AML-associated allele behaves as a dominant negative, linking DDX18 dysfunction to hematopoietic disease.","evidence":"zebrafish insertional mutagenesis with p53 and Bcl-xl epistasis and wild-type/mutant mRNA rescue","pmids":["21653321"],"confidence":"High","gaps":["Molecular trigger of p53 activation upon Ddx18 loss not defined","Biochemical defect of E76del allele not characterized"]},{"year":2021,"claim":"Connected DDX18 to microRNA processing, showing it promotes miR-21 maturation via Drosha to suppress PTEN and activate AKT.","evidence":"Co-IP (DDX18-Drosha), small RNA-seq, western blot, xenograft/PDX in gastric cancer","pmids":["33489896"],"confidence":"Medium","gaps":["Whether DDX18 helicase activity is required for miR-21 processing untested","Generality beyond miR-21 unknown"]},{"year":2022,"claim":"Defined a direct role for DDX18 in R-loop homeostasis and DNA repair, with PARP-1 mediating its recruitment and RNase H1 rescue proving R-loops as the causal intermediate.","evidence":"shRNA depletion, RNase H1 overexpression rescue, gammaH2AX/RPA32/RAD51 foci assays, PARP-1/DDX18/R-loop Co-IP","pmids":["35858569"],"confidence":"High","gaps":["Direct R-loop unwinding activity not biochemically reconstituted","How PARP-1 selects DDX18 to specific R-loops unknown"]},{"year":2023,"claim":"Revealed DDX18 as a chromatin-acting transcriptional regulator that counteracts PRC2/H3K27me3 at the STAT1 promoter to drive PD-L1-mediated immune evasion.","evidence":"DDX18 and H3K27me3 ChIP, PRC2 Co-IP, knockdown with STAT1/PD-L1 readouts, anti-PD-L1 combination in vivo (pancreatic cancer)","pmids":["37620449"],"confidence":"Medium","gaps":["Mechanism by which DDX18 inhibits PRC2 assembly unresolved","Whether RNA binding is required for promoter occupancy unknown"]},{"year":2023,"claim":"Identified epigenetic control of DDX18 itself through ALKBH1-mediated DNA 6mA demethylation at its promoter.","evidence":"MeDIP-seq, dual-luciferase reporter, dot blot, siRNA knockdown and DDX18 overexpression rescue, patient-derived organoids","pmids":["36976498"],"confidence":"Medium","gaps":["Direct demethylation of DDX18 promoter by ALKBH1 not shown biochemically","Other regulators of the promoter not excluded"]},{"year":2024,"claim":"Established CDK4 as a direct transcriptional target of DDX18 driving G1 progression, while ruling out c-Myc as a DDX18 transcriptional regulator.","evidence":"RNA-seq, ChIP (DDX18 on CDK4 promoter; c-Myc on DDX18 promoter), siRNA, cell-cycle analysis, xenograft","pmids":["38732173"],"confidence":"Medium","gaps":["How a helicase achieves sequence-specific promoter activation unresolved","Cofactors at the CDK4 promoter not defined"]},{"year":2024,"claim":"Demonstrated DDX18 organizes nucleolar phase separation and nuclear architecture via NPM1, linking nucleolar integrity to stem-cell pluripotency.","evidence":"Hi-C, DNA/RNA-FISH, condensate analysis, DDX18-NPM1 Co-IP, NoCasDrop targeting, knockdown in hESCs","pmids":["39738032"],"confidence":"High","gaps":["Which nucleolar RNAs drive the interaction not fully defined","Role of helicase catalysis in condensate formation untested"]},{"year":2025,"claim":"Placed DDX18 in a YY1-driven transcriptional axis promoting EMT and AKT/mTOR signaling.","evidence":"ChIP, dual-luciferase reporter, knockdown/overexpression, AKT inhibitor rescue, xenograft in esophageal cancer","pmids":["40394670"],"confidence":"Medium","gaps":["Direct DDX18 effectors in AKT/mTOR activation not identified","Relationship to its nucleolar function unclear"]},{"year":2025,"claim":"Implicated DDX18 in nucleolar pH stress responses by enabling SRSF1 nucleolar localization.","evidence":"immunofluorescence of SRSF1 shuttling, interaction assay, SRSF1 knockdown with pH/phase readouts (preprint)","pmids":["bio_10.1101_2025.04.12.648491"],"confidence":"Low","gaps":["Preprint; biochemical validation of DDX18-SRSF1 binding not fully detailed","Direction of regulation unconfirmed"]},{"year":2025,"claim":"Reported DDX18 interaction with REXO4 promoting HCC growth and metastasis through EMT and MAPK signaling.","evidence":"Co-IP, immunofluorescence colocalization, knockdown/overexpression with REXO4 rescue, xenograft, MAPK/EMT western blots","pmids":["40950356"],"confidence":"Low","gaps":["Single Co-IP without reciprocal mechanistic dissection","How the interaction engages MAPK/EMT not biochemically resolved"]},{"year":2026,"claim":"Positioned DDX18 downstream of NOP58 in DNA-damage repair underlying radioresistance.","evidence":"pull-down, siRNA, DDX18 overexpression rescue, gammaH2AX, comet and clonogenic assays","pmids":["41834519"],"confidence":"Low","gaps":["Pull-down without reciprocal validation","Mechanism of NOP58-DDX18 cooperation in repair unresolved"]},{"year":null,"claim":"Whether DDX18's enzymatic helicase activity is the unifying biochemical basis for its roles in R-loop resolution, nucleolar condensation, miRNA processing, and promoter regulation remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vitro reconstitution of DDX18 RNA/R-loop unwinding reported in the corpus","How a single helicase achieves sequence-specific transcriptional and structural functions is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,8]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1]}],"complexes":[],"partners":["PARP1","NPM1","DROSHA","REXO4","NOP58","SRSF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NVP1","full_name":"ATP-dependent RNA helicase DDX18","aliases":["DEAD box protein 18","Myc-regulated DEAD box protein","MrDb"],"length_aa":670,"mass_kda":75.4,"function":"ATP-dependent RNA helicase that plays a role in the regulation of R-loop homeostasis in both endogenous R-loop-prone regions and at sites of DNA damage. At endogenous loci such as actively transcribed genes, may act as a helicase to resolve the formation of R-loop during transcription and prevent the interference of R-loop with DNA-replication machinery. Also participates in the removal of DNA-lesion-associated R-loop (PubMed:35858569). Plays an essential role for establishing pluripotency during embryogenesis and for pluripotency maintenance in embryonic stem cells. Mechanistically, prevents the polycomb repressive complex 2 (PRC2) from accessing rDNA loci and protects the active chromatin status in nucleolus (By similarity)","subcellular_location":"Nucleus, nucleolus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q9NVP1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DDX18","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"FKBP5","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2},{"gene":"SF3B1","stoichiometry":0.2},{"gene":"SRP9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DDX18","total_profiled":1310},"omim":[{"mim_id":"615428","title":"DEAD-BOX HELICASE 47; DDX47","url":"https://www.omim.org/entry/615428"},{"mim_id":"611534","title":"NUCLEOLAR PROTEIN 8; NOL8","url":"https://www.omim.org/entry/611534"},{"mim_id":"606355","title":"DEAD-BOX HELICASE 18; DDX18","url":"https://www.omim.org/entry/606355"},{"mim_id":"190080","title":"MYC PROTOONCOGENE, bHLH TRANSCRIPTION FACTOR; MYC","url":"https://www.omim.org/entry/190080"},{"mim_id":"154950","title":"MAX PROTEIN; MAX","url":"https://www.omim.org/entry/154950"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Nucleoli rim","reliability":"Enhanced"},{"location":"Mitotic chromosome","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DDX18"},"hgnc":{"alias_symbol":["MrDb","Has1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NVP1","domains":[{"cath_id":"3.40.50.300","chopping":"189-388","consensus_level":"high","plddt":89.4267,"start":189,"end":388},{"cath_id":"3.40.50.300","chopping":"401-562","consensus_level":"high","plddt":87.3774,"start":401,"end":562}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVP1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVP1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NVP1-F1-predicted_aligned_error_v6.png","plddt_mean":72.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDX18","jax_strain_url":"https://www.jax.org/strain/search?query=DDX18"},"sequence":{"accession":"Q9NVP1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NVP1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NVP1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NVP1"}},"corpus_meta":[{"pmid":"6243629","id":"PMC_6243629","title":"Cluster 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Animal","url":"https://pubmed.ncbi.nlm.nih.gov/39134870","citation_count":1,"is_preprint":false},{"pmid":"39061935","id":"PMC_39061935","title":"In Vivo-Matured Oocyte Resists Post-Ovulatory Aging through the Hub Genes DDX18 and DNAJC7 in Pigs.","date":"2024","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39061935","citation_count":1,"is_preprint":false},{"pmid":"40996707","id":"PMC_40996707","title":"MRdb: a comprehensive database of univariate and multivariate Mendelian randomization with large-scale GWAS summary data.","date":"2025","source":"Database : the journal of biological databases and curation","url":"https://pubmed.ncbi.nlm.nih.gov/40996707","citation_count":0,"is_preprint":false},{"pmid":"40950356","id":"PMC_40950356","title":"DDX18 promotes growth and metastasis of hepatocellular carcinoma via activating EMT and MAPK signaling.","date":"2025","source":"Journal of gastrointestinal oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40950356","citation_count":0,"is_preprint":false},{"pmid":"41834519","id":"PMC_41834519","title":"NOP58 modulates radiosensitivity in non-small cell lung cancer via DDX18-mediated DNA damage repair.","date":"2026","source":"Journal of radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/41834519","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.12.648491","title":"Splicing factor SRSF1 is a pH-stat to restore nucleolar integrity and function","date":"2025-04-14","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.12.648491","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12570,"output_tokens":3672,"usd":0.046395,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11381,"output_tokens":3982,"usd":0.078228,"stage2_stop_reason":"end_turn"},"total_usd":0.124623,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2022,\n      \"finding\": \"PARP-1 mediates the association of DDX18 with R-loops, and DDX18 depletion causes aberrant endogenous R-loop accumulation, DNA-replication defects, reduced RPA32 and RAD51 foci formation after irradiation, γH2AX accumulation, and genome instability; RNase H1 overexpression rescues all DNA-repair defects caused by DDX18 depletion, confirming R-loop as the causal intermediate.\",\n      \"method\": \"shRNA depletion, RNase H1 overexpression rescue, γH2AX immunofluorescence, RPA32/RAD51 foci assay, Co-IP (PARP-1/DDX18/R-loop association)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, foci assays, RNase H1 rescue) in a single focused study, RNase H1 rescue provides direct causal link to R-loops\",\n      \"pmids\": [\"35858569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX18 is a nucleolus-resident protein that regulates nucleolus phase separation and nuclear organization by interacting with NPM1 in the granular nucleolar component, driven by specific nucleolar RNAs; loss of DDX18 disrupts nucleolar substructures, impairs centromere clustering, and disrupts perinucleolar heterochromatin (PNH) formation, leading to loss of pluripotency in human embryonic stem cells.\",\n      \"method\": \"Hi-C, DNA/RNA-FISH, biomolecular condensate analysis, Co-IP (DDX18–NPM1), NoCasDrop nucleolar targeting tool, DDX18 knockdown in hESCs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Hi-C, FISH, condensate analysis, Co-IP, functional rescue with NoCasDrop) in a single rigorous study\",\n      \"pmids\": [\"39738032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In zebrafish, loss of Ddx18 causes p53-dependent G1 cell-cycle arrest and hematopoietic defects; loss of p53, but not Bcl-xl overexpression, rescues myeloid cells, placing Ddx18 upstream of p53-dependent G1 arrest; a human AML mutation DDX18-E76del acts as a dominant-negative allele, failing to rescue hematopoiesis in ddx18 mutant embryos.\",\n      \"method\": \"Zebrafish insertional mutagenesis, p53 loss-of-function epistasis, Bcl-xl overexpression epistasis, mRNA rescue experiments with wild-type and mutant DDX18\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (p53 rescue vs Bcl-xl non-rescue), dominant-negative rescue experiments, multiple alleles tested\",\n      \"pmids\": [\"21653321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DDX18 (MrDb) is a nucleolar protein ubiquitously expressed in tumor cells; inhibition by dominant-negative mutant or shRNA reduces tumor cell proliferation without inducing cell-cycle arrest or apoptosis.\",\n      \"method\": \"Subcellular fractionation/immunofluorescence (nucleolar localization), dominant-negative mutant expression, shRNA knockdown, cell proliferation assay, cell-cycle analysis, apoptosis assay\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment plus functional knockdown with defined proliferation phenotype, single lab, two orthogonal inhibition approaches\",\n      \"pmids\": [\"18351129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDX18 interacts with PRRSV nsp2 (via nsp2 N-terminus) and nsp10 (via both N- and C-termini); expression of nsp2 or nsp10 redistributes DDX18 from the nucleus to the cytoplasm; DDX18 silencing down-regulates PRRSV replication.\",\n      \"method\": \"Co-immunoprecipitation, deletion-mapping of binding regions, immunofluorescence (subcellular redistribution), siRNA knockdown, viral replication assay\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP with binding-domain mapping, localization shift, and functional knockdown, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28648849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX18 promotes maturation of microRNA-21 through direct interaction with Drosha; this reduces PTEN levels and upregulates AKT signaling in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (DDX18–Drosha), small RNA sequencing, western blotting, xenograft and PDX models\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP showing direct DDX18–Drosha interaction plus functional readouts (miR-21 maturation, PTEN/AKT), single lab\",\n      \"pmids\": [\"33489896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DDX18 deposits on the STAT1 promoter region and counteracts H3K27me3 deposition by modulating formation of the PRC2 complex, thereby transcriptionally upregulating STAT1, which in turn elevates PD-L1 expression and promotes immune evasion in pancreatic cancer.\",\n      \"method\": \"ChIP (DDX18 binding to STAT1 promoter), H3K27me3 ChIP, PRC2 complex co-IP, DDX18 knockdown with STAT1/PD-L1 expression readouts, anti-PD-L1 combination treatment in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and Co-IP data support direct promoter occupancy and PRC2 interaction, single lab, multiple complementary approaches\",\n      \"pmids\": [\"37620449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALKBH1 (DNA 6mA demethylase) regulates DDX18 expression by erasing DNA N6-methyladenine at the DDX18 promoter, thereby increasing DDX18 transcription; dual-luciferase reporter assay confirmed that 6mA levels modulate DDX18 promoter activity; exogenous DDX18 overexpression rescues proliferation arrested by ALKBH1 knockdown.\",\n      \"method\": \"MeDIP-seq, RNA sequencing, dual-luciferase reporter assay, Dot blotting, qRT-PCR, siRNA knockdown, overexpression rescue, patient-derived organoid assay\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (MeDIP-seq, reporter assay, rescue experiment) establishing epigenetic regulation of DDX18 promoter, single lab\",\n      \"pmids\": [\"36976498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX18 directly transcriptionally activates CDK4 expression (identified by RNA-seq and ChIP); DDX18 depletion induces G1 cell-cycle arrest; c-Myc binds the DDX18 promoter but does not influence DDX18 expression (negative result for c-Myc as DDX18 transcriptional regulator).\",\n      \"method\": \"RNA sequencing, chromatin immunoprecipitation (DDX18 on CDK4 promoter; c-Myc on DDX18 promoter), siRNA knockdown, cell-cycle analysis, in vivo xenograft\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP identifies CDK4 as direct transcriptional target of DDX18, supported by RNA-seq and cell-cycle readout; c-Myc negative result by ChIP, single lab\",\n      \"pmids\": [\"38732173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YY1 binds to and stimulates DDX18 transcription (confirmed by dual-luciferase reporter and ChIP assays); DDX18 promotes EMT and activates the AKT/mTOR signaling pathway in esophageal cancer; AKT inhibitors abrogate the oncogenic effects of DDX18.\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, DDX18 knockdown/overexpression, AKT inhibitor treatment, rescue experiments, xenograft model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP + luciferase confirm direct YY1–DDX18 promoter interaction; AKT inhibitor rescue places DDX18 in pathway, single lab\",\n      \"pmids\": [\"40394670\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX18 expression positively correlates with R-loop accumulation in colorectal cancer; elevated DDX18 delays completion of DNA damage repair and increases double-strand DNA breaks, promoting genomic instability and enhancing sensitivity to DNA-damaging agents.\",\n      \"method\": \"Colon cancer tissue/cell lines/patient-derived organoids, R-loop detection, DSB assays (γH2AX), DDX18 knockdown, chemosensitivity assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, primarily correlative with limited mechanistic resolution; no direct biochemical assay of DDX18 R-loop unwinding activity\",\n      \"pmids\": [\"39577603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX18 interacts with REXO4 (confirmed by Co-IP and immunofluorescence colocalization); DDX18/REXO4 axis promotes HCC tumor growth and metastasis by regulating EMT and MAPK signaling; overexpression of REXO4 reverses the inhibitory effects of DDX18 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, DDX18 knockdown/overexpression, REXO4 overexpression rescue, xenograft model, western blot for MAPK/EMT markers\",\n      \"journal\": \"Journal of gastrointestinal oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP establishes DDX18–REXO4 interaction but mechanism linking this interaction to MAPK/EMT is not biochemically resolved; single lab\",\n      \"pmids\": [\"40950356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NOP58 directly interacts with DDX18 (confirmed by pull-down assay) and regulates DDX18 expression; DDX18 overexpression reverses the radiosensitizing effects of NOP58 knockdown, indicating that NOP58 promotes radioresistance through DDX18-mediated DNA damage repair.\",\n      \"method\": \"Pull-down assay, siRNA knockdown, DDX18 overexpression rescue, γH2AX immunofluorescence, comet assay, clonogenic survival assay\",\n      \"journal\": \"Journal of radiation research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pull-down confirms NOP58–DDX18 physical interaction, functional rescue supports pathway placement, but single lab with limited mechanistic resolution\",\n      \"pmids\": [\"41834519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX18 (as a nucleolar-resident protein) interacts with SRSF1, which is recruited to the nucleolus under pH stress; this interaction is required for SRSF1 nucleolar localization and the restoration of nucleolar pH homeostasis and multiphase organization.\",\n      \"method\": \"Immunofluorescence (SRSF1 nuclear speckle-to-nucleolus shuttling), protein interaction assay (molecular interaction with DDX18 described), SRSF1 knockdown with nucleolar pH and phase readouts\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, interaction described but biochemical validation of DDX18–SRSF1 binding not fully detailed in abstract; single lab\",\n      \"pmids\": [\"bio_10.1101_2025.04.12.648491\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"DDX18 is a nucleolus-resident DEAD-box RNA helicase that maintains R-loop homeostasis (recruited to R-loops by PARP-1), regulates nucleolus phase separation and nuclear architecture by interacting with NPM1, transcriptionally controls target genes (including CDK4 and STAT1) partly through modulating PRC2/H3K27me3 deposition, promotes microRNA-21 maturation via Drosha interaction, and is required for normal cell-cycle progression and genome stability, with its own expression controlled by YY1 transcription and ALKBH1-mediated promoter demethylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDX18 is a nucleolus-resident DEAD-box RNA helicase that maintains genome stability and nuclear architecture while serving as a transcriptional regulator of cell-cycle and immune-evasion programs [#0, #1, #8]. Within the nucleolus, DDX18 organizes the granular component through an RNA-driven interaction with NPM1, sustaining nucleolar phase separation, perinucleolar heterochromatin formation, and centromere clustering; its loss disrupts these substructures and abolishes pluripotency in human embryonic stem cells [#1]. DDX18 also governs R-loop homeostasis: PARP-1 recruits DDX18 to R-loops, and its depletion drives aberrant R-loop accumulation, replication defects, impaired RPA32/RAD51 focus formation, and genome instability that is reversed by RNase H1 overexpression, establishing R-loops as the causal intermediate [#0]. Beyond RNA metabolism, DDX18 acts on chromatin as a transcriptional activator, directly occupying the CDK4 promoter to promote G1 progression [#8] and binding the STAT1 promoter to counteract PRC2-mediated H3K27me3 deposition, thereby elevating STAT1 and downstream PD-L1 to drive immune evasion [#6]. DDX18 additionally promotes microRNA-21 maturation through interaction with Drosha, lowering PTEN and activating AKT signaling [#5]. Genetic studies place DDX18 upstream of p53-dependent G1 arrest, with a leukemia-associated E76del allele acting as a dominant negative [#2]. Its own expression is controlled by YY1 transcriptional activation [#9] and by ALKBH1-mediated erasure of promoter DNA N6-methyladenine [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established DDX18 as a nucleolar protein whose activity supports tumor cell proliferation, distinguishing a growth-promoting role from cell-cycle or apoptotic checkpoints.\",\n      \"evidence\": \"subcellular fractionation/immunofluorescence and dominant-negative/shRNA inhibition with proliferation, cell-cycle, and apoptosis readouts in tumor cells\",\n      \"pmids\": [\"18351129\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular substrate or helicase target identified\", \"Mechanism linking nucleolar residence to proliferation not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed DDX18 genetically upstream of p53-dependent G1 arrest and showed an AML-associated allele behaves as a dominant negative, linking DDX18 dysfunction to hematopoietic disease.\",\n      \"evidence\": \"zebrafish insertional mutagenesis with p53 and Bcl-xl epistasis and wild-type/mutant mRNA rescue\",\n      \"pmids\": [\"21653321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger of p53 activation upon Ddx18 loss not defined\", \"Biochemical defect of E76del allele not characterized\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected DDX18 to microRNA processing, showing it promotes miR-21 maturation via Drosha to suppress PTEN and activate AKT.\",\n      \"evidence\": \"Co-IP (DDX18-Drosha), small RNA-seq, western blot, xenograft/PDX in gastric cancer\",\n      \"pmids\": [\"33489896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DDX18 helicase activity is required for miR-21 processing untested\", \"Generality beyond miR-21 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a direct role for DDX18 in R-loop homeostasis and DNA repair, with PARP-1 mediating its recruitment and RNase H1 rescue proving R-loops as the causal intermediate.\",\n      \"evidence\": \"shRNA depletion, RNase H1 overexpression rescue, gammaH2AX/RPA32/RAD51 foci assays, PARP-1/DDX18/R-loop Co-IP\",\n      \"pmids\": [\"35858569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct R-loop unwinding activity not biochemically reconstituted\", \"How PARP-1 selects DDX18 to specific R-loops unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed DDX18 as a chromatin-acting transcriptional regulator that counteracts PRC2/H3K27me3 at the STAT1 promoter to drive PD-L1-mediated immune evasion.\",\n      \"evidence\": \"DDX18 and H3K27me3 ChIP, PRC2 Co-IP, knockdown with STAT1/PD-L1 readouts, anti-PD-L1 combination in vivo (pancreatic cancer)\",\n      \"pmids\": [\"37620449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which DDX18 inhibits PRC2 assembly unresolved\", \"Whether RNA binding is required for promoter occupancy unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified epigenetic control of DDX18 itself through ALKBH1-mediated DNA 6mA demethylation at its promoter.\",\n      \"evidence\": \"MeDIP-seq, dual-luciferase reporter, dot blot, siRNA knockdown and DDX18 overexpression rescue, patient-derived organoids\",\n      \"pmids\": [\"36976498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct demethylation of DDX18 promoter by ALKBH1 not shown biochemically\", \"Other regulators of the promoter not excluded\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established CDK4 as a direct transcriptional target of DDX18 driving G1 progression, while ruling out c-Myc as a DDX18 transcriptional regulator.\",\n      \"evidence\": \"RNA-seq, ChIP (DDX18 on CDK4 promoter; c-Myc on DDX18 promoter), siRNA, cell-cycle analysis, xenograft\",\n      \"pmids\": [\"38732173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a helicase achieves sequence-specific promoter activation unresolved\", \"Cofactors at the CDK4 promoter not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated DDX18 organizes nucleolar phase separation and nuclear architecture via NPM1, linking nucleolar integrity to stem-cell pluripotency.\",\n      \"evidence\": \"Hi-C, DNA/RNA-FISH, condensate analysis, DDX18-NPM1 Co-IP, NoCasDrop targeting, knockdown in hESCs\",\n      \"pmids\": [\"39738032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which nucleolar RNAs drive the interaction not fully defined\", \"Role of helicase catalysis in condensate formation untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed DDX18 in a YY1-driven transcriptional axis promoting EMT and AKT/mTOR signaling.\",\n      \"evidence\": \"ChIP, dual-luciferase reporter, knockdown/overexpression, AKT inhibitor rescue, xenograft in esophageal cancer\",\n      \"pmids\": [\"40394670\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct DDX18 effectors in AKT/mTOR activation not identified\", \"Relationship to its nucleolar function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated DDX18 in nucleolar pH stress responses by enabling SRSF1 nucleolar localization.\",\n      \"evidence\": \"immunofluorescence of SRSF1 shuttling, interaction assay, SRSF1 knockdown with pH/phase readouts (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.12.648491\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint; biochemical validation of DDX18-SRSF1 binding not fully detailed\", \"Direction of regulation unconfirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported DDX18 interaction with REXO4 promoting HCC growth and metastasis through EMT and MAPK signaling.\",\n      \"evidence\": \"Co-IP, immunofluorescence colocalization, knockdown/overexpression with REXO4 rescue, xenograft, MAPK/EMT western blots\",\n      \"pmids\": [\"40950356\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal mechanistic dissection\", \"How the interaction engages MAPK/EMT not biochemically resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Positioned DDX18 downstream of NOP58 in DNA-damage repair underlying radioresistance.\",\n      \"evidence\": \"pull-down, siRNA, DDX18 overexpression rescue, gammaH2AX, comet and clonogenic assays\",\n      \"pmids\": [\"41834519\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pull-down without reciprocal validation\", \"Mechanism of NOP58-DDX18 cooperation in repair unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether DDX18's enzymatic helicase activity is the unifying biochemical basis for its roles in R-loop resolution, nucleolar condensation, miRNA processing, and promoter regulation remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro reconstitution of DDX18 RNA/R-loop unwinding reported in the corpus\", \"How a single helicase achieves sequence-specific transcriptional and structural functions is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PARP1\", \"NPM1\", \"DROSHA\", \"REXO4\", \"NOP58\", \"SRSF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}