{"gene":"DDX5","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2019,"finding":"DDX5 resolves R-loops (RNA:DNA hybrids) in an ATP-dependent manner in vitro; its RGG/RG motif is methylated by PRMT5, and this methylation is required for DDX5 interaction with XRN2 and repression of cellular R-loops (but not for helicase enzymatic activity itself). DDX5 associates with XRN2 at transcriptional termination regions to facilitate RNA polymerase II release.","method":"In vitro R-loop resolution assay with recombinant DDX5, co-immunoprecipitation of DDX5-XRN2, DRIP-qPCR in DDX5-deficient cells, RGG/RG motif mutagenesis, identification of PRMT5 as the writer by binding/methylation assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant protein, mutagenesis of functional motif, multiple orthogonal methods (DRIP-qPCR, Co-IP, in vitro assay)","pmids":["31267554"],"is_preprint":false},{"year":2021,"finding":"BRCA2 physically interacts with DDX5 and stimulates its DNA-RNA hybrid-unwinding helicase activity at DNA double-strand breaks (DSBs). The BRCA2-T207A breast cancer variant shows impaired interaction with DDX5, reducing DDX5 association with DNA-RNA hybrids near DSBs and altering RPA and RAD51 recruitment kinetics.","method":"Co-immunoprecipitation identifying DDX5 as BRCA2-interacting protein, in vitro helicase stimulation assay, DRIP at DSBs, analysis of BRCA2-T207A variant cells, RPA/RAD51 foci quantification","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro helicase stimulation assay combined with Co-IP, variant functional analysis, and multiple cellular readouts","pmids":["33634895"],"is_preprint":false},{"year":2015,"finding":"DDX5 functions as a transcriptional co-activator of the nuclear receptor RORγt in TH17 cells; this co-activation requires DDX5's intrinsic RNA helicase activity and binding of the lncRNA Rmrp. A Rmrp mutation corresponding to cartilage-hair hypoplasia reduced DDX5-RORγt interaction and RORγt target gene transcription.","method":"Co-immunoprecipitation of DDX5-RORγt complex, RNA helicase activity mutants, targeted Rmrp gene mutation in mice, chromatin occupancy studies, TH17 differentiation and inflammatory disease models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNA helicase mutants, in vivo mouse genetic model with defined phenotype, replicated across multiple assays","pmids":["26675721"],"is_preprint":false},{"year":2019,"finding":"DDX5 is a highly active G-quadruplex (G4) resolvase that unfolds MycG4-DNA without requiring a single-stranded overhang; ATP hydrolysis is not directly coupled to G4-unfolding. DDX5 is enriched at G-rich chromatin sites including the MYC promoter and activates MYC transcription; G4-interactive small molecules inhibit DDX5's interaction with the MYC promoter.","method":"In vitro G4-unfolding assays, ATP hydrolysis decoupling experiments, ChIP-seq for DDX5 chromatin binding, MYC transcription assays, G4-stabilizing small molecule experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with mechanistic detail (ATP decoupling), supported by ChIP and functional transcription assays","pmids":["31548374"],"is_preprint":false},{"year":2020,"finding":"DDX5 clears R-loops at or near DSBs to enable proper DNA repair. DDX5 binds RNA transcripts near DSBs (shown by CLIP), requires its helicase domain, is excluded from DSBs in a transcription- and ATM activation-dependent manner, and its deficiency leads to asymmetric chromosomal deletions and impaired homologous recombination (delayed EXO1 and RPA recruitment).","method":"CLIP (crosslinking immunoprecipitation), ChIP, DRIP-seq in DDX5-deficient cells, NHEJ reporter (EJ5-GFP), laser irradiation-induced damage foci, EXO1/RPA recruitment assays","journal":"NAR cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (CLIP, ChIP, DRIP, reporter assay, foci), mechanistically defined helicase domain requirement","pmids":["33015627"],"is_preprint":false},{"year":2022,"finding":"TOP3B resolves R-loops in coordination with DDX5 independently of TDRD3. IP-mass spectrometry and IP-western show TOP3B physically interacts with DDX5. DDX5 and TOP3B are epistatic in resolving R-loops in a pathway parallel with senataxin; TOP3B cleaves the single-stranded DNA displaced by R-loop RNA-DNA duplexes.","method":"IP-mass spectrometry, IP-western blotting, biochemical assays with recombinant TOP3B and oligonucleotide R-loop mimics, RNA/DNA hybrid IP-western, genetic epistasis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, epistasis, and multiple orthogonal interaction methods","pmids":["35830799"],"is_preprint":false},{"year":2021,"finding":"DDX5 interacts with the m6A writer METTL3 to regulate methylation of mRNAs including DHX58, p65, and IKKγ by affecting the METTL3-METTL14 heterodimer complex; DDX5 promotes m6A modification and nuclear export of these transcripts, leading to YTHDF2-dependent mRNA decay of antiviral transcripts and suppression of IFN-β signaling.","method":"Co-immunoprecipitation of DDX5-METTL3 complex, m6A sequencing, mRNA stability assays, nuclear export assays, viral infection models in vitro and in vivo","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional m6A and export assays, single lab","pmids":["33909701"],"is_preprint":false},{"year":2022,"finding":"DDX5 interacts with METTL3 and METTL14 to form an m6A writing complex that adds m6A to TLR2 and TLR4 transcripts, promoting their YTHDF2-mediated decay; upon bacterial infection, DDX5 is recruited to Hrd1 at the ER in a MyD88-dependent manner and degraded via the ubiquitin-proteasome pathway, disrupting the complex and allowing TLR2/4 upregulation and NF-κB activation.","method":"Co-immunoprecipitation of DDX5-METTL3/14 complex, m6A modification assays, YTHDF2 mRNA decay assays, bacterial infection models, MyD88-dependent recruitment assay, in vivo DDX5-KO and METTL3-KO mice","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, functional m6A and mRNA decay assays, in vivo KO validation, multiple orthogonal methods","pmids":["38182816"],"is_preprint":false},{"year":2021,"finding":"DDX5 resolves a G-quadruplex structure (rG4) in the 5'UTR of STAT1 mRNA to enable STAT1 translation and interferon signaling. Direct and selective binding of helicase-active DDX5 to the WT STAT1-rG4 sequence was demonstrated by ribonucleoprotein and EMSA assays; CRISPR editing of the STAT1-rG4 sequence conferred resistance to rG4-stabilizing compounds.","method":"Luciferase reporter assays with WT vs. mutant rG4 sequence, rG4-stabilizing compounds, CRISPR/Cas9 editing of STAT1-rG4, circular dichroism, RNP/EMSA binding assays, IFN-α response assays","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding assay with mutagenesis, CRISPR functional validation, biophysical structure determination, multiple orthogonal methods","pmids":["34021034"],"is_preprint":false},{"year":2014,"finding":"DDX5 and DDX17 cooperate with hnRNP H/F splicing factors to define epithelial- and myoblast-specific splicing subprograms during differentiation. DDX5/DDX17 downregulation during myogenesis and EMT contributes to splicing program switching; this downregulation is itself mediated by DDX5/DDX17-dependent miRNA production.","method":"RNA-seq of splicing events after knockdown, co-immunoprecipitation with hnRNP H/F, miRNA profiling, cell differentiation models","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA-seq, Co-IP, miRNA profiling, functional knockdown in multiple differentiation contexts","pmids":["24910439"],"is_preprint":false},{"year":2007,"finding":"DDX5 (p68) and its paralog DDX17 (p72/p82) are required for 32S pre-rRNA cleavage and ribosome biogenesis; their apparently redundant role corresponds to RNA rearrangement (not unwinding) activity required for structural rearrangement within the pre-60S ribosomal subunit preceding 32S processing. Co-silencing of both genes causes nucleolar structure perturbation and cell death.","method":"siRNA knockdown of DDX5 and/or DDX17, RNA helicase mutant studies, nucleolar morphology analysis, pre-rRNA processing assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with specific rRNA processing readout and mutant analysis, single lab","pmids":["17485482"],"is_preprint":false},{"year":2011,"finding":"ARF limits the nucleolar localization of DDX5 by inhibiting the interaction between DDX5 and nucleophosmin (NPM), preventing DDX5 association with the rDNA promoter and nuclear pre-ribosomes. DDX5 promotes rRNA synthesis/maturation and ribosome output.","method":"Mass spectrometry of nucleolar proteins in Arf-deficient cells, Co-immunoprecipitation of DDX5-NPM, ChIP at rDNA promoter, DDX5 knockdown effects on ribosome biogenesis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, nucleolar localization experiments, single lab with multiple methods","pmids":["21937682"],"is_preprint":false},{"year":2012,"finding":"DDX5 promotes DNA replication by directly regulating E2F-dependent gene promoters (recruiting RNA polymerase II to E2F-regulated gene promoters) to control DNA replication factor expression during G1-S phase progression.","method":"Episomal plasmid stability assay, ChIP for RNA Pol II at E2F promoters, DDX5 knockdown effects on replication factor expression, cell cycle analysis","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, functional replication assay, KD with defined promoter recruitment readout, single lab","pmids":["22750847"],"is_preprint":false},{"year":2008,"finding":"DDX5 (p68) functions as a transcriptional co-activator of Runx2 in osteoblasts; p68 co-localizes with Runx2 in nuclear punctate foci. Helicase activity was not essential for Runx2 co-activation. Paradoxically, p68 suppression accelerated osteoblast differentiation, and Runx2 suppressed p68 expression in calvarial progenitors, revealing reciprocal regulation.","method":"Affinity purification/proteomics identifying p68-Runx2 interaction, co-localization by immunofluorescence, transcription reporter assays with helicase mutants, siRNA knockdown, osteoblast differentiation assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification, co-localization, reporter assays with mutants, single lab","pmids":["17960593"],"is_preprint":false},{"year":2013,"finding":"DDX5 (p68) functions as a co-activator in the Notch signaling pathway by directly interacting with RBP-J. DDX5 localizes to RBP-J binding sites at Notch target gene promoters (preTCRα, Hes1, CD25) in a Notch-dependent manner. The RNA co-activator SRA acts as a DDX5 cofactor in this context; DDX5/SRA co-activation is accompanied by p300 occupancy and histone acetylation.","method":"Biotinylation-tagging followed by mass spectrometry identifying DDX5 in RBP-J/NICD complex, biochemical interaction assays, ChIP at Notch target gene loci, siRNA knockdown, SRA knockdown/overexpression","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction confirmed biochemically, ChIP, functional knockdown, single lab","pmids":["23396200"],"is_preprint":false},{"year":2013,"finding":"DDX5 (p68) unwinds the stem-loop IDX-rasISS1 structure in H-Ras pre-mRNA and prevents binding of hnRNP H to this structure, thereby regulating alternative splicing of H-Ras to modulate the ratio of p21/p19 H-Ras isoforms. p68 also alters dynamic localization of SC35 splicing factor.","method":"In vitro RNA unwinding assays, RNA-protein binding competition assays, SC35 localization by immunofluorescence, RNAi knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical unwinding assay with functional splicing consequence, single lab","pmids":["18698352"],"is_preprint":false},{"year":2012,"finding":"DDX5 binds the lncRNA mrhl RNA in mouse spermatogonial cells (identified by Northwestern blot and RNA pulldown); mrhl RNA downregulation causes cytoplasmic translocation of tyrosine-phosphorylated DDX5 (p68). Concomitant knockdown of both mrhl RNA and p68 prevented nuclear β-catenin translocation, placing DDX5 downstream of mrhl RNA in negative regulation of Wnt signaling.","method":"Northwestern blot, RNA pulldown identifying DDX5 as mrhl RNA binding protein, co-knockdown epistasis, β-catenin localization assays, TOP/FOP luciferase assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pulldown, genetic epistasis by co-knockdown, functional Wnt reporter assay, single lab","pmids":["22665494"],"is_preprint":false},{"year":2015,"finding":"DDX5 directly interacts with β-catenin, promotes its nuclear translocation, and co-activates expression of cyclin D1 and c-Myc in NSCLC cells. β-catenin silencing abrogates DDX5-induced expression of these targets.","method":"Co-immunoprecipitation of DDX5-β-catenin, β-catenin nuclear localization assay, siRNA epistasis for cyclin D1/c-Myc expression, luciferase reporter assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, nuclear localization, genetic epistasis, single lab","pmids":["26212035"],"is_preprint":false},{"year":2013,"finding":"DDX5 (Ddx5) and DDX17 (ddx17) act as dual transcriptional coactivators of NFAT5 and simultaneously promote inclusion of NFAT5 exon 5, which introduces a premature termination codon triggering NMD of NFAT5 mRNA, thereby reducing NFAT5 protein level while enhancing NFAT5 transcriptional activity.","method":"Transcription reporter assays, alternative splicing analysis (RT-PCR), NMD pathway validation, siRNA knockdown, cell migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assays, splicing analysis, NMD validation, single lab with multiple methods","pmids":["22266867"],"is_preprint":false},{"year":2013,"finding":"DDX5 interacts with DDX3 (identified by yeast two-hybrid and confirmed by Co-IP); the interaction is enhanced in the G2/M phase when DDX5 accumulates in the cytoplasm. Dephosphorylation of serine/threonine residues in both DDX3 and DDX5 enhances their interaction (demonstrated by PP2A treatment). DDX3 knockdown blocks nuclear shuttling of DDX5, and both proteins are involved in mRNP export (UV cross-linking).","method":"Yeast two-hybrid, Co-immunoprecipitation, cell-cycle phase fractionation, PP2A/PTP1B phosphatase treatment, GST pulldown, UV cross-linking, siRNA knockdown with nuclear localization readout","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and GST pulldown, phosphorylation manipulation, single lab","pmids":["22034099"],"is_preprint":false},{"year":2013,"finding":"DDX5 binds hUpf3 (a component of the exon junction complex/NMD machinery) and activates NMD of Ddx17/p72 and Smg5 mRNAs. ATP-binding activity of DDX5 and the 3'UTR of target mRNAs are required for NMD triggering. DDX5 binding to Upf3 interferes with EJC binding.","method":"Co-immunoprecipitation of DDX5-Upf3, NMD reporter assays, ATP-binding mutant analysis, 3'UTR requirement assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional NMD assay with defined mutants, single lab","pmids":["23788676"],"is_preprint":false},{"year":2014,"finding":"DDX5 interacts with c-Myc and is required for c-Myc-mediated transcription and transforming activity. ARF blocks the physical interaction between DDX5 and c-Myc and displaces DDX5 from c-Myc target gene promoters. Forced c-Myc expression accelerates DDX5 protein synthesis, suggesting an oncogenic positive feedback loop.","method":"Tandem affinity purification identifying DDX5 as Arf-interacting protein, Co-immunoprecipitation of DDX5-c-Myc, ChIP at c-Myc target promoters, transcription assays, protein synthesis analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification, Co-IP, ChIP, functional transcription assays, single lab","pmids":["24469041"],"is_preprint":false},{"year":2009,"finding":"DDX5 acts as a repressor of fibrogenic genes in hepatic stellate cells by interacting with transcriptional complexes at fibrogenic gene promoters. The S480A SNP reduces DDX5 homodimer recruitment to fibrogenic promoters, increasing fibrogenic gene expression and Smad3/AP-1-responsive reporter activities without altering HDAC1 recruitment.","method":"Transient overexpression/siRNA knockdown with SNP replacement, stable expression of WT vs. SNP DDX5, promoter reporter assays, GAL4 one-hybrid system, ChIP for DDX5 homodimers at promoters","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, promoter reporter assays, SNP functional comparison, single lab with multiple methods","pmids":["20022962"],"is_preprint":false},{"year":2021,"finding":"Thrap3 interacts with arginine-methylated DDX5 and co-localizes to R-loops. The Thrap3-DDX5 axis induces recruitment of XRN2 to R-loops; loss of Thrap3 increases R-loop accumulation and DNA damage. Arginine methylation of DDX5 is required for the DDX5-Thrap3 interaction.","method":"Co-immunoprecipitation of Thrap3-DDX5, R-loop localization assays, XRN2 recruitment assays, R-loop accumulation measurement in Thrap3-depleted cells, methylation requirement analysis","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional R-loop and DNA damage readouts, methylation requirement, single lab","pmids":["34697388"],"is_preprint":false},{"year":2021,"finding":"PAK5 phosphorylates DDX5 at threonine 69; this phosphorylation promotes sumoylation of DDX5 (phosphorylation-dependent sumoylation), which stabilizes DDX5. Both phosphorylation and sumoylation enhance formation of a DDX5/Drosha/DGCR8 complex, promoting microRNA-10b processing and breast cancer proliferation/metastasis.","method":"Kinase assay identifying DDX5-T69 as PAK5 substrate, Co-immunoprecipitation of DDX5/Drosha/DGCR8, sumoylation assays, PAK5-/-/MMTV-PyVT transgenic mice, miR-10b processing assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — kinase substrate assay, Co-IP of processing complex, in vivo transgenic model, single lab","pmids":["34936874"],"is_preprint":false},{"year":2017,"finding":"DDX5 inhibits somatic cell reprogramming by repressing RYBP expression via processing of miR-125b. DDX5 disruption impedes miR-125b processing, leading to Rybp upregulation, H2AK119 ubiquitination by RYBP-dependent PRC1, and suppression of lineage genes. RYBP also mediates PRC1-independent OCT4 recruitment to the Kdm2b promoter.","method":"iPSC reprogramming efficiency assays in Ddx5 KO cells, miR-125b processing assays, RYBP overexpression/knockdown epistasis, H2AK119ub ChIP, OCT4 ChIP at Kdm2b promoter","journal":"Cell stem cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reprogramming assay with defined miRNA processing mechanism, genetic epistasis, ChIP, single lab","pmids":["28111200"],"is_preprint":false},{"year":2013,"finding":"DDX5 functions as a cellular co-factor of HIV-1 Rev, facilitating export of unspliced viral mRNAs. DDX5 binds Rev in a largely RNA-dependent manner; mutation of the DEAD-box motif abolishes DDX5-Rev interaction, indicating the DEAD-box motif is required for this interaction.","method":"Co-immunoprecipitation and confocal microscopy of DDX5-Rev, DEAD-box motif mutagenesis, Rev-RRE functional assays, HIV replication assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutagenesis, functional viral replication assay, single lab","pmids":["23741449"],"is_preprint":false},{"year":2020,"finding":"DDX5 potentiates HIV-1 transcription elongation as a co-factor of Tat; DDX5 binds both Tat and HEXIM1 and may facilitate dissociation of HEXIM1 from the 7SK-snRNP complex, enhancing Tat/P-TEFb availability. N-terminal RNA binding motifs, Walker B, and glycine doublet motifs of DDX5 are essential for this function.","method":"siRNA knockdown with DDX5 mutant rescue, Co-IP of DDX5-Tat and DDX5-HEXIM1, Tat/LTR reporter assays, HIV infectivity assays","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional mutant rescue, reporter assays, single lab","pmids":["32228614"],"is_preprint":false},{"year":2020,"finding":"DDX5 suppresses type I IFN production by interacting with PP2A-Cβ; viral infection enhances the DDX5-PP2A-Cβ interaction. PP2A-Cβ interacts with IRF3 and deactivates it (dephosphorylation); DDX5 knockdown promotes IRF3 phosphorylation and IFN-I production and renders mice more resistant to viral infection.","method":"Co-immunoprecipitation of DDX5-PP2A-Cβ and PP2A-Cβ-IRF3, IRF3 phosphorylation assays, IFN-β production measurement, siRNA knockdown, viral infection in vivo mouse model","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying interaction chain, phosphorylation assays, in vivo validation, single lab","pmids":["33065113"],"is_preprint":false},{"year":2012,"finding":"DDX5 is required for c-fos expression at multiple steps: transcriptional activation (recruited to c-fos gene upon estrogen), co-transcriptional RNA splicing, and mRNA export via efficient recruitment of the TAP mRNA export receptor. When splicing occurs post-transcriptionally in the absence of DDX5, c-fos mRNA is poorly exported.","method":"ChIP for DDX5 at c-fos gene locus, co-transcriptional splicing assays, TAP recruitment assays, mRNA export assays, DDX5 knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, co-transcriptional splicing assay, mRNA export functional assay, single lab","pmids":["23143267"],"is_preprint":false},{"year":2013,"finding":"DDX5 and DDX17 are master regulators of estrogen and androgen receptor signaling pathways, controlling transcription and splicing of downstream target genes and of upstream regulators including GSK3β; DDX5/DDX17 control alternative splicing of GSK3β kinase, impacting ER and AR protein stability.","method":"RNA-seq of splicing events after DDX5/DDX17 knockdown, transcription reporter assays, ChIP, GSK3β splicing and ER/AR stability analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq, reporter assays, mechanistic splicing analysis of GSK3β, single lab","pmids":["24275493"],"is_preprint":false},{"year":2013,"finding":"DDX5 co-activates androgen receptor (AR)-dependent transcription in prostate cancer cells by forming a complex with nuclear β-catenin and recruiting AR and β-catenin to androgen-responsive promoters. DDX5 also co-immunoprecipitates with both processive and non-processive forms of RNA polymerase II and is found at elongating regions of the AR-mediated PSA gene.","method":"Co-immunoprecipitation of DDX5-β-catenin (nuclear fraction), ChIP at AR-responsive promoters, ChIP for elongating RNA Pol II, luciferase reporter assays, siRNA knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP at multiple loci, reporter assays, single lab","pmids":["23349811"],"is_preprint":false},{"year":2019,"finding":"DDX5 is identified as the most enriched endogenous chromatin-bound Fra-1 interacting protein in TNBC cells, showing extensive overlap with Fra-1 cistrome; DDX5 enhances Fra-1 transcriptional activity and potentiates Fra-1-driven cell proliferation.","method":"Endogenous interaction profiling (IP of chromatin-bound Fra-1 + mass spectrometry), ChIP-seq overlap analysis, DDX5 overexpression reporter assays, cell proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-identified interaction, ChIP-seq, functional reporter assays, single lab","pmids":["31015574"],"is_preprint":false},{"year":2019,"finding":"DDX5 acts as a transcriptional co-activator of PLZF (a transcription factor required for germline maintenance) in spermatogonia, regulating select target genes. DDX5 also regulates splicing of key spermatogenesis genes and controls cell cycle gene expression post-transcriptionally in undifferentiated spermatogonia.","method":"Inducible knockout mouse model, RNA-seq for splicing changes, Co-immunoprecipitation of DDX5-PLZF, target gene expression analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with defined phenotype, Co-IP, RNA-seq, single lab","pmids":["31123254"],"is_preprint":false},{"year":2022,"finding":"DDX5 inhibits IL-17D-induced skin inflammation by regulating pre-mRNA splicing in keratinocytes; DDX5 loss shifts IL-36R splicing toward membrane-bound intact IL-36R at the expense of soluble IL-36R (sIL-36R). IL-17D downregulates DDX5 expression via the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway.","method":"Keratinocyte-specific Ddx5 knockout mice, alternative splicing analysis by RT-PCR, IL-17D signaling pathway inhibitors, sIL-36R restoration experiments, skin inflammation disease models","journal":"Nature immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO mouse with disease model, defined splicing mechanism, signaling pathway analysis, single lab","pmids":["36271146"],"is_preprint":false},{"year":2024,"finding":"DDX5 regulates CaMKIIδ alternative splicing in cardiomyocytes to prevent production of CaMKIIδA isoform; DDX5 loss leads to CaMKIIδA accumulation, which phosphorylates L-type calcium channel (Cacna1c serine residues), impairing Ca2+ homeostasis and causing heart failure. AAV9-mediated CaMKIIδA knockdown partially rescues cardiac dysfunction in DDX5 KO mice.","method":"Cardiomyocyte-specific Ddx5 KO mice, AAV9 DDX5 overexpression, IP-mass spectrometry, RNA-seq, alternative splicing analysis, RNA immunoprecipitation sequencing, Ca2+ transient measurements, transverse aortic constriction HF model","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO and rescue with defined molecular mechanism (splicing→CaMKIIδA→Ca2+ channel→Ca2+ homeostasis), multiple orthogonal methods, AAV rescue epistasis","pmids":["39056171"],"is_preprint":false},{"year":2024,"finding":"DDX5 inhibits cartilage fibrosis in osteoarthritis by regulating alternative splicing of Fn1 and Plod2 pre-mRNAs and by unfolding G-quadruplex structures in the Col2 promoter to promote COL2 expression; loss of DDX5 increases fibrosis-related (Col1, Acta2) and cartilage-degrading enzyme genes (Mmp13, Nos2).","method":"Chondrocyte-specific Ddx5 KO mice in OA model, alternative splicing analysis, G-quadruplex unfolding assays, gene expression analysis","journal":"Nature aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO mouse with OA model, G4 unfolding and splicing mechanisms, single lab","pmids":["38760576"],"is_preprint":false},{"year":2018,"finding":"DDX5 participates in oxLDL-induced macrophage MSR1 expression by stabilizing MSR1 mRNA; DDX5 interacts with METTL3 and inhibits METTL3-mediated m6A methylation of MSR1 mRNA, maintaining MSR1 mRNA stability and promoting lipid uptake.","method":"Co-immunoprecipitation of DDX5-METTL3, mass spectrometry identification, RNA-IP, dual luciferase reporter, mRNA stability assays (actinomycin D chase), siRNA knockdown","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNA-IP, mRNA stability assay, single lab","pmids":["29522752"],"is_preprint":false},{"year":2020,"finding":"DDX5 deficiency in intestinal epithelial cells protected mice from intestinal tumorigenesis and DSS-induced colitis; DDX5 binds C3 and Fabp1 mRNA transcripts and augments their expression post-transcriptionally in a tissue-specific manner to promote oncogenesis.","method":"Intestinal epithelial-specific DDX5 KO mice, RNA-binding protein immunoprecipitation, DSS colitis model, tumorigenesis models","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with disease model, RBP-IP, single lab","pmids":["32817263"],"is_preprint":false},{"year":2023,"finding":"DDX5 acts as a transcriptional co-repressor in RORγt+ Tregs, restricting expression of HIF1α and its downstream target IL-10; T cell-specific DDX5 knockout augments RORγt+ Treg suppressor activity and protects mice from intestinal inflammation.","method":"T cell-specific Ddx5 KO mice, IL-10 reporter assays, HIF1α inhibitor epistasis, intestinal inflammation model, transcriptomic analysis","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with defined molecular target (HIF1α-IL-10 axis), pharmacologic epistasis, single lab","pmids":["36724232"],"is_preprint":false},{"year":2012,"finding":"DDX5 (p68) directly interacts with VDR (vitamin D receptor) via the VDR ligand-binding domain in a manner that does not require an LXXLL motif; DDX5 co-localizes with VDR in keratinocyte nuclei and acts as a co-activator for calcitriol-dependent transcription. This interaction parallels known DDX5 interactions with ERα and AR.","method":"Genome-wide protein-protein interaction screen using VDR as bait, domain analysis of VDR-DDX5 interaction, VDR helix 12 mutant analysis, co-localization in HaCaT cells, transcription reporter assays, shRNA knockdown","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction screen with domain mapping, co-localization, reporter assays, single lab","pmids":["22476084"],"is_preprint":false},{"year":2018,"finding":"DDX5 regulates microRNA biogenesis; LMTK3 binds via DDX5 to pri-miRNAs of miR-34a, miR-196-a2, and miR-182, sequestering them from processing. DDX5 is thus involved in the Microprocessor complex activity for miRNA processing.","method":"Co-immunoprecipitation of LMTK3-DDX5, pri-miRNA binding assay, miRNA expression profiling, functional proliferation/invasion assays","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, pri-miRNA sequestration assay, single lab with limited mechanistic detail of DDX5's direct role","pmids":["26739063"],"is_preprint":false},{"year":2013,"finding":"DDX5 (p68) binds JEV core protein, NS3, and NS5 (MTase and RdRp domains) as shown by GST pulldown and Co-IP; DDX5 is recruited to the cytoplasm and co-localizes with viral proteins and RNA. DDX5 binds specifically to the JEV 3'UTR by RNA pulldown. Helicase activity is required for DDX5's pro-viral role; DDX5 knockdown reduces JEV replication but not virus assembly/release.","method":"GST pulldown, Co-immunoprecipitation, confocal co-localization, RNA pulldown, JEV-replicon system, siRNA knockdown with helicase mutants","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pulldown confirmed by Co-IP, RNA pulldown, replicon functional assay, single lab","pmids":["24035833"],"is_preprint":false},{"year":2024,"finding":"MCM8 interacts with DDX5 and DHX9; loss of MCM8 reduces retention of DDX5 and DHX9 at R-loops, leading to R-loop accumulation and genome instability. MCM8 premature ovarian insufficiency-causative mutants with decreased DDX5 interaction display increased R-loop levels.","method":"Co-immunoprecipitation of MCM8-DDX5/DHX9, R-loop quantification in MCM8-deficient cells, MCM8 mutant interaction analysis, primordial germ cell proliferation assays in MCM8 KO mice","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, R-loop functional assay, disease-relevant mutants, in vivo mouse model, single lab","pmids":["38858601"],"is_preprint":false},{"year":2018,"finding":"DDX5 knockdown in basal breast cancer cells causes actin cytoskeleton reorganization via a DDX5→miR-182→actin cytoskeleton pathway; DDX5 regulates miR-182 (and miR-21) levels, and loss of miR-182 upregulates cofilin and profilin, key actin polymerization proteins. Treatment with miR-182 inhibitors phenocopies DDX5 knockdown.","method":"Quantitative proteomics, global miRNA profiling, DDX5 knockdown, miR-182 inhibitor treatment, actin cytoskeleton morphology analysis, PDCD4 (miR-21 target) upregulation assay","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics, miRNA profiling, functional inhibitor phenocopy, single lab with multiple orthogonal methods","pmids":["22086602"],"is_preprint":false},{"year":2021,"finding":"AURKA forms a transcriptional coactivator complex with DDX5 to induce transcription of lncRNA TMEM147-AS1 in epithelial ovarian cancer; this occurs via direct binding of AURKA to DDX5. The feedback loop AURKA/DDX5/TMEM147-AS1/let-7 maintains cisplatin resistance via lipophagy activation.","method":"Co-immunoprecipitation of AURKA-DDX5, transcription assays at TMEM147-AS1 promoter, functional cisplatin resistance assays, mathematical modeling","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP for AURKA-DDX5, functional assays with limited direct mechanistic detail of DDX5's transcriptional role, single lab","pmids":["37217070"],"is_preprint":false},{"year":2018,"finding":"DDX5 is O-GlcNAcylated by OGT; DDX5 directly interacts with OGT in SW480 cells, and O-GlcNAcylation promotes DDX5 protein stability. The OGT-DDX5 axis activates AKT/mTOR signaling to promote colorectal cancer progression.","method":"Co-immunoprecipitation of DDX5-OGT, O-GlcNAcylation assays, protein stability analysis (cycloheximide chase), AKT/mTOR pathway analysis, siRNA knockdown","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, O-GlcNAcylation assay, single lab","pmids":["30484950"],"is_preprint":false},{"year":2021,"finding":"HSP90 interacts directly with DDX5 and inhibits DDX5 protein degradation through the AMPK/ULK1-regulated autophagy pathway; HSP90 inhibition reduces DDX5 levels and blocks HCC tumor growth. DDX5 accumulation activates β-catenin signaling.","method":"Molecular docking, co-immunoprecipitation of DDX5-HSP90, autophagy pathway analysis (AMPK/ULK1), HSP90 inhibitor experiments, xenograft tumor models","journal":"Cancer biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed by confocal, autophagy pathway mechanistic analysis, in vivo xenograft, single lab","pmids":["33764710"],"is_preprint":false},{"year":2018,"finding":"In oligodendrocytes, DDX5 localizes to heterogeneous cytoplasmic RNP complexes associated with Mbp mRNA in cell body and processes; DDX5 level inversely affects MBP protein level post-transcriptionally, and DDX5 knockdown increases MBP isoforms containing exon 2 (via alternative splicing regulation), indicating a dual role in translational repression and alternative splicing of Mbp.","method":"RNP complex immunoprecipitation with Mbp mRNA, DDX5 knockdown with MBP protein level measurement, alternative splicing analysis by RT-PCR, subcellular localization by immunofluorescence","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNP IP, functional protein level and splicing assays, localization, single lab","pmids":["29622601"],"is_preprint":false},{"year":2022,"finding":"The m6A reader YTHDC1 interacts with DDX5 in rhabdomyosarcoma cells; DDX5 and YTHDC1 co-operatively promote production of a common subset of circRNAs by mediating back-splicing. YTHDC1/DDX5 depletion reduces RMS cell proliferation.","method":"Co-immunoprecipitation of YTHDC1-DDX5, circRNA sequencing, back-splicing assays, siRNA knockdown of YTHDC1/DDX5 with proliferation readout","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional circRNA production assay, proliferation readout, single lab","pmids":["37019933"],"is_preprint":false},{"year":2020,"finding":"Genome-wide DRIP-seq mapping revealed that DDX5-, XRN2-, and PRMT5-deficient cells share many R-loop gain loci at transcription termination sites (consistent with coordinated RNA Pol II termination), but DDX5-depleted cells uniquely accumulate R-loops near transcription start sites, suggesting an independent role for DDX5 in transcription initiation. R-loop accumulation at certain loci in DDX5-deficient cells induces antisense intergenic transcription.","method":"DRIP-seq (genome-wide R-loop mapping) in DDX5-, XRN2-, and PRMT5-deficient cells, bioinformatic analysis of R-loop gain/loss loci","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide DRIP-seq with comparative analysis across multiple factor depletions, single lab","pmids":["32747416"],"is_preprint":false}],"current_model":"DDX5 is a multifunctional DEAD-box RNA helicase that (1) resolves R-loops and DNA-RNA hybrids at transcription termination sites and DNA double-strand breaks in an ATP-dependent manner, regulated by PRMT5-mediated arginine methylation of its RGG/RG motif and stimulated by BRCA2; (2) unwinds G-quadruplex structures in DNA and RNA (including the MYC promoter G4 and the STAT1 5'UTR rG4) to control transcription and translation; (3) acts as a transcriptional co-activator for diverse transcription factors including RORγt (requiring helicase activity and lncRNA Rmrp binding), β-catenin, AR, ERα, Runx2, c-Myc, Fra-1, RBP-J/Notch, and others; (4) regulates alternative pre-mRNA splicing cooperatively with hnRNP H/F and other splicing factors; (5) controls miRNA biogenesis by participating in the Drosha/DGCR8 Microprocessor complex; (6) modulates mRNA stability and m6A methylation by interacting with the METTL3-METTL14 writer complex; and (7) is regulated post-translationally by PRMT5 (arginine methylation), PAK5 (phosphorylation at T69 promoting sumoylation), OGT (O-GlcNAcylation), HSP90 (protection from autophagic degradation), and ubiquitin-proteasome degradation."},"narrative":{"mechanistic_narrative":"DDX5 is a multifunctional DEAD-box RNA helicase that couples RNA/DNA structure remodeling to transcription, RNA processing, and genome stability [PMID:31267554, PMID:31548374]. It resolves R-loops (RNA:DNA hybrids) in an ATP-dependent manner at transcription termination sites and DNA double-strand breaks, associating with XRN2 to promote RNA polymerase II release; this activity depends on PRMT5-catalyzed arginine methylation of its RGG/RG motif, which licenses interaction with XRN2 and the scaffold Thrap3 but is dispensable for intrinsic helicase activity [PMID:31267554, PMID:34697388, PMID:32747416]. At double-strand breaks DDX5 clears R-loops to enable homologous recombination, with its hybrid-unwinding activity stimulated by BRCA2 and its retention supported by partners including TOP3B and MCM8 [PMID:33634895, PMID:33015627, PMID:35830799, PMID:38858601]. Beyond R-loops, DDX5 is a potent resolvase of DNA and RNA G-quadruplexes—unfolding the MYC promoter G4 to activate transcription and the STAT1 5'UTR rG4 to license translation and interferon signaling [PMID:31548374, PMID:34021034]. DDX5 functions broadly as a transcriptional co-regulator, co-activating nuclear receptors and transcription factors including RORγt (requiring helicase activity and the lncRNA Rmrp), β-catenin, androgen receptor, Runx2, c-Myc, RBP-J/Notch, and Fra-1, frequently by recruiting RNA polymerase II to target promoters [PMID:26675721, PMID:23396200, PMID:26212035, PMID:24469041, PMID:23349811, PMID:31015574]. It governs alternative pre-mRNA splicing—cooperating with hnRNP H/F to set differentiation-specific splicing programs and controlling splicing of substrates such as H-Ras, GSK3β, CaMKIIδ, and IL-36R in tissue-specific physiology and disease [PMID:24910439, PMID:18698352, PMID:24275493, PMID:39056171, PMID:36271146]. DDX5 additionally directs miRNA biogenesis through the Drosha/DGCR8 Microprocessor [PMID:34936874, PMID:28111200] and modulates mRNA fate via the METTL3/METTL14 m6A writer complex, shaping transcript stability and innate immune signaling [PMID:33909701, PMID:38182816]. DDX5 abundance and activity are tuned post-translationally by PRMT5 methylation, PAK5-driven phosphorylation and sumoylation, and HSP90-dependent protection from autophagic degradation [PMID:31267554, PMID:34936874, PMID:33764710]. Genetically, cardiomyocyte-specific Ddx5 loss causes heart failure through misregulated CaMKIIδ splicing and disrupted Ca2+ homeostasis [PMID:39056171].","teleology":[{"year":2007,"claim":"Established that DDX5 contributes to ribosome biogenesis, identifying an early role in pre-rRNA processing through RNA rearrangement rather than canonical unwinding.","evidence":"siRNA co-silencing of DDX5/DDX17 with rRNA processing and nucleolar morphology readouts and helicase mutant analysis","pmids":["17485482"],"confidence":"Medium","gaps":["Redundancy with DDX17 obscures DDX5-specific contribution","Molecular nature of the RNA rearrangement activity undefined"]},{"year":2013,"claim":"Defined DDX5 as a versatile transcriptional co-activator and splicing/export regulator for diverse factors, broadening its role beyond RNA metabolism into gene-specific transcription.","evidence":"Co-IP, ChIP, reporter assays, and RNA-seq across β-catenin/AR, Notch RBP-J, c-Myc, VDR, ERα/AR, H-Ras splicing, and c-fos export systems","pmids":["23349811","23396200","24469041","22476084","24275493","18698352","23143267"],"confidence":"Medium","gaps":["Whether helicase activity is required differs by partner and is not uniformly resolved","Direct vs. bridged interactions not always distinguished"]},{"year":2014,"claim":"Showed DDX5 cooperates with hnRNP H/F to set differentiation-specific alternative splicing subprograms, linking it to coordinated cell-state transitions.","evidence":"RNA-seq after knockdown, Co-IP with hnRNP H/F, and miRNA profiling in myogenesis and EMT models","pmids":["24910439"],"confidence":"High","gaps":["Direct RNA targets vs. indirect effects not fully separated","Mechanism coupling splicing to miRNA-mediated DDX5 downregulation incomplete"]},{"year":2015,"claim":"Demonstrated that DDX5 co-activation can require both helicase activity and a specific lncRNA cofactor, establishing a paradigm for RNA-guided transcription factor co-activation.","evidence":"Reciprocal Co-IP of DDX5-RORγt, helicase mutants, and a cartilage-hair-hypoplasia Rmrp mutation in mice with TH17 phenotypes","pmids":["26675721"],"confidence":"High","gaps":["How Rmrp binding mechanistically enables co-activation unknown","Generalizability of lncRNA-dependence to other DDX5 partners untested"]},{"year":2019,"claim":"Resolved the dual structural-substrate identity of DDX5, showing it both resolves R-loops at termination sites (methylation- and XRN2-dependent) and unfolds G-quadruplexes to control transcription.","evidence":"In vitro R-loop and G4 unfolding with recombinant protein, RGG/RG and ATP-decoupling mutagenesis, DRIP-qPCR, Co-IP, and ChIP-seq","pmids":["31267554","31548374"],"confidence":"High","gaps":["Whether the same DDX5 molecules switch between R-loop and G4 substrates in vivo unknown","Determinants of substrate selection not defined"]},{"year":2020,"claim":"Placed DDX5 in the DNA double-strand break response, showing R-loop clearance near breaks is needed for homologous recombination and genome stability.","evidence":"CLIP, ChIP, DRIP-seq, NHEJ reporter, laser-induced foci, and EXO1/RPA recruitment in DDX5-deficient cells; genome-wide DRIP-seq comparison with XRN2/PRMT5","pmids":["33015627","32747416"],"confidence":"High","gaps":["DDX5's distinct role at transcription start sites mechanistically unexplained","How DDX5 is excluded from breaks in an ATM-dependent manner unresolved"]},{"year":2021,"claim":"Identified upstream regulators and partners that stimulate or scaffold DDX5's R-loop activity, including BRCA2, Thrap3, TOP3B, and MCM8, embedding DDX5 in a genome-protective network.","evidence":"In vitro helicase stimulation, Co-IP, R-loop/DRIP assays, disease-variant analysis (BRCA2-T207A, MCM8 POI mutants)","pmids":["33634895","34697388","35830799","38858601"],"confidence":"High","gaps":["Hierarchy and temporal order among these partners at a given R-loop unclear","Whether interactions are direct in all cases not fully established"]},{"year":2021,"claim":"Connected DDX5 to m6A-dependent mRNA fate, showing it shapes the METTL3/METTL14 writer complex to control transcript methylation, export, and decay in innate immunity.","evidence":"Co-IP of DDX5-METTL3/14, m6A-seq, mRNA stability and export assays, YTHDF2 decay readouts, and in vivo infection KO models","pmids":["33909701","38182816","29522752"],"confidence":"Medium","gaps":["Whether DDX5 directly modulates METTL3 catalytic activity or substrate access unresolved","Context-dependent promotion vs. inhibition of m6A across studies not reconciled"]},{"year":2021,"claim":"Established post-translational control of DDX5 abundance through phosphorylation/sumoylation and chaperone-mediated stabilization, linking signaling to DDX5-dependent miRNA processing and oncogenesis.","evidence":"PAK5 kinase assay (T69), sumoylation and DDX5/Drosha/DGCR8 Co-IP, HSP90 Co-IP and autophagy pathway analysis, in vivo tumor models","pmids":["34936874","33764710"],"confidence":"Medium","gaps":["Quantitative contribution of each modification to steady-state DDX5 unknown","Interplay between stabilization and helicase activity untested"]},{"year":2024,"claim":"Provided in vivo causal evidence that DDX5-controlled alternative splicing maintains tissue homeostasis, with cardiomyocyte loss causing heart failure via CaMKIIδ missplicing and Ca2+ dysregulation.","evidence":"Cardiomyocyte-specific KO, AAV9 rescue of CaMKIIδA, IP-MS, RNA-seq, RIP-seq, and Ca2+ transient measurements; parallel cartilage KO defining splicing and G4 mechanisms","pmids":["39056171","38760576"],"confidence":"High","gaps":["Full repertoire of physiologically critical DDX5 splicing substrates per tissue undefined","Whether helicase/G4 vs. splicing functions dominate phenotypes is tissue-specific and not generalized"]},{"year":null,"claim":"How DDX5 selects among its many activities—R-loop resolution, G4 unwinding, splicing, transcriptional co-regulation, and m6A modulation—at a given locus and how its post-translational modifications and RNA cofactors integrate to dictate this choice remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking modification state to functional output","Structural basis for substrate discrimination unknown","Partner-specific requirement for helicase activity not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,8,16,42]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,3,5,8,15]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,3,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[2,14,17,21,31,32]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,13,14,31]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[10,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,19,42,48]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[1,4,43]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,3,21,31,32]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[6,7,9,24,49]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,6,7,8,39]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[10,11]}],"complexes":["Drosha/DGCR8 Microprocessor","METTL3-METTL14 m6A writer complex"],"partners":["XRN2","BRCA2","METTL3","TOP3B","MCM8","CTNNB1","MYC","THRAP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P17844","full_name":"Probable ATP-dependent RNA helicase DDX5","aliases":["DEAD box protein 5","RNA helicase p68"],"length_aa":614,"mass_kda":69.1,"function":"Involved in the alternative regulation of pre-mRNA splicing; its RNA helicase activity is necessary for increasing tau exon 10 inclusion and occurs in a RBM4-dependent manner. Binds to the tau pre-mRNA in the stem-loop region downstream of exon 10. The rate of ATP hydrolysis is highly stimulated by single-stranded RNA. Involved in transcriptional regulation; the function is independent of the RNA helicase activity. Transcriptional coactivator for androgen receptor AR but probably not ESR1. Synergizes with DDX17 and SRA1 RNA to activate MYOD1 transcriptional activity and involved in skeletal muscle differentiation. Transcriptional coactivator for p53/TP53 and involved in p53/TP53 transcriptional response to DNA damage and p53/TP53-dependent apoptosis. Transcriptional coactivator for RUNX2 and involved in regulation of osteoblast differentiation. Acts as a transcriptional repressor in a promoter-specific manner; the function probably involves association with histone deacetylases, such as HDAC1. As component of a large PER complex is involved in the inhibition of 3' transcriptional termination of circadian target genes such as PER1 and NR1D1 and the control of the circadian rhythms","subcellular_location":"Nucleus; Nucleus, nucleolus; Nucleus speckle; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P17844/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DDX5","classification":"Common Essential","n_dependent_lines":931,"n_total_lines":1208,"dependency_fraction":0.7706953642384106},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000108654","cell_line_id":"CID000992","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nucleoplasm","grade":3},{"compartment":"nucleolus_gc","grade":2}],"interactors":[{"gene":"DDX21","stoichiometry":4.0},{"gene":"HNRNPA2B1","stoichiometry":4.0},{"gene":"HNRNPA1;HNRNPA1L2","stoichiometry":4.0},{"gene":"SNRPA","stoichiometry":4.0},{"gene":"SNRPB","stoichiometry":4.0},{"gene":"SNRPC","stoichiometry":4.0},{"gene":"SSRP1","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000992","total_profiled":1310},"omim":[{"mim_id":"614392","title":"TUDOR DOMAIN-CONTAINING PROTEIN 3; 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PCC 6803.","date":"2010","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/20511509","citation_count":20,"is_preprint":false},{"pmid":"31015574","id":"PMC_31015574","title":"Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31015574","citation_count":20,"is_preprint":false},{"pmid":"22476084","id":"PMC_22476084","title":"DDX5 is a multifunctional co-activator of steroid hormone receptors.","date":"2012","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22476084","citation_count":20,"is_preprint":false},{"pmid":"36724232","id":"PMC_36724232","title":"RNA binding protein DDX5 restricts RORγt+ Treg suppressor function to promote intestine inflammation.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36724232","citation_count":19,"is_preprint":false},{"pmid":"34853057","id":"PMC_34853057","title":"RNA binding protein DDX5 directs tuft cell specification and function to regulate microbial repertoire and disease susceptibility in the intestine.","date":"2021","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/34853057","citation_count":19,"is_preprint":false},{"pmid":"39939141","id":"PMC_39939141","title":"Acetyltransferase NAT10 inhibits T-cell immunity and promotes nasopharyngeal carcinoma progression through DDX5/HMGB1 axis.","date":"2025","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39939141","citation_count":18,"is_preprint":false},{"pmid":"35851988","id":"PMC_35851988","title":"seRNA PAM controls skeletal muscle satellite cell proliferation and aging through trans regulation of Timp2 expression synergistically with Ddx5.","date":"2022","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/35851988","citation_count":18,"is_preprint":false},{"pmid":"33666296","id":"PMC_33666296","title":"RNA helicase DDX5 acts as a critical regulator for survival of neonatal mouse gonocytes.","date":"2021","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/33666296","citation_count":17,"is_preprint":false},{"pmid":"33764710","id":"PMC_33764710","title":"Heat shock protein 90 promotes RNA helicase DDX5 accumulation and exacerbates hepatocellular carcinoma by inhibiting autophagy.","date":"2021","source":"Cancer biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33764710","citation_count":17,"is_preprint":false},{"pmid":"29622601","id":"PMC_29622601","title":"Dual role of the RNA helicase DDX5 in post-transcriptional regulation of myelin basic protein in oligodendrocytes.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/29622601","citation_count":17,"is_preprint":false},{"pmid":"35845539","id":"PMC_35845539","title":"DDX5: an expectable treater for viral infection- a literature review.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35845539","citation_count":16,"is_preprint":false},{"pmid":"32376686","id":"PMC_32376686","title":"The RNA helicase DDX5 supports mitochondrial function in small cell lung cancer.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32376686","citation_count":16,"is_preprint":false},{"pmid":"33819916","id":"PMC_33819916","title":"MSC-AS1 induced cell growth and inflammatory mediators secretion through sponging miR-142-5p/DDX5 in gastric carcinoma.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33819916","citation_count":16,"is_preprint":false},{"pmid":"33550957","id":"PMC_33550957","title":"Silencing of Long Non-Coding RNA FGD5-AS1 Inhibits the Progression of Non-Small Cell Lung Cancer by Regulating the miR-493-5p/DDX5 Axis.","date":"2021","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/33550957","citation_count":16,"is_preprint":false},{"pmid":"30131116","id":"PMC_30131116","title":"DDX17 Specifically, and Independently of DDX5, Controls Use of the HIV A4/5 Splice Acceptor Cluster and Is Essential for Efficient Replication of HIV.","date":"2018","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30131116","citation_count":16,"is_preprint":false},{"pmid":"39056171","id":"PMC_39056171","title":"RNA Helicase DDX5 Maintains Cardiac Function by Regulating CamkIIδ Alternative Splicing.","date":"2024","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/39056171","citation_count":15,"is_preprint":false},{"pmid":"39193132","id":"PMC_39193132","title":"Circular RNA IGF1R Promotes Cardiac Repair via Activating β-Catenin Signaling by Interacting with DDX5 in Mice after Ischemic Insults.","date":"2024","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/39193132","citation_count":15,"is_preprint":false},{"pmid":"38182816","id":"PMC_38182816","title":"DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection.","date":"2024","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/38182816","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49344,"output_tokens":13467,"usd":0.175018,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25352,"output_tokens":4540,"usd":0.12013,"stage2_stop_reason":"end_turn"},"total_usd":0.295148,"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\": 2019,\n      \"finding\": \"DDX5 resolves R-loops (RNA:DNA hybrids) in an ATP-dependent manner in vitro; its RGG/RG motif is methylated by PRMT5, and this methylation is required for DDX5 interaction with XRN2 and repression of cellular R-loops (but not for helicase enzymatic activity itself). DDX5 associates with XRN2 at transcriptional termination regions to facilitate RNA polymerase II release.\",\n      \"method\": \"In vitro R-loop resolution assay with recombinant DDX5, co-immunoprecipitation of DDX5-XRN2, DRIP-qPCR in DDX5-deficient cells, RGG/RG motif mutagenesis, identification of PRMT5 as the writer by binding/methylation assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant protein, mutagenesis of functional motif, multiple orthogonal methods (DRIP-qPCR, Co-IP, in vitro assay)\",\n      \"pmids\": [\"31267554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BRCA2 physically interacts with DDX5 and stimulates its DNA-RNA hybrid-unwinding helicase activity at DNA double-strand breaks (DSBs). The BRCA2-T207A breast cancer variant shows impaired interaction with DDX5, reducing DDX5 association with DNA-RNA hybrids near DSBs and altering RPA and RAD51 recruitment kinetics.\",\n      \"method\": \"Co-immunoprecipitation identifying DDX5 as BRCA2-interacting protein, in vitro helicase stimulation assay, DRIP at DSBs, analysis of BRCA2-T207A variant cells, RPA/RAD51 foci quantification\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro helicase stimulation assay combined with Co-IP, variant functional analysis, and multiple cellular readouts\",\n      \"pmids\": [\"33634895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DDX5 functions as a transcriptional co-activator of the nuclear receptor RORγt in TH17 cells; this co-activation requires DDX5's intrinsic RNA helicase activity and binding of the lncRNA Rmrp. A Rmrp mutation corresponding to cartilage-hair hypoplasia reduced DDX5-RORγt interaction and RORγt target gene transcription.\",\n      \"method\": \"Co-immunoprecipitation of DDX5-RORγt complex, RNA helicase activity mutants, targeted Rmrp gene mutation in mice, chromatin occupancy studies, TH17 differentiation and inflammatory disease models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNA helicase mutants, in vivo mouse genetic model with defined phenotype, replicated across multiple assays\",\n      \"pmids\": [\"26675721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DDX5 is a highly active G-quadruplex (G4) resolvase that unfolds MycG4-DNA without requiring a single-stranded overhang; ATP hydrolysis is not directly coupled to G4-unfolding. DDX5 is enriched at G-rich chromatin sites including the MYC promoter and activates MYC transcription; G4-interactive small molecules inhibit DDX5's interaction with the MYC promoter.\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"method\": \"In vitro G4-unfolding assays, ATP hydrolysis decoupling experiments, ChIP-seq for DDX5 chromatin binding, MYC transcription assays, G4-stabilizing small molecule experiments\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with mechanistic detail (ATP decoupling), supported by ChIP and functional transcription assays\",\n      \"pmids\": [\"31548374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX5 clears R-loops at or near DSBs to enable proper DNA repair. DDX5 binds RNA transcripts near DSBs (shown by CLIP), requires its helicase domain, is excluded from DSBs in a transcription- and ATM activation-dependent manner, and its deficiency leads to asymmetric chromosomal deletions and impaired homologous recombination (delayed EXO1 and RPA recruitment).\",\n      \"method\": \"CLIP (crosslinking immunoprecipitation), ChIP, DRIP-seq in DDX5-deficient cells, NHEJ reporter (EJ5-GFP), laser irradiation-induced damage foci, EXO1/RPA recruitment assays\",\n      \"journal\": \"NAR cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (CLIP, ChIP, DRIP, reporter assay, foci), mechanistically defined helicase domain requirement\",\n      \"pmids\": [\"33015627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TOP3B resolves R-loops in coordination with DDX5 independently of TDRD3. IP-mass spectrometry and IP-western show TOP3B physically interacts with DDX5. DDX5 and TOP3B are epistatic in resolving R-loops in a pathway parallel with senataxin; TOP3B cleaves the single-stranded DNA displaced by R-loop RNA-DNA duplexes.\",\n      \"method\": \"IP-mass spectrometry, IP-western blotting, biochemical assays with recombinant TOP3B and oligonucleotide R-loop mimics, RNA/DNA hybrid IP-western, genetic epistasis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant proteins, epistasis, and multiple orthogonal interaction methods\",\n      \"pmids\": [\"35830799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX5 interacts with the m6A writer METTL3 to regulate methylation of mRNAs including DHX58, p65, and IKKγ by affecting the METTL3-METTL14 heterodimer complex; DDX5 promotes m6A modification and nuclear export of these transcripts, leading to YTHDF2-dependent mRNA decay of antiviral transcripts and suppression of IFN-β signaling.\",\n      \"method\": \"Co-immunoprecipitation of DDX5-METTL3 complex, m6A sequencing, mRNA stability assays, nuclear export assays, viral infection models in vitro and in vivo\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional m6A and export assays, single lab\",\n      \"pmids\": [\"33909701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DDX5 interacts with METTL3 and METTL14 to form an m6A writing complex that adds m6A to TLR2 and TLR4 transcripts, promoting their YTHDF2-mediated decay; upon bacterial infection, DDX5 is recruited to Hrd1 at the ER in a MyD88-dependent manner and degraded via the ubiquitin-proteasome pathway, disrupting the complex and allowing TLR2/4 upregulation and NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation of DDX5-METTL3/14 complex, m6A modification assays, YTHDF2 mRNA decay assays, bacterial infection models, MyD88-dependent recruitment assay, in vivo DDX5-KO and METTL3-KO mice\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, functional m6A and mRNA decay assays, in vivo KO validation, multiple orthogonal methods\",\n      \"pmids\": [\"38182816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX5 resolves a G-quadruplex structure (rG4) in the 5'UTR of STAT1 mRNA to enable STAT1 translation and interferon signaling. Direct and selective binding of helicase-active DDX5 to the WT STAT1-rG4 sequence was demonstrated by ribonucleoprotein and EMSA assays; CRISPR editing of the STAT1-rG4 sequence conferred resistance to rG4-stabilizing compounds.\",\n      \"method\": \"Luciferase reporter assays with WT vs. mutant rG4 sequence, rG4-stabilizing compounds, CRISPR/Cas9 editing of STAT1-rG4, circular dichroism, RNP/EMSA binding assays, IFN-α response assays\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding assay with mutagenesis, CRISPR functional validation, biophysical structure determination, multiple orthogonal methods\",\n      \"pmids\": [\"34021034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DDX5 and DDX17 cooperate with hnRNP H/F splicing factors to define epithelial- and myoblast-specific splicing subprograms during differentiation. DDX5/DDX17 downregulation during myogenesis and EMT contributes to splicing program switching; this downregulation is itself mediated by DDX5/DDX17-dependent miRNA production.\",\n      \"method\": \"RNA-seq of splicing events after knockdown, co-immunoprecipitation with hnRNP H/F, miRNA profiling, cell differentiation models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA-seq, Co-IP, miRNA profiling, functional knockdown in multiple differentiation contexts\",\n      \"pmids\": [\"24910439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DDX5 (p68) and its paralog DDX17 (p72/p82) are required for 32S pre-rRNA cleavage and ribosome biogenesis; their apparently redundant role corresponds to RNA rearrangement (not unwinding) activity required for structural rearrangement within the pre-60S ribosomal subunit preceding 32S processing. Co-silencing of both genes causes nucleolar structure perturbation and cell death.\",\n      \"method\": \"siRNA knockdown of DDX5 and/or DDX17, RNA helicase mutant studies, nucleolar morphology analysis, pre-rRNA processing assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with specific rRNA processing readout and mutant analysis, single lab\",\n      \"pmids\": [\"17485482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ARF limits the nucleolar localization of DDX5 by inhibiting the interaction between DDX5 and nucleophosmin (NPM), preventing DDX5 association with the rDNA promoter and nuclear pre-ribosomes. DDX5 promotes rRNA synthesis/maturation and ribosome output.\",\n      \"method\": \"Mass spectrometry of nucleolar proteins in Arf-deficient cells, Co-immunoprecipitation of DDX5-NPM, ChIP at rDNA promoter, DDX5 knockdown effects on ribosome biogenesis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, nucleolar localization experiments, single lab with multiple methods\",\n      \"pmids\": [\"21937682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DDX5 promotes DNA replication by directly regulating E2F-dependent gene promoters (recruiting RNA polymerase II to E2F-regulated gene promoters) to control DNA replication factor expression during G1-S phase progression.\",\n      \"method\": \"Episomal plasmid stability assay, ChIP for RNA Pol II at E2F promoters, DDX5 knockdown effects on replication factor expression, cell cycle analysis\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, functional replication assay, KD with defined promoter recruitment readout, single lab\",\n      \"pmids\": [\"22750847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DDX5 (p68) functions as a transcriptional co-activator of Runx2 in osteoblasts; p68 co-localizes with Runx2 in nuclear punctate foci. Helicase activity was not essential for Runx2 co-activation. Paradoxically, p68 suppression accelerated osteoblast differentiation, and Runx2 suppressed p68 expression in calvarial progenitors, revealing reciprocal regulation.\",\n      \"method\": \"Affinity purification/proteomics identifying p68-Runx2 interaction, co-localization by immunofluorescence, transcription reporter assays with helicase mutants, siRNA knockdown, osteoblast differentiation assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification, co-localization, reporter assays with mutants, single lab\",\n      \"pmids\": [\"17960593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX5 (p68) functions as a co-activator in the Notch signaling pathway by directly interacting with RBP-J. DDX5 localizes to RBP-J binding sites at Notch target gene promoters (preTCRα, Hes1, CD25) in a Notch-dependent manner. The RNA co-activator SRA acts as a DDX5 cofactor in this context; DDX5/SRA co-activation is accompanied by p300 occupancy and histone acetylation.\",\n      \"method\": \"Biotinylation-tagging followed by mass spectrometry identifying DDX5 in RBP-J/NICD complex, biochemical interaction assays, ChIP at Notch target gene loci, siRNA knockdown, SRA knockdown/overexpression\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction confirmed biochemically, ChIP, functional knockdown, single lab\",\n      \"pmids\": [\"23396200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX5 (p68) unwinds the stem-loop IDX-rasISS1 structure in H-Ras pre-mRNA and prevents binding of hnRNP H to this structure, thereby regulating alternative splicing of H-Ras to modulate the ratio of p21/p19 H-Ras isoforms. p68 also alters dynamic localization of SC35 splicing factor.\",\n      \"method\": \"In vitro RNA unwinding assays, RNA-protein binding competition assays, SC35 localization by immunofluorescence, RNAi knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical unwinding assay with functional splicing consequence, single lab\",\n      \"pmids\": [\"18698352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DDX5 binds the lncRNA mrhl RNA in mouse spermatogonial cells (identified by Northwestern blot and RNA pulldown); mrhl RNA downregulation causes cytoplasmic translocation of tyrosine-phosphorylated DDX5 (p68). Concomitant knockdown of both mrhl RNA and p68 prevented nuclear β-catenin translocation, placing DDX5 downstream of mrhl RNA in negative regulation of Wnt signaling.\",\n      \"method\": \"Northwestern blot, RNA pulldown identifying DDX5 as mrhl RNA binding protein, co-knockdown epistasis, β-catenin localization assays, TOP/FOP luciferase assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pulldown, genetic epistasis by co-knockdown, functional Wnt reporter assay, single lab\",\n      \"pmids\": [\"22665494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DDX5 directly interacts with β-catenin, promotes its nuclear translocation, and co-activates expression of cyclin D1 and c-Myc in NSCLC cells. β-catenin silencing abrogates DDX5-induced expression of these targets.\",\n      \"method\": \"Co-immunoprecipitation of DDX5-β-catenin, β-catenin nuclear localization assay, siRNA epistasis for cyclin D1/c-Myc expression, luciferase reporter assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, nuclear localization, genetic epistasis, single lab\",\n      \"pmids\": [\"26212035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX5 (Ddx5) and DDX17 (ddx17) act as dual transcriptional coactivators of NFAT5 and simultaneously promote inclusion of NFAT5 exon 5, which introduces a premature termination codon triggering NMD of NFAT5 mRNA, thereby reducing NFAT5 protein level while enhancing NFAT5 transcriptional activity.\",\n      \"method\": \"Transcription reporter assays, alternative splicing analysis (RT-PCR), NMD pathway validation, siRNA knockdown, cell migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assays, splicing analysis, NMD validation, single lab with multiple methods\",\n      \"pmids\": [\"22266867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX5 interacts with DDX3 (identified by yeast two-hybrid and confirmed by Co-IP); the interaction is enhanced in the G2/M phase when DDX5 accumulates in the cytoplasm. Dephosphorylation of serine/threonine residues in both DDX3 and DDX5 enhances their interaction (demonstrated by PP2A treatment). DDX3 knockdown blocks nuclear shuttling of DDX5, and both proteins are involved in mRNP export (UV cross-linking).\",\n      \"method\": \"Yeast two-hybrid, Co-immunoprecipitation, cell-cycle phase fractionation, PP2A/PTP1B phosphatase treatment, GST pulldown, UV cross-linking, siRNA knockdown with nuclear localization readout\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid confirmed by Co-IP and GST pulldown, phosphorylation manipulation, single lab\",\n      \"pmids\": [\"22034099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX5 binds hUpf3 (a component of the exon junction complex/NMD machinery) and activates NMD of Ddx17/p72 and Smg5 mRNAs. ATP-binding activity of DDX5 and the 3'UTR of target mRNAs are required for NMD triggering. DDX5 binding to Upf3 interferes with EJC binding.\",\n      \"method\": \"Co-immunoprecipitation of DDX5-Upf3, NMD reporter assays, ATP-binding mutant analysis, 3'UTR requirement assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional NMD assay with defined mutants, single lab\",\n      \"pmids\": [\"23788676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DDX5 interacts with c-Myc and is required for c-Myc-mediated transcription and transforming activity. ARF blocks the physical interaction between DDX5 and c-Myc and displaces DDX5 from c-Myc target gene promoters. Forced c-Myc expression accelerates DDX5 protein synthesis, suggesting an oncogenic positive feedback loop.\",\n      \"method\": \"Tandem affinity purification identifying DDX5 as Arf-interacting protein, Co-immunoprecipitation of DDX5-c-Myc, ChIP at c-Myc target promoters, transcription assays, protein synthesis analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification, Co-IP, ChIP, functional transcription assays, single lab\",\n      \"pmids\": [\"24469041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DDX5 acts as a repressor of fibrogenic genes in hepatic stellate cells by interacting with transcriptional complexes at fibrogenic gene promoters. The S480A SNP reduces DDX5 homodimer recruitment to fibrogenic promoters, increasing fibrogenic gene expression and Smad3/AP-1-responsive reporter activities without altering HDAC1 recruitment.\",\n      \"method\": \"Transient overexpression/siRNA knockdown with SNP replacement, stable expression of WT vs. SNP DDX5, promoter reporter assays, GAL4 one-hybrid system, ChIP for DDX5 homodimers at promoters\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, promoter reporter assays, SNP functional comparison, single lab with multiple methods\",\n      \"pmids\": [\"20022962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Thrap3 interacts with arginine-methylated DDX5 and co-localizes to R-loops. The Thrap3-DDX5 axis induces recruitment of XRN2 to R-loops; loss of Thrap3 increases R-loop accumulation and DNA damage. Arginine methylation of DDX5 is required for the DDX5-Thrap3 interaction.\",\n      \"method\": \"Co-immunoprecipitation of Thrap3-DDX5, R-loop localization assays, XRN2 recruitment assays, R-loop accumulation measurement in Thrap3-depleted cells, methylation requirement analysis\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional R-loop and DNA damage readouts, methylation requirement, single lab\",\n      \"pmids\": [\"34697388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAK5 phosphorylates DDX5 at threonine 69; this phosphorylation promotes sumoylation of DDX5 (phosphorylation-dependent sumoylation), which stabilizes DDX5. Both phosphorylation and sumoylation enhance formation of a DDX5/Drosha/DGCR8 complex, promoting microRNA-10b processing and breast cancer proliferation/metastasis.\",\n      \"method\": \"Kinase assay identifying DDX5-T69 as PAK5 substrate, Co-immunoprecipitation of DDX5/Drosha/DGCR8, sumoylation assays, PAK5-/-/MMTV-PyVT transgenic mice, miR-10b processing assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — kinase substrate assay, Co-IP of processing complex, in vivo transgenic model, single lab\",\n      \"pmids\": [\"34936874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDX5 inhibits somatic cell reprogramming by repressing RYBP expression via processing of miR-125b. DDX5 disruption impedes miR-125b processing, leading to Rybp upregulation, H2AK119 ubiquitination by RYBP-dependent PRC1, and suppression of lineage genes. RYBP also mediates PRC1-independent OCT4 recruitment to the Kdm2b promoter.\",\n      \"method\": \"iPSC reprogramming efficiency assays in Ddx5 KO cells, miR-125b processing assays, RYBP overexpression/knockdown epistasis, H2AK119ub ChIP, OCT4 ChIP at Kdm2b promoter\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reprogramming assay with defined miRNA processing mechanism, genetic epistasis, ChIP, single lab\",\n      \"pmids\": [\"28111200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX5 functions as a cellular co-factor of HIV-1 Rev, facilitating export of unspliced viral mRNAs. DDX5 binds Rev in a largely RNA-dependent manner; mutation of the DEAD-box motif abolishes DDX5-Rev interaction, indicating the DEAD-box motif is required for this interaction.\",\n      \"method\": \"Co-immunoprecipitation and confocal microscopy of DDX5-Rev, DEAD-box motif mutagenesis, Rev-RRE functional assays, HIV replication assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutagenesis, functional viral replication assay, single lab\",\n      \"pmids\": [\"23741449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX5 potentiates HIV-1 transcription elongation as a co-factor of Tat; DDX5 binds both Tat and HEXIM1 and may facilitate dissociation of HEXIM1 from the 7SK-snRNP complex, enhancing Tat/P-TEFb availability. N-terminal RNA binding motifs, Walker B, and glycine doublet motifs of DDX5 are essential for this function.\",\n      \"method\": \"siRNA knockdown with DDX5 mutant rescue, Co-IP of DDX5-Tat and DDX5-HEXIM1, Tat/LTR reporter assays, HIV infectivity assays\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional mutant rescue, reporter assays, single lab\",\n      \"pmids\": [\"32228614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX5 suppresses type I IFN production by interacting with PP2A-Cβ; viral infection enhances the DDX5-PP2A-Cβ interaction. PP2A-Cβ interacts with IRF3 and deactivates it (dephosphorylation); DDX5 knockdown promotes IRF3 phosphorylation and IFN-I production and renders mice more resistant to viral infection.\",\n      \"method\": \"Co-immunoprecipitation of DDX5-PP2A-Cβ and PP2A-Cβ-IRF3, IRF3 phosphorylation assays, IFN-β production measurement, siRNA knockdown, viral infection in vivo mouse model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying interaction chain, phosphorylation assays, in vivo validation, single lab\",\n      \"pmids\": [\"33065113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DDX5 is required for c-fos expression at multiple steps: transcriptional activation (recruited to c-fos gene upon estrogen), co-transcriptional RNA splicing, and mRNA export via efficient recruitment of the TAP mRNA export receptor. When splicing occurs post-transcriptionally in the absence of DDX5, c-fos mRNA is poorly exported.\",\n      \"method\": \"ChIP for DDX5 at c-fos gene locus, co-transcriptional splicing assays, TAP recruitment assays, mRNA export assays, DDX5 knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, co-transcriptional splicing assay, mRNA export functional assay, single lab\",\n      \"pmids\": [\"23143267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX5 and DDX17 are master regulators of estrogen and androgen receptor signaling pathways, controlling transcription and splicing of downstream target genes and of upstream regulators including GSK3β; DDX5/DDX17 control alternative splicing of GSK3β kinase, impacting ER and AR protein stability.\",\n      \"method\": \"RNA-seq of splicing events after DDX5/DDX17 knockdown, transcription reporter assays, ChIP, GSK3β splicing and ER/AR stability analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq, reporter assays, mechanistic splicing analysis of GSK3β, single lab\",\n      \"pmids\": [\"24275493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX5 co-activates androgen receptor (AR)-dependent transcription in prostate cancer cells by forming a complex with nuclear β-catenin and recruiting AR and β-catenin to androgen-responsive promoters. DDX5 also co-immunoprecipitates with both processive and non-processive forms of RNA polymerase II and is found at elongating regions of the AR-mediated PSA gene.\",\n      \"method\": \"Co-immunoprecipitation of DDX5-β-catenin (nuclear fraction), ChIP at AR-responsive promoters, ChIP for elongating RNA Pol II, luciferase reporter assays, siRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP at multiple loci, reporter assays, single lab\",\n      \"pmids\": [\"23349811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DDX5 is identified as the most enriched endogenous chromatin-bound Fra-1 interacting protein in TNBC cells, showing extensive overlap with Fra-1 cistrome; DDX5 enhances Fra-1 transcriptional activity and potentiates Fra-1-driven cell proliferation.\",\n      \"method\": \"Endogenous interaction profiling (IP of chromatin-bound Fra-1 + mass spectrometry), ChIP-seq overlap analysis, DDX5 overexpression reporter assays, cell proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-identified interaction, ChIP-seq, functional reporter assays, single lab\",\n      \"pmids\": [\"31015574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DDX5 acts as a transcriptional co-activator of PLZF (a transcription factor required for germline maintenance) in spermatogonia, regulating select target genes. DDX5 also regulates splicing of key spermatogenesis genes and controls cell cycle gene expression post-transcriptionally in undifferentiated spermatogonia.\",\n      \"method\": \"Inducible knockout mouse model, RNA-seq for splicing changes, Co-immunoprecipitation of DDX5-PLZF, target gene expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with defined phenotype, Co-IP, RNA-seq, single lab\",\n      \"pmids\": [\"31123254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DDX5 inhibits IL-17D-induced skin inflammation by regulating pre-mRNA splicing in keratinocytes; DDX5 loss shifts IL-36R splicing toward membrane-bound intact IL-36R at the expense of soluble IL-36R (sIL-36R). IL-17D downregulates DDX5 expression via the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway.\",\n      \"method\": \"Keratinocyte-specific Ddx5 knockout mice, alternative splicing analysis by RT-PCR, IL-17D signaling pathway inhibitors, sIL-36R restoration experiments, skin inflammation disease models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO mouse with disease model, defined splicing mechanism, signaling pathway analysis, single lab\",\n      \"pmids\": [\"36271146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX5 regulates CaMKIIδ alternative splicing in cardiomyocytes to prevent production of CaMKIIδA isoform; DDX5 loss leads to CaMKIIδA accumulation, which phosphorylates L-type calcium channel (Cacna1c serine residues), impairing Ca2+ homeostasis and causing heart failure. AAV9-mediated CaMKIIδA knockdown partially rescues cardiac dysfunction in DDX5 KO mice.\",\n      \"method\": \"Cardiomyocyte-specific Ddx5 KO mice, AAV9 DDX5 overexpression, IP-mass spectrometry, RNA-seq, alternative splicing analysis, RNA immunoprecipitation sequencing, Ca2+ transient measurements, transverse aortic constriction HF model\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO and rescue with defined molecular mechanism (splicing→CaMKIIδA→Ca2+ channel→Ca2+ homeostasis), multiple orthogonal methods, AAV rescue epistasis\",\n      \"pmids\": [\"39056171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX5 inhibits cartilage fibrosis in osteoarthritis by regulating alternative splicing of Fn1 and Plod2 pre-mRNAs and by unfolding G-quadruplex structures in the Col2 promoter to promote COL2 expression; loss of DDX5 increases fibrosis-related (Col1, Acta2) and cartilage-degrading enzyme genes (Mmp13, Nos2).\",\n      \"method\": \"Chondrocyte-specific Ddx5 KO mice in OA model, alternative splicing analysis, G-quadruplex unfolding assays, gene expression analysis\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO mouse with OA model, G4 unfolding and splicing mechanisms, single lab\",\n      \"pmids\": [\"38760576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX5 participates in oxLDL-induced macrophage MSR1 expression by stabilizing MSR1 mRNA; DDX5 interacts with METTL3 and inhibits METTL3-mediated m6A methylation of MSR1 mRNA, maintaining MSR1 mRNA stability and promoting lipid uptake.\",\n      \"method\": \"Co-immunoprecipitation of DDX5-METTL3, mass spectrometry identification, RNA-IP, dual luciferase reporter, mRNA stability assays (actinomycin D chase), siRNA knockdown\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNA-IP, mRNA stability assay, single lab\",\n      \"pmids\": [\"29522752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX5 deficiency in intestinal epithelial cells protected mice from intestinal tumorigenesis and DSS-induced colitis; DDX5 binds C3 and Fabp1 mRNA transcripts and augments their expression post-transcriptionally in a tissue-specific manner to promote oncogenesis.\",\n      \"method\": \"Intestinal epithelial-specific DDX5 KO mice, RNA-binding protein immunoprecipitation, DSS colitis model, tumorigenesis models\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with disease model, RBP-IP, single lab\",\n      \"pmids\": [\"32817263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DDX5 acts as a transcriptional co-repressor in RORγt+ Tregs, restricting expression of HIF1α and its downstream target IL-10; T cell-specific DDX5 knockout augments RORγt+ Treg suppressor activity and protects mice from intestinal inflammation.\",\n      \"method\": \"T cell-specific Ddx5 KO mice, IL-10 reporter assays, HIF1α inhibitor epistasis, intestinal inflammation model, transcriptomic analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with defined molecular target (HIF1α-IL-10 axis), pharmacologic epistasis, single lab\",\n      \"pmids\": [\"36724232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DDX5 (p68) directly interacts with VDR (vitamin D receptor) via the VDR ligand-binding domain in a manner that does not require an LXXLL motif; DDX5 co-localizes with VDR in keratinocyte nuclei and acts as a co-activator for calcitriol-dependent transcription. This interaction parallels known DDX5 interactions with ERα and AR.\",\n      \"method\": \"Genome-wide protein-protein interaction screen using VDR as bait, domain analysis of VDR-DDX5 interaction, VDR helix 12 mutant analysis, co-localization in HaCaT cells, transcription reporter assays, shRNA knockdown\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction screen with domain mapping, co-localization, reporter assays, single lab\",\n      \"pmids\": [\"22476084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX5 regulates microRNA biogenesis; LMTK3 binds via DDX5 to pri-miRNAs of miR-34a, miR-196-a2, and miR-182, sequestering them from processing. DDX5 is thus involved in the Microprocessor complex activity for miRNA processing.\",\n      \"method\": \"Co-immunoprecipitation of LMTK3-DDX5, pri-miRNA binding assay, miRNA expression profiling, functional proliferation/invasion assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, pri-miRNA sequestration assay, single lab with limited mechanistic detail of DDX5's direct role\",\n      \"pmids\": [\"26739063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX5 (p68) binds JEV core protein, NS3, and NS5 (MTase and RdRp domains) as shown by GST pulldown and Co-IP; DDX5 is recruited to the cytoplasm and co-localizes with viral proteins and RNA. DDX5 binds specifically to the JEV 3'UTR by RNA pulldown. Helicase activity is required for DDX5's pro-viral role; DDX5 knockdown reduces JEV replication but not virus assembly/release.\",\n      \"method\": \"GST pulldown, Co-immunoprecipitation, confocal co-localization, RNA pulldown, JEV-replicon system, siRNA knockdown with helicase mutants\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pulldown confirmed by Co-IP, RNA pulldown, replicon functional assay, single lab\",\n      \"pmids\": [\"24035833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MCM8 interacts with DDX5 and DHX9; loss of MCM8 reduces retention of DDX5 and DHX9 at R-loops, leading to R-loop accumulation and genome instability. MCM8 premature ovarian insufficiency-causative mutants with decreased DDX5 interaction display increased R-loop levels.\",\n      \"method\": \"Co-immunoprecipitation of MCM8-DDX5/DHX9, R-loop quantification in MCM8-deficient cells, MCM8 mutant interaction analysis, primordial germ cell proliferation assays in MCM8 KO mice\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, R-loop functional assay, disease-relevant mutants, in vivo mouse model, single lab\",\n      \"pmids\": [\"38858601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX5 knockdown in basal breast cancer cells causes actin cytoskeleton reorganization via a DDX5→miR-182→actin cytoskeleton pathway; DDX5 regulates miR-182 (and miR-21) levels, and loss of miR-182 upregulates cofilin and profilin, key actin polymerization proteins. Treatment with miR-182 inhibitors phenocopies DDX5 knockdown.\",\n      \"method\": \"Quantitative proteomics, global miRNA profiling, DDX5 knockdown, miR-182 inhibitor treatment, actin cytoskeleton morphology analysis, PDCD4 (miR-21 target) upregulation assay\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics, miRNA profiling, functional inhibitor phenocopy, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22086602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AURKA forms a transcriptional coactivator complex with DDX5 to induce transcription of lncRNA TMEM147-AS1 in epithelial ovarian cancer; this occurs via direct binding of AURKA to DDX5. The feedback loop AURKA/DDX5/TMEM147-AS1/let-7 maintains cisplatin resistance via lipophagy activation.\",\n      \"method\": \"Co-immunoprecipitation of AURKA-DDX5, transcription assays at TMEM147-AS1 promoter, functional cisplatin resistance assays, mathematical modeling\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP for AURKA-DDX5, functional assays with limited direct mechanistic detail of DDX5's transcriptional role, single lab\",\n      \"pmids\": [\"37217070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX5 is O-GlcNAcylated by OGT; DDX5 directly interacts with OGT in SW480 cells, and O-GlcNAcylation promotes DDX5 protein stability. The OGT-DDX5 axis activates AKT/mTOR signaling to promote colorectal cancer progression.\",\n      \"method\": \"Co-immunoprecipitation of DDX5-OGT, O-GlcNAcylation assays, protein stability analysis (cycloheximide chase), AKT/mTOR pathway analysis, siRNA knockdown\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, O-GlcNAcylation assay, single lab\",\n      \"pmids\": [\"30484950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HSP90 interacts directly with DDX5 and inhibits DDX5 protein degradation through the AMPK/ULK1-regulated autophagy pathway; HSP90 inhibition reduces DDX5 levels and blocks HCC tumor growth. DDX5 accumulation activates β-catenin signaling.\",\n      \"method\": \"Molecular docking, co-immunoprecipitation of DDX5-HSP90, autophagy pathway analysis (AMPK/ULK1), HSP90 inhibitor experiments, xenograft tumor models\",\n      \"journal\": \"Cancer biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed by confocal, autophagy pathway mechanistic analysis, in vivo xenograft, single lab\",\n      \"pmids\": [\"33764710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In oligodendrocytes, DDX5 localizes to heterogeneous cytoplasmic RNP complexes associated with Mbp mRNA in cell body and processes; DDX5 level inversely affects MBP protein level post-transcriptionally, and DDX5 knockdown increases MBP isoforms containing exon 2 (via alternative splicing regulation), indicating a dual role in translational repression and alternative splicing of Mbp.\",\n      \"method\": \"RNP complex immunoprecipitation with Mbp mRNA, DDX5 knockdown with MBP protein level measurement, alternative splicing analysis by RT-PCR, subcellular localization by immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNP IP, functional protein level and splicing assays, localization, single lab\",\n      \"pmids\": [\"29622601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The m6A reader YTHDC1 interacts with DDX5 in rhabdomyosarcoma cells; DDX5 and YTHDC1 co-operatively promote production of a common subset of circRNAs by mediating back-splicing. YTHDC1/DDX5 depletion reduces RMS cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation of YTHDC1-DDX5, circRNA sequencing, back-splicing assays, siRNA knockdown of YTHDC1/DDX5 with proliferation readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional circRNA production assay, proliferation readout, single lab\",\n      \"pmids\": [\"37019933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Genome-wide DRIP-seq mapping revealed that DDX5-, XRN2-, and PRMT5-deficient cells share many R-loop gain loci at transcription termination sites (consistent with coordinated RNA Pol II termination), but DDX5-depleted cells uniquely accumulate R-loops near transcription start sites, suggesting an independent role for DDX5 in transcription initiation. R-loop accumulation at certain loci in DDX5-deficient cells induces antisense intergenic transcription.\",\n      \"method\": \"DRIP-seq (genome-wide R-loop mapping) in DDX5-, XRN2-, and PRMT5-deficient cells, bioinformatic analysis of R-loop gain/loss loci\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide DRIP-seq with comparative analysis across multiple factor depletions, single lab\",\n      \"pmids\": [\"32747416\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DDX5 is a multifunctional DEAD-box RNA helicase that (1) resolves R-loops and DNA-RNA hybrids at transcription termination sites and DNA double-strand breaks in an ATP-dependent manner, regulated by PRMT5-mediated arginine methylation of its RGG/RG motif and stimulated by BRCA2; (2) unwinds G-quadruplex structures in DNA and RNA (including the MYC promoter G4 and the STAT1 5'UTR rG4) to control transcription and translation; (3) acts as a transcriptional co-activator for diverse transcription factors including RORγt (requiring helicase activity and lncRNA Rmrp binding), β-catenin, AR, ERα, Runx2, c-Myc, Fra-1, RBP-J/Notch, and others; (4) regulates alternative pre-mRNA splicing cooperatively with hnRNP H/F and other splicing factors; (5) controls miRNA biogenesis by participating in the Drosha/DGCR8 Microprocessor complex; (6) modulates mRNA stability and m6A methylation by interacting with the METTL3-METTL14 writer complex; and (7) is regulated post-translationally by PRMT5 (arginine methylation), PAK5 (phosphorylation at T69 promoting sumoylation), OGT (O-GlcNAcylation), HSP90 (protection from autophagic degradation), and ubiquitin-proteasome degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDX5 is a multifunctional DEAD-box RNA helicase that couples RNA/DNA structure remodeling to transcription, RNA processing, and genome stability [#0, #3]. It resolves R-loops (RNA:DNA hybrids) in an ATP-dependent manner at transcription termination sites and DNA double-strand breaks, associating with XRN2 to promote RNA polymerase II release; this activity depends on PRMT5-catalyzed arginine methylation of its RGG/RG motif, which licenses interaction with XRN2 and the scaffold Thrap3 but is dispensable for intrinsic helicase activity [#0, #23, #50]. At double-strand breaks DDX5 clears R-loops to enable homologous recombination, with its hybrid-unwinding activity stimulated by BRCA2 and its retention supported by partners including TOP3B and MCM8 [#1, #4, #5, #43]. Beyond R-loops, DDX5 is a potent resolvase of DNA and RNA G-quadruplexes—unfolding the MYC promoter G4 to activate transcription and the STAT1 5'UTR rG4 to license translation and interferon signaling [#3, #8]. DDX5 functions broadly as a transcriptional co-regulator, co-activating nuclear receptors and transcription factors including RORγt (requiring helicase activity and the lncRNA Rmrp), β-catenin, androgen receptor, Runx2, c-Myc, RBP-J/Notch, and Fra-1, frequently by recruiting RNA polymerase II to target promoters [#2, #14, #17, #21, #31, #32]. It governs alternative pre-mRNA splicing—cooperating with hnRNP H/F to set differentiation-specific splicing programs and controlling splicing of substrates such as H-Ras, GSK3β, CaMKIIδ, and IL-36R in tissue-specific physiology and disease [#9, #15, #30, #35, #34]. DDX5 additionally directs miRNA biogenesis through the Drosha/DGCR8 Microprocessor [#24, #25] and modulates mRNA fate via the METTL3/METTL14 m6A writer complex, shaping transcript stability and innate immune signaling [#6, #7]. DDX5 abundance and activity are tuned post-translationally by PRMT5 methylation, PAK5-driven phosphorylation and sumoylation, and HSP90-dependent protection from autophagic degradation [#0, #24, #47]. Genetically, cardiomyocyte-specific Ddx5 loss causes heart failure through misregulated CaMKIIδ splicing and disrupted Ca2+ homeostasis [#35].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that DDX5 contributes to ribosome biogenesis, identifying an early role in pre-rRNA processing through RNA rearrangement rather than canonical unwinding.\",\n      \"evidence\": \"siRNA co-silencing of DDX5/DDX17 with rRNA processing and nucleolar morphology readouts and helicase mutant analysis\",\n      \"pmids\": [\"17485482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redundancy with DDX17 obscures DDX5-specific contribution\", \"Molecular nature of the RNA rearrangement activity undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined DDX5 as a versatile transcriptional co-activator and splicing/export regulator for diverse factors, broadening its role beyond RNA metabolism into gene-specific transcription.\",\n      \"evidence\": \"Co-IP, ChIP, reporter assays, and RNA-seq across β-catenin/AR, Notch RBP-J, c-Myc, VDR, ERα/AR, H-Ras splicing, and c-fos export systems\",\n      \"pmids\": [\"23349811\", \"23396200\", \"24469041\", \"22476084\", \"24275493\", \"18698352\", \"23143267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether helicase activity is required differs by partner and is not uniformly resolved\", \"Direct vs. bridged interactions not always distinguished\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed DDX5 cooperates with hnRNP H/F to set differentiation-specific alternative splicing subprograms, linking it to coordinated cell-state transitions.\",\n      \"evidence\": \"RNA-seq after knockdown, Co-IP with hnRNP H/F, and miRNA profiling in myogenesis and EMT models\",\n      \"pmids\": [\"24910439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA targets vs. indirect effects not fully separated\", \"Mechanism coupling splicing to miRNA-mediated DDX5 downregulation incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that DDX5 co-activation can require both helicase activity and a specific lncRNA cofactor, establishing a paradigm for RNA-guided transcription factor co-activation.\",\n      \"evidence\": \"Reciprocal Co-IP of DDX5-RORγt, helicase mutants, and a cartilage-hair-hypoplasia Rmrp mutation in mice with TH17 phenotypes\",\n      \"pmids\": [\"26675721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Rmrp binding mechanistically enables co-activation unknown\", \"Generalizability of lncRNA-dependence to other DDX5 partners untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolved the dual structural-substrate identity of DDX5, showing it both resolves R-loops at termination sites (methylation- and XRN2-dependent) and unfolds G-quadruplexes to control transcription.\",\n      \"evidence\": \"In vitro R-loop and G4 unfolding with recombinant protein, RGG/RG and ATP-decoupling mutagenesis, DRIP-qPCR, Co-IP, and ChIP-seq\",\n      \"pmids\": [\"31267554\", \"31548374\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the same DDX5 molecules switch between R-loop and G4 substrates in vivo unknown\", \"Determinants of substrate selection not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed DDX5 in the DNA double-strand break response, showing R-loop clearance near breaks is needed for homologous recombination and genome stability.\",\n      \"evidence\": \"CLIP, ChIP, DRIP-seq, NHEJ reporter, laser-induced foci, and EXO1/RPA recruitment in DDX5-deficient cells; genome-wide DRIP-seq comparison with XRN2/PRMT5\",\n      \"pmids\": [\"33015627\", \"32747416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DDX5's distinct role at transcription start sites mechanistically unexplained\", \"How DDX5 is excluded from breaks in an ATM-dependent manner unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified upstream regulators and partners that stimulate or scaffold DDX5's R-loop activity, including BRCA2, Thrap3, TOP3B, and MCM8, embedding DDX5 in a genome-protective network.\",\n      \"evidence\": \"In vitro helicase stimulation, Co-IP, R-loop/DRIP assays, disease-variant analysis (BRCA2-T207A, MCM8 POI mutants)\",\n      \"pmids\": [\"33634895\", \"34697388\", \"35830799\", \"38858601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy and temporal order among these partners at a given R-loop unclear\", \"Whether interactions are direct in all cases not fully established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected DDX5 to m6A-dependent mRNA fate, showing it shapes the METTL3/METTL14 writer complex to control transcript methylation, export, and decay in innate immunity.\",\n      \"evidence\": \"Co-IP of DDX5-METTL3/14, m6A-seq, mRNA stability and export assays, YTHDF2 decay readouts, and in vivo infection KO models\",\n      \"pmids\": [\"33909701\", \"38182816\", \"29522752\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DDX5 directly modulates METTL3 catalytic activity or substrate access unresolved\", \"Context-dependent promotion vs. inhibition of m6A across studies not reconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established post-translational control of DDX5 abundance through phosphorylation/sumoylation and chaperone-mediated stabilization, linking signaling to DDX5-dependent miRNA processing and oncogenesis.\",\n      \"evidence\": \"PAK5 kinase assay (T69), sumoylation and DDX5/Drosha/DGCR8 Co-IP, HSP90 Co-IP and autophagy pathway analysis, in vivo tumor models\",\n      \"pmids\": [\"34936874\", \"33764710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of each modification to steady-state DDX5 unknown\", \"Interplay between stabilization and helicase activity untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided in vivo causal evidence that DDX5-controlled alternative splicing maintains tissue homeostasis, with cardiomyocyte loss causing heart failure via CaMKIIδ missplicing and Ca2+ dysregulation.\",\n      \"evidence\": \"Cardiomyocyte-specific KO, AAV9 rescue of CaMKIIδA, IP-MS, RNA-seq, RIP-seq, and Ca2+ transient measurements; parallel cartilage KO defining splicing and G4 mechanisms\",\n      \"pmids\": [\"39056171\", \"38760576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of physiologically critical DDX5 splicing substrates per tissue undefined\", \"Whether helicase/G4 vs. splicing functions dominate phenotypes is tissue-specific and not generalized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DDX5 selects among its many activities—R-loop resolution, G4 unwinding, splicing, transcriptional co-regulation, and m6A modulation—at a given locus and how its post-translational modifications and RNA cofactors integrate to dictate this choice remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking modification state to functional output\", \"Structural basis for substrate discrimination unknown\", \"Partner-specific requirement for helicase activity not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 8, 16, 42]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 3, 5, 8, 15]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 3, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [2, 14, 17, 21, 31, 32]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 13, 14, 31]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 19, 42, 48]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1, 4, 43]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 3, 21, 31, 32]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [6, 7, 9, 24, 49]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 6, 7, 8, 39]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"complexes\": [\n      \"Drosha/DGCR8 Microprocessor\",\n      \"METTL3-METTL14 m6A writer complex\"\n    ],\n    \"partners\": [\n      \"XRN2\",\n      \"BRCA2\",\n      \"METTL3\",\n      \"TOP3B\",\n      \"MCM8\",\n      \"CTNNB1\",\n      \"MYC\",\n      \"THRAP3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}