{"gene":"DHX9","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2017,"finding":"DHX9 binds specifically to inverted-repeat Alu elements transcribed as parts of genes; loss of DHX9 increases circular RNA production, causes translational repression of reporters containing inverted-repeat Alu elements, and produces transcriptional rewiring. DHX9 interacts with the interferon-inducible ADAR isoform p150 (but not p110) in an RNA-independent manner. Co-depletion of ADAR and DHX9 augments dsRNA accumulation and circular RNA production, revealing a functional link between the two enzymes.","method":"Biochemical purification, RNA immunoprecipitation, reporter assays, siRNA knockdown, circular RNA quantification, co-IP","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical purification, reporter assays, co-IP, RNA-seq) in a single rigorous study with clear mechanistic readouts","pmids":["28355180"],"is_preprint":false},{"year":2011,"finding":"DHX9 preferentially unwinds RNA-containing displacement loops (R-loops) and DNA/RNA-based G-quadruplexes over simple DNA-DNA duplexes in vitro, suggesting these structures are biologically relevant substrates.","method":"In vitro helicase assays using defined nucleic acid substrates (partial duplexes, D-loops, R-loops, G-quadruplexes)","journal":"DNA repair","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple defined substrates, single lab, multiple orthogonal substrate comparisons","pmids":["21561811"],"is_preprint":false},{"year":2011,"finding":"DHX9 functions as a dsRNA sensor in myeloid dendritic cells, binding polyinosine-polycytidylic acid via its dsRNA-binding motifs and interacting with the adaptor IPS-1 (MAVS) via DHX9's HelicC-HA2-DUF domain and IPS-1's CARD domain to activate NF-κB and IRF3 signaling in response to dsRNA.","method":"siRNA knockdown, dsRNA binding assays, co-immunoprecipitation with domain mapping, cytokine production assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping, functional knockdown with defined cytokine readout, single lab with multiple orthogonal methods","pmids":["21957149"],"is_preprint":false},{"year":2018,"finding":"DHX9 (RNA helicase A) promotes the formation of R-loops in cells with impaired splicing through prolonged association with RNA Polymerase II, producing DNA-RNA hybrids that trap RNA Pol II on chromatin and can block DNA replication.","method":"R-loop immunofluorescence (S9.6 antibody), chromatin immunoprecipitation, DRIP-seq, proximity ligation assay, siRNA knockdown of splicing factors","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP, DRIP-seq, and proximity ligation combined in single study with defined mechanistic pathway; single lab but multiple orthogonal methods","pmids":["30341290"],"is_preprint":false},{"year":2018,"finding":"DHX9 and DHX36 helicase depletion promotes translation of rG4-associated upstream open reading frames (uORFs) while reducing translation of downstream coding regions; transcriptome-wide binding analysis shows DHX9 directly interacts with rG4 substrates in 5'-UTRs to regulate translation.","method":"Ribosome profiling (Ribo-seq), CLIP-seq for DHX9 binding site identification, siRNA knockdown, luciferase reporter assays","journal":"Genome biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — transcriptome-wide ribosome profiling plus direct binding site identification (CLIP-seq) plus functional reporters, multiple orthogonal methods","pmids":["30591072"],"is_preprint":false},{"year":2010,"finding":"DHX9 unwinds triple-helical DNA structures (H-DNA/intramolecular triplexes) in vitro with 3'→5' polarity with respect to the displaced third strand, requiring a 3'-single-stranded overhang and ATP hydrolysis; DHX9 co-immunoprecipitates with triplex DNA structures in mammalian cells.","method":"In vitro helicase assay with triplex substrates, co-immunoprecipitation with triplex DNA, ATP hydrolysis assays, kinetic analysis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with defined substrates plus mutational/substrate-specificity analysis plus cellular co-IP, single lab","pmids":["20669935"],"is_preprint":false},{"year":2010,"finding":"DHX9 stimulates WRN helicase unwinding of RNA-containing Okazaki fragment-like substrates and RNA-containing 'chicken-foot' structures in vitro, suggesting cooperative action at replication forks; DHX9 and WRN engage in direct protein-protein interaction.","method":"In vitro helicase assays with synthetic substrates, protein-protein interaction assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with defined substrates, single lab, no in vivo functional validation of the cooperative mechanism","pmids":["20385589"],"is_preprint":false},{"year":2013,"finding":"DHX9 is required for RISC assembly via its dsRNA-binding domains (dsRBD1 and dsRBD2); crystal structures of dsRBD1 and dsRBD2 in complex with dsRNA reveal that dsRBD1 has higher siRNA-binding affinity and a crystallographic dsRBD1 pair cooperatively recognizes dsRNA. Both dsRBDs are required for RISC association mediated by dsRNA.","method":"Crystal structure determination, isothermal titration calorimetry (ITC), co-immunoprecipitation with mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures plus ITC thermodynamics plus mutagenesis-validated co-IP, multiple orthogonal methods in a single study","pmids":["23361462"],"is_preprint":false},{"year":2013,"finding":"DHX9 depletion increases mutagenesis at H-DNA structures in human cells, predominantly causing deletions; DHX9 associates with H-DNA in supercoiled plasmids and is enriched at H-DNA regions in chromatin by ChIP, implicating DHX9 in processing intramolecular triplex DNA in vivo.","method":"siRNA knockdown mutation-reporter assay, in vitro binding assay, chromatin immunoprecipitation (ChIP) in U2OS cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional mutation-reporter assay plus ChIP plus in vitro binding, multiple orthogonal methods, single lab","pmids":["24049074"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the conserved helicase domain 1 (DEIH motif) of human DHX9 reveals a RecA-like core more similar to viral NS3 helicases than DEAD-box proteins; DHX9 lacks base-selective contacts and forms an unspecific stacking interaction with the nucleotide base, allowing hydrolysis of ATP, GTP, CTP, and UTP.","method":"X-ray crystallography, NTPase biochemical assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with biochemical validation of NTPase activity, multiple NTP substrates tested","pmids":["20510246"],"is_preprint":false},{"year":2017,"finding":"DHX9 binds to IGS-rRNA at rRNA genes upon embryonic stem cell (ESC) differentiation, processes IGS-rRNA into pRNA, and thereby guides the repressor TIP5 to establish heterochromatin at rRNA genes; DHX9 depletion prevents ESC differentiation, a phenotype rescued by addition of pRNA but not IGS-rRNA or TIP5-binding-deficient pRNA mutants.","method":"RNA immunoprecipitation, ChIP, siRNA knockdown, differentiation assays, rescue experiments with RNA addition","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RIP, ChIP, functional rescue with defined RNA species, KD phenotype), clear epistatic ordering","pmids":["28588071"],"is_preprint":false},{"year":2021,"finding":"DHX9 promotes BRCA1 recruitment to RNA at sites of DNA damage as part of the RNA Polymerase II transcription complex, facilitating DNA end resection and homologous recombination (HR). DHX9-deficient cells fail to recruit RPA and RAD51 to DSBs, are defective in HR, hypersensitive to camptothecin and Olaparib, and show impaired ATR-mediated damage signaling and replication restart.","method":"siRNA knockdown, immunofluorescence for RPA/RAD51 foci, co-immunoprecipitation, HR reporter assay, drug sensitivity assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IP, foci assays, HR reporter, drug sensitivity), pathway placement via epistasis, single lab","pmids":["34226554"],"is_preprint":false},{"year":2021,"finding":"TDRD3 directly interacts with DHX9 via its Tudor domain, recruits DHX9 to target gene promoters to resolve R-loops in a helicase-activity-dependent manner, and stimulates DHX9 helicase activity via its OB-fold domain that likely binds the ssDNA in the R-loop.","method":"Co-immunoprecipitation, ChIP, DRIP (DNA-RNA immunoprecipitation), helicase activity assays, domain-mapping mutagenesis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain mapping, ChIP, DRIP, in vitro helicase stimulation assay, multiple orthogonal methods","pmids":["34329467"],"is_preprint":false},{"year":2014,"finding":"Suppression of DHX9 in primary human diploid fibroblasts induces premature senescence in a p53-dependent manner; DHX9 associates with origins of replication by ChIP, and its suppression reduces nascent DNA synthesis, demonstrating an essential role in DNA replication and cell cycle progression.","method":"siRNA/shRNA knockdown, senescence-associated β-galactosidase assay, ChIP at replication origins, nascent DNA labeling, gene expression profiling","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — functional KD with defined cellular phenotype, ChIP, replication assay, p53 pathway validation; multiple orthogonal methods, single lab","pmids":["24990949"],"is_preprint":false},{"year":2018,"finding":"DHX9 functions as a bidirectional regulator of A-to-I RNA editing in cancer cells, at least partially dependent on its helicase activity: DHX9 silencing preferentially represses ADAR1-specific editing while augmenting ADAR2-specific substrate editing.","method":"siRNA knockdown, transcriptome-wide RNA editing analysis, helicase-dead mutant expression","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — transcriptome-wide editing analysis plus helicase-dead mutant, but single lab and mechanistic link to ADAR specificity not fully resolved","pmids":["29796672"],"is_preprint":false},{"year":2018,"finding":"DHX9 forms a complex with RNA Polymerase II and EWS-FLI1 to enhance transcription in Ewing sarcoma cells; UV irradiation causes enhanced RNAPII phosphorylation and decreased processivity, leading to alternative splicing inclusion of DHX9 exon 6A that targets DHX9 mRNA to NMD-mediated decay, reducing DHX9 protein levels.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, minigene splicing assays, RT-PCR for alternative isoforms, UV irradiation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, splicing mechanism validated by minigene, multiple orthogonal methods, single lab","pmids":["26450900"],"is_preprint":false},{"year":2017,"finding":"Human Nup98 binds to DHX9 via its FG/GLFG repeat region interacting with N- and C-terminal regions of DHX9 in an RNA-facilitated manner; Nup98 binding stimulates DHX9 ATPase activity and supports DHX9-stimulated transcription; Nup98 and DHX9 bind interdependently to similar gene loci.","method":"In vitro binding assays, ATPase activity assays, transcriptional reporter assay, ChIP-seq, co-immunoprecipitation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ATPase stimulation assay plus ChIP-seq plus reporter assay plus binding domain mapping; multiple orthogonal methods","pmids":["28221134"],"is_preprint":false},{"year":2013,"finding":"Myxoma virus M029 protein interacts with DHX9/RHA in a dsRNA-independent manner in infected cells; M029 not only inhibits PKR but also conscripts DHX9 as a pro-viral effector to promote viral replication specifically in myeloid THP1 cells, as PKR depletion rescue of M029-minus viruses is reversed by DHX9 knockdown.","method":"Proteomic co-immunoprecipitation, siRNA knockdown of DHX9, virus replication assays, epistasis (PKR KD + DHX9 KD double knockdown)","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double KD) plus co-IP proteomics, single lab","pmids":["23853588"],"is_preprint":false},{"year":2016,"finding":"PRRSV nucleocapsid (N) protein interacts with cellular DHX9 and redistributes it from the nucleus to the cytoplasm; knockdown of DHX9 increases production of short subgenomic mRNAs while DHX9 overexpression promotes synthesis of longer subgenomic mRNAs and genomic RNA, suggesting DHX9 acts as an antiattenuation factor for continuous elongation during viral RNA synthesis.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, viral RNA quantification by RT-qPCR, immunofluorescence for localization","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, functional KD and OE with defined viral RNA readouts, localization imaging; single lab","pmids":["27009951"],"is_preprint":false},{"year":2016,"finding":"DHX9/RHA binds to the double-stranded PBS-segment of the HIV-1 5'-UTR dimer; ITC shows one RHA molecule binds per RNA strand independently of nucleocapsid protein; NMR with deuterium labeling defines the structural basis of this interaction; disruption of this binding (single A-to-C substitution) attenuates virion infectivity.","method":"Isothermal titration calorimetry (ITC), NMR spectroscopy, cell-based viral infectivity assays, mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ITC thermodynamics plus NMR structure plus functional mutagenesis and infectivity assay; multiple orthogonal Tier 1 methods","pmids":["27107641"],"is_preprint":false},{"year":2019,"finding":"Virion-associated DHX9/RHA enhances the processivity of HIV-1 reverse transcriptase (RT) during elongation phase of (-)cDNA synthesis; pre-steady-state and steady-state kinetics show RHA has little impact on single-nucleotide incorporation rate but increases RT processivity, as demonstrated by primer extension in the presence of trap dsDNA.","method":"In vitro reverse transcription reconstitution, pre-steady-state and steady-state kinetic assays, primer extension with trap assay, quantification of reverse-transcription intermediates in infected T cells","journal":"Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with kinetic analysis plus cellular RT intermediate quantification; multiple orthogonal methods","pmids":["31175158"],"is_preprint":false},{"year":2019,"finding":"DHX9 is recruited to CHIKV replication complexes at the plasma membrane via interaction with nsP3's C-terminal hypervariable domain; during early infection DHX9 negatively controls viral RNA synthesis but is required for optimal translation of mature nonstructural proteins; at later stages DHX9 is degraded via the proteasome.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence for colocalization, viral RNA quantification, proteasome inhibitor experiments","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain identification, KD with defined viral RNA/protein readouts, localization imaging; single lab","pmids":["30463980"],"is_preprint":false},{"year":2014,"finding":"During FMDV infection, JMJD6 arginine demethylase physically interacts with DHX9 (preferring JMJD6 monomers) and demethylates RHA arginine residues at its C-terminus; this demethylation promotes DHX9 redistribution from nucleus to cytoplasm and facilitates viral protein synthesis and virus replication.","method":"Reciprocal co-immunoprecipitation, NOG inhibitor of JmjC demethylases, modified biochemical demethylation assay, immunofluorescence for subcellular localization","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, biochemical demethylation assay, pharmacological inhibition with NOG; single lab","pmids":["24606677"],"is_preprint":false},{"year":2004,"finding":"DHX9/RHA is SUMOylated by Ubc9 (E2 SUMO ligase); the N-terminal domain (residues 1–137) of RHA is sufficient for Ubc9 interaction; Ubc9 interaction activates RHA transcriptional activity in a CREB-mediated reporter assay, and Ubc9 catalytic activity is dispensable for the transcription activation function.","method":"Co-immunoprecipitation, domain-mapping truncation mutants, in vitro and in vivo SUMO conjugation assay, transcriptional reporter assay","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, in vitro SUMO conjugation, functional reporter assay; single lab, multiple methods","pmids":["15312759"],"is_preprint":false},{"year":2024,"finding":"ATR kinase phosphorylates DHX9 at serine 321 (S321) upon DNA damage; this phosphorylation promotes DHX9 interaction with γH2AX, BRCA1, and RPA, and is required for DHX9 association with R-loops under genotoxic stress. Non-phosphorylatable DHX9-S321A causes R-loop accumulation and hypersensitivity to genotoxic agents; phosphomimetic DHX9-S321D prevents R-loop accumulation and confers resistance. In vitro binding confirms direct DHX9–RPA interaction.","method":"Phospho-mapping mass spectrometry, ATR inhibitor treatment, phosphomimetic/non-phosphorylatable mutants, co-immunoprecipitation, DRIP assay, in vitro binding assay, drug sensitivity assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-specific mutagenesis of phosphorylation site with functional phenotype, in vitro binding, DRIP, co-IP; multiple orthogonal methods","pmids":["37930853"],"is_preprint":false},{"year":2024,"finding":"DHX9 SUMOylation at lysine 120 (K120) is required for genome stability; SUMO2 modification at K120 enables DHX9 to interact with R-loop-associated proteins PARP1 and DDX21 via SUMO-interacting motifs. The K120R mutant (non-SUMOylatable) shows R-loop accumulation, increased DNA damage, and cell death; fusing SUMO2 to K120R rescues these defects.","method":"Site-directed mutagenesis (K120R), SUMO2 fusion rescue construct, co-immunoprecipitation, DRIP assay, γH2AX immunofluorescence, cell viability assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — defined mutagenesis of modification site, SUMO2 fusion rescue, co-IP with SIM-dependent partners, DRIP; multiple orthogonal methods","pmids":["39019926"],"is_preprint":false},{"year":2024,"finding":"DHX9 depletion in SCLC leads to cytoplasmic dsRNA accumulation triggering tumor-intrinsic innate immunity, and simultaneously causes aberrant R-loop accumulation leading to DNA damage-derived cytoplasmic DNA and replication stress; in vivo, DHX9 deletion reduces tumor growth and enhances immunogenic tumor microenvironment, improving response to immune-checkpoint blockade.","method":"CRISPR-based screen, CRISPR knockout, immunofluorescence for dsRNA and R-loops, DNA damage markers, in vivo tumor models, immune profiling","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen plus in vivo tumor models plus mechanistic molecular readouts (dsRNA, R-loops, DNA damage), replicated across multiple approaches","pmids":["38189443"],"is_preprint":false},{"year":2024,"finding":"DHX9 forms stress granules (SGs) distinct from classical SGs upon UV irradiation; DHX9 SGs are enriched in damaged intron RNA rather than mature mRNA. UV-induced RNA crosslinking impedes intron splicing and decay, triggering DHX9 SGs in daughter cells. DHX9 modulates dsRNA abundance within SGs and promotes cell survival; autophagy receptor p62 is required for DHX9 SG disassembly.","method":"FANCI technology for damaged RNA identification, immunofluorescence, RNA sequencing of SG fractions, p62 knockout/knockdown, cell viability assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — novel technology (FANCI) plus multiple imaging and sequencing approaches, clear mechanistic distinctions from classical SGs, cell viability functional readout","pmids":["38503283"],"is_preprint":false},{"year":2024,"finding":"DHX9 deficiency in intestinal stem cells (ISCs) causes abnormal R-loop accumulation leading to genomic instability and cGAS-STING-mediated inflammatory response, impairing ISC function; conditional Dhx9 knockout in intestinal epithelium increases susceptibility to experimental colitis with reduction in ISC and Paneth cell numbers.","method":"Conditional ISC-specific and Paneth cell-specific Dhx9 knockout mice, DRIP for R-loops, cGAS-STING pathway marker analysis, histology, colitis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific in vivo knockout with multiple pathway readouts (R-loops, cGAS-STING, inflammation), replicated in multiple conditional KO lines","pmids":["38594251"],"is_preprint":false},{"year":2023,"finding":"Nuclear DHX9 directly binds STAT1 and recruits RNA Pol II to interferon-stimulated gene (ISG) promoters to participate in STAT1-mediated ISG transcription; myeloid- or hepatocyte-specific DHX9 knockout mice are more susceptible to RNA virus infections, and this antiviral role is downstream of type I interferon, dependent on STAT1 (not MAVS).","method":"Myeloid- and hepatocyte-specific DHX9 knockout mice, double-KO with MAVS or STAT1, co-immunoprecipitation, ChIP for Pol II at ISG promoters, viral infection models","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo cell-type-specific KO with double-KO epistasis, co-IP, ChIP; pathway placement defined by genetic epistasis with MAVS and STAT1","pmids":["36735791"],"is_preprint":false},{"year":2018,"finding":"DHX9 interacts with p65 (NF-κB subunit) and RNA Polymerase II in chromatin at NF-κB binding sites; nuclear DHX9 is essential for recruitment of RNAPII (but not p65) to NF-κB target gene promoters, requiring its ATPase/helicase activity; macrophage- and fibroblast-specific DHX9 knockout/knockdown impairs antiviral innate immunity against DNA viruses.","method":"Macrophage-specific KO, fibroblast-specific KD, co-immunoprecipitation of multiprotein complex, ChIP for p65 and RNAPII at NF-κB promoters, helicase-dead mutant, viral replication assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO, ChIP with RNAPII and p65, helicase-dead mutant epistasis, multiple orthogonal methods","pmids":["30137501"],"is_preprint":false},{"year":2021,"finding":"DHX9 interacts with p65 and RNAPII to enhance p65 phosphorylation and nuclear translocation, facilitating NF-κB-mediated transcription of downstream targets (Survivin, Snail) to promote colorectal cancer malignant phenotypes.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, overexpression, xenograft and hepatic metastasis mouse models","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP, in vivo models; single lab; overlaps with findings in PMID 30137501","pmids":["34773477"],"is_preprint":false},{"year":2019,"finding":"DHX9 binds the 3'-UTR of CDK6 mRNA and post-transcriptionally suppresses CDK6 expression; lnc-UCID (lncRNA) interacts with DHX9 via its 850-1030 nt domain and sequesters DHX9 from CDK6-3'UTR, thereby enhancing CDK6 expression and promoting G1/S transition.","method":"RNA immunoprecipitation, RNA pulldown, co-immunoprecipitation, luciferase reporter of CDK6-3'UTR, siRNA knockdown, gain/loss-of-function studies, xenograft models","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and RNA pulldown plus functional CDK6-3'UTR reporter, competitive binding mechanism validated; single lab","pmids":["30865310"],"is_preprint":false},{"year":2018,"finding":"DHX9 is associated with HBV viral RNAs; DHX9 knockdown increases HBV-derived circular RNA production while decreasing viral protein levels (without affecting HBV DNA levels), demonstrating DHX9 is a novel regulator of viral circular RNA biogenesis.","method":"Co-immunoprecipitation/RNA binding assay, siRNA knockdown, circular RNA quantification, viral protein and DNA assays in HBV-producing cell lines and primary hepatocytes","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA binding demonstrated, functional KD with defined molecular readouts in multiple cell systems; single lab","pmids":["29765512"],"is_preprint":false},{"year":2019,"finding":"DHX9 interacts with the EBV SM protein (co-immunoprecipitation, nuclear co-localization) and restricts EBV lytic replication; DHX9 depletion increases EBV late gene expression and virion production; DHX9 enhances innate antiviral pathways (ISGs), and SM inhibits DHX9's transcription-activating function through cAMP response elements (CREs).","method":"Mass spectrometry, co-immunoprecipitation, immunofluorescence, siRNA knockdown, viral gene expression and titer assays, CRE reporter assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP (mass spec + co-IP), KD functional assays, CRE reporter; single lab, multiple orthogonal methods","pmids":["30541834"],"is_preprint":false},{"year":2019,"finding":"DHX9 induces alternative splicing of KLF5 mRNA by bridging YB-1 protein in vascular smooth muscle cells; smooth muscle cell-specific DHX9 conditional knockout alters transcriptional and alternative splicing profiles of smooth muscle cell phenotype-related genes and exacerbates aortic dissection.","method":"Vascular smooth muscle cell-specific DHX9 conditional knockout mice, RNA-seq, alternative splicing analysis, co-immunoprecipitation (DHX9-YB-1 interaction), aortic dissection model","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with RNA-seq plus co-IP for bridging mechanism; single lab","pmids":["31116584"],"is_preprint":false},{"year":2022,"finding":"DHX9 interacts with Androgen Receptor (AR) in prostate cancer cells; AR binds the DHX9 promoter to induce DHX9 expression; DHX9 depletion reduces AR recruitment to target gene promoters and AR-driven transcription in response to DHT; enzalutamide-mediated AR inhibition represses DHX9 expression, establishing a DHX9/AR positive feedback axis.","method":"Co-immunoprecipitation, ChIP, RNA-seq, promoter reporter assay, siRNA knockdown, cell proliferation and migration assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ChIP of AR at DHX9 promoter, RNA-seq, pharmacological validation; single lab","pmids":["35590370"],"is_preprint":false},{"year":2022,"finding":"Pol η (DNA polymerase eta) interacts with DHX9 (identified by proximity labeling and affinity pulldown-MS); Pol η promotes DHX9 recruitment to G4-structure loci in chromatin; deficiency in either Pol η or DHX9 impairs replication across G4 regions, indicating cooperative action at G4 sites during replication.","method":"Proximity labeling (BioID), affinity pulldown with LC-MS/MS, ChIP-seq, co-immunoprecipitation, replication assay at G4 loci, siRNA knockdown","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent interaction discovery methods (proximity labeling + pulldown-MS) plus ChIP-seq plus replication assay; single lab","pmids":["35905379"],"is_preprint":false},{"year":2020,"finding":"USP42 interacts with DHX9 and promotes R-loop resolution at DNA double-strand breaks (DSBs); USP42 localization to nuclear speckles is required for efficient HR; DHX9's DNA-RNA helicase activity is required for DSB-induced R-loop resolution and BRCA1 recruitment.","method":"Co-immunoprecipitation, siRNA knockdown, HR reporter assay, DRIP for R-loops, BRCA1 foci immunofluorescence","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, functional HR assay, DRIP, BRCA1 recruitment assay; single lab","pmids":["32541651"],"is_preprint":false},{"year":2024,"finding":"AKT1 kinase domain directly interacts with DHX9 and facilitates DHX9 recruitment to R-loops; AKT inhibition reduces DHX9 association with R-loops and increases ATRi-induced R-loop-mediated replication stress; the interaction is direct as shown by in vitro binding analysis.","method":"Quantitative high-throughput drug combination screen, co-immunoprecipitation, in vitro binding assay, DRIP for R-loops, replication stress markers","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus co-IP plus DRIP, pharmacological modulation; single lab","pmids":["38241710"],"is_preprint":false},{"year":2020,"finding":"Oxaliplatin induces PI3KK-mediated phosphorylation of DHX9 at two sites near substrate-binding domains; non-phosphorylatable DHX9 mutants or PI3KK inhibitor blockage decreases oxaliplatin-induced circCCDC66 circular RNA expression and impairs development of chemoresistance.","method":"Site-directed mutagenesis (non-phosphorylatable DHX9 mutants), PI3KK inhibitors, circular RNA quantification, drug resistance assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of phosphorylation sites with functional readout (circRNA and drug resistance); single lab","pmids":["32187976"],"is_preprint":false},{"year":2023,"finding":"DHX9 pathogenic variants cause neurodevelopmental disorders and Charcot-Marie-Tooth disease; NLS missense variants cause abnormal cytoplasmic DHX9 accumulation (loss of nuclear localization), CMT2-associated variants cause aberrant nucleolar DHX9 accumulation, and an NDD variant (p.Arg141Gln) increases R-loop levels and DNA double-strand breaks without altering localization. Two variants (p.Gly411Glu, p.Arg761Gln) alter DHX9 ATPase activity. Dhx9-/- mice show hypoactivity, tremor, and sensorineural hearing loss.","method":"Exome sequencing with family analysis, human cell line DHX9 variant expression (localization by immunofluorescence), patient fibroblast localization, ATPase activity assays, R-loop measurement (S9.6), γH2AX foci, Dhx9 knockout mice","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (ATPase assay, cell imaging, R-loop quantification, mouse KO model), variant-specific mechanistic phenotyping, 20 patients with genotype-phenotype correlations","pmids":["37467750"],"is_preprint":false},{"year":2018,"finding":"MDM2 E3 ubiquitin ligase interacts with DHX9 and mediates its ubiquitin-proteasome-dependent degradation; lnc-CCDST lncRNA binds DHX9 and serves as a scaffold to facilitate the DHX9–MDM2 interaction, promoting DHX9 degradation and suppressing cervical cancer motility and angiogenesis.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, in vitro and in vivo migration/invasion/angiogenesis assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, scaffold mechanism via lncRNA; single lab","pmids":["30518908"],"is_preprint":false},{"year":2021,"finding":"SPOP E3 ubiquitin ligase binds DHX9 via a canonical SPOP-binding motif in DHX9 and induces its ubiquitination and proteasomal degradation; SPOP depletion increases DHX9 levels and promotes choriocarcinoma migration and invasion; DHX9 siRNA partially rescues the pro-migratory effect of SPOP knockdown.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, binding motif identification, migration/invasion assays","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, ubiquitination assay, SPOP-binding motif mutation, functional rescue; single lab","pmids":["32905556"],"is_preprint":false},{"year":2019,"finding":"DHX9 interacts with APOBEC3B (A3B) in the presence of HBV; DHX9 does not affect A3B deaminase activity but inhibits A3B binding to HBV pregenomic RNA (pgRNA), thereby attenuating A3B's anti-HBV effect.","method":"Co-immunoprecipitation and mass spectrometry, in vitro deaminase assay, pgRNA binding assay, HBV DNA replication quantification","journal":"Emerging microbes & infections","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with MS, in vitro binding assay, functional deaminase and HBV replication readouts; single lab","pmids":["32056513"],"is_preprint":false},{"year":2025,"finding":"DHX9 unwinds inhibitory RNA G-quadruplex (rG4) structures near the translation initiation site of PCMT1 mRNA; circCLASP2 acts as a molecular scaffold bringing DHX9 to PCMT1 mRNA, increasing PCMT1 translation and promoting cytoskeletal changes in nasopharyngeal carcinoma.","method":"RNA immunoprecipitation, RNA pulldown, ribosomal gradient sedimentation, dual-luciferase reporter, immunofluorescence, in vitro and in vivo NPC assays","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP, RNA pulldown, ribosome profiling, rG4 reporter assay; single lab","pmids":["40050914"],"is_preprint":false}],"current_model":"DHX9 is an abundant nuclear DExH-box RNA/DNA helicase that maintains genome stability and regulates gene expression by unwinding diverse non-canonical nucleic acid structures (R-loops, G-quadruplexes, inverted-repeat Alu dsRNA, intramolecular triplexes/H-DNA) in a 3'→5', ATP-dependent manner; it associates with RNA Polymerase II and transcription factors (including NF-κB p65, STAT1, and AR) to co-activate gene transcription, facilitates RISC assembly and RNA editing via its dsRNA-binding domains, acts as an innate immune dsRNA sensor signaling through IPS-1/MAVS, promotes homologous recombination by recruiting BRCA1 to RNA at damage sites, and is regulated by post-translational modifications including ATR-mediated S321 phosphorylation, SUMOylation at K120, arginine demethylation by JMJD6, and ubiquitin-mediated degradation by MDM2, SPOP, and PRPF19."},"narrative":{"mechanistic_narrative":"DHX9 is an abundant nuclear DExH-box helicase that maintains genome stability and shapes gene expression by recognizing and unwinding diverse non-canonical nucleic acid structures, including R-loops, DNA/RNA G-quadruplexes, intramolecular triplex H-DNA, and inverted-repeat Alu dsRNA [PMID:21561811, PMID:20669935, PMID:28355180]. Its catalytic core is a RecA-like helicase domain structurally closer to viral NS3 helicases than to DEAD-box proteins, lacking base-selective contacts so that it hydrolyzes ATP, GTP, CTP, and UTP, and it unwinds substrates with 3'→5' polarity in an ATP-dependent manner [PMID:20510246, PMID:20669935]. At the genome level, DHX9 resolves transcription-associated R-loops and processes triplex DNA to suppress mutagenesis and replication stress, and its loss drives premature senescence, aberrant R-loop accumulation, DNA double-strand breaks, and cGAS-STING- or dsRNA-triggered innate immune activation [PMID:30341290, PMID:24049074, PMID:24990949, PMID:38594251, PMID:38189443]. It promotes homologous recombination by resolving R-loops at double-strand breaks and recruiting BRCA1, RPA, and RAD51, an activity coordinated by partners such as TDRD3, USP42, and Polη, and gated by ATR-mediated S321 phosphorylation and SUMO2 modification at K120 that license its association with R-loop-bound factors including γH2AX, RPA, PARP1, and DDX21 [PMID:34226554, PMID:34329467, PMID:32541651, PMID:35905379, PMID:37930853, PMID:39019926]. As a transcriptional co-activator, DHX9 associates with RNA Polymerase II and bridges it to sequence-specific factors—NF-κB p65, STAT1, and the androgen receptor—and to Nup98, with its ATPase/helicase activity required for RNAPII recruitment to target promoters [PMID:30137501, PMID:36735791, PMID:35590370, PMID:28221134]. Through its dsRNA-binding domains it controls post-transcriptional outcomes: it is required for RISC assembly, regulates A-to-I editing bidirectionally with ADAR, suppresses circular RNA biogenesis from inverted-repeat Alu elements, and unwinds rG4 structures in 5'-UTRs to govern translation [PMID:23361462, PMID:29796672, PMID:28355180, PMID:30591072]. DHX9 additionally functions in innate antiviral immunity as a dsRNA sensor signaling through IPS-1/MAVS [PMID:21957149], and is exploited by numerous viruses as a host factor. Pathogenic DHX9 variants cause neurodevelopmental disorders and Charcot-Marie-Tooth disease, with distinct variants causing mislocalization, altered ATPase activity, or elevated R-loops and DNA damage [PMID:37467750].","teleology":[{"year":2010,"claim":"Establishing the structural and biochemical basis of DHX9 catalysis answered how this helicase engages nucleotides and nucleic acid substrates, distinguishing it mechanistically from DEAD-box enzymes.","evidence":"X-ray crystallography of helicase domain 1 plus NTPase assays, and in vitro triplex helicase assays with kinetic analysis","pmids":["20510246","20669935"],"confidence":"High","gaps":["No full-length structure with substrate engaged","Mechanism of substrate-structure selectivity not resolved at atomic level"]},{"year":2010,"claim":"Demonstrating cooperative unwinding with WRN at RNA-containing replication intermediates placed DHX9 at the replication fork, though without in vivo validation.","evidence":"In vitro helicase assays with Okazaki-fragment-like and chicken-foot substrates plus protein-protein interaction assays","pmids":["20385589"],"confidence":"Medium","gaps":["No in vivo confirmation of cooperative mechanism","Direct interaction interface not mapped"]},{"year":2011,"claim":"Defining R-loops and G-quadruplexes as preferred substrates over simple duplexes identified the physiologically relevant structures DHX9 acts on.","evidence":"In vitro helicase assays on defined partial duplex, D-loop, R-loop, and G-quadruplex substrates","pmids":["21561811"],"confidence":"High","gaps":["Cellular substrate preference not directly tested in this study","No genome-wide substrate map"]},{"year":2011,"claim":"Identifying DHX9 as a dsRNA sensor signaling through IPS-1/MAVS established a role in innate immune detection of viral RNA, defining the domain interfaces involved.","evidence":"siRNA knockdown, dsRNA binding assays, co-IP with HelicC-HA2-DUF/CARD domain mapping, cytokine readouts in dendritic cells","pmids":["21957149"],"confidence":"High","gaps":["Relative contribution versus canonical RNA sensors unclear","In vivo requirement not established here"]},{"year":2013,"claim":"Structural and functional dissection of the dsRNA-binding domains showed how DHX9 is incorporated into RISC, linking its dsRNA recognition to gene silencing.","evidence":"Crystal structures of dsRBD1/dsRBD2 with dsRNA, ITC, mutagenesis-validated co-IP","pmids":["23361462"],"confidence":"High","gaps":["Coupling between dsRBD binding and helicase core not resolved","Step in RISC assembly not pinpointed"]},{"year":2013,"claim":"Showing that DHX9 depletion increases H-DNA-induced mutagenesis demonstrated an in vivo genome-protective role at triplex-forming sequences.","evidence":"siRNA mutation-reporter assay, in vitro binding, ChIP at H-DNA regions in U2OS cells","pmids":["24049074"],"confidence":"High","gaps":["Mechanism converting unresolved triplex to deletions unclear","Downstream repair factors not identified"]},{"year":2014,"claim":"Linking DHX9 to p53-dependent senescence and origin firing established its essentiality for DNA replication and proliferation.","evidence":"siRNA/shRNA knockdown, SA-β-gal assay, ChIP at replication origins, nascent DNA labeling in human fibroblasts","pmids":["24990949"],"confidence":"High","gaps":["Molecular role at origins not defined","Connection to R-loop resolution at origins untested here"]},{"year":2017,"claim":"Revealing DHX9 control of inverted-repeat Alu dsRNA and circular RNA production, with an RNA-independent ADAR1-p150 interaction, connected dsRNA structure resolution to circRNA biogenesis and editing.","evidence":"Biochemical purification, RIP, reporter assays, circRNA quantification, ADAR/DHX9 co-depletion and co-IP","pmids":["28355180"],"confidence":"High","gaps":["Catalytic mechanism on Alu dsRNA in cells not directly shown","Functional consequence of ADAR1-p150 interaction incompletely defined"]},{"year":2017,"claim":"Defining DHX9 processing of IGS-rRNA into pRNA to guide TIP5 placed DHX9 in heterochromatin establishment and stem cell differentiation.","evidence":"RIP, ChIP, knockdown with rescue by defined RNA species, ESC differentiation assays","pmids":["28588071"],"confidence":"High","gaps":["Whether helicase activity per se generates pRNA not isolated","Generality across rRNA loci unclear"]},{"year":2017,"claim":"Identifying Nup98 as a stimulator of DHX9 ATPase and co-occupant of gene loci connected nucleoporin function to DHX9-dependent transcription.","evidence":"In vitro binding and ATPase assays, ChIP-seq, transcriptional reporter, co-IP","pmids":["28221134"],"confidence":"High","gaps":["Mechanism of ATPase stimulation not structurally defined","Subnuclear site of action unclear"]},{"year":2018,"claim":"Showing DHX9-driven R-loop formation through prolonged RNAPII association upon splicing impairment defined a context where DHX9 generates rather than resolves hybrids that trap Pol II and block replication.","evidence":"S9.6 IF, ChIP, DRIP-seq, proximity ligation, splicing-factor knockdown","pmids":["30341290"],"confidence":"High","gaps":["Reconciling R-loop-forming versus R-loop-resolving roles unresolved","Determinants of switch between activities unknown"]},{"year":2018,"claim":"Transcriptome-wide profiling showed DHX9 binds 5'-UTR rG4 substrates to regulate uORF and downstream translation, extending its role to translational control.","evidence":"Ribo-seq, CLIP-seq, knockdown, luciferase reporters","pmids":["30591072"],"confidence":"High","gaps":["Division of labor with DHX36 not fully separated","In vivo translational impact untested"]},{"year":2018,"claim":"Establishing the DHX9-p65-RNAPII axis showed DHX9 is required for RNAPII recruitment to NF-κB promoters via its helicase activity and contributes to antiviral immunity against DNA viruses.","evidence":"Macrophage-specific KO, fibroblast KD, multiprotein co-IP, ChIP for p65/RNAPII, helicase-dead mutant, viral assays","pmids":["30137501"],"confidence":"High","gaps":["How helicase activity enables Pol II loading mechanistically unclear","Promoter structures unwound not identified"]},{"year":2018,"claim":"Bidirectional regulation of A-to-I editing demonstrated DHX9 differentially modulates ADAR1 versus ADAR2 substrate editing, partly via helicase activity.","evidence":"siRNA knockdown, transcriptome-wide editing analysis, helicase-dead mutant in cancer cells","pmids":["29796672"],"confidence":"Medium","gaps":["Mechanistic basis of ADAR isoform specificity unresolved","Single lab without structural support"]},{"year":2021,"claim":"Defining DHX9-mediated BRCA1 recruitment to RNA at damage sites placed DHX9 mechanistically within homologous recombination and end resection.","evidence":"Knockdown, RPA/RAD51 foci, co-IP, HR reporter, camptothecin/Olaparib sensitivity","pmids":["34226554"],"confidence":"High","gaps":["Direct biochemical role in resection not reconstituted","RNA species recruiting BRCA1 not defined"]},{"year":2021,"claim":"Identifying TDRD3 as a recruiter and stimulator of DHX9 helicase activity at promoters established a mechanism for targeted R-loop resolution.","evidence":"Reciprocal co-IP with domain mapping, ChIP, DRIP, in vitro helicase stimulation","pmids":["34329467"],"confidence":"High","gaps":["Promoter selectivity determinants unclear","Interplay with other R-loop resolvers not addressed"]},{"year":2020,"claim":"USP42 was shown to partner DHX9 for R-loop resolution at DSBs and HR, reinforcing the helicase-dependent R-loop/BRCA1 axis.","evidence":"Co-IP, knockdown, HR reporter, DRIP, BRCA1 foci","pmids":["32541651"],"confidence":"Medium","gaps":["Whether USP42 deubiquitinates DHX9 not established","Single lab"]},{"year":2022,"claim":"Polη was identified as recruiting DHX9 to G4 loci, defining cooperative action enabling replication through G-quadruplex regions.","evidence":"BioID, affinity pulldown-MS, ChIP-seq, co-IP, replication assay at G4 loci","pmids":["35905379"],"confidence":"Medium","gaps":["Order of recruitment versus unwinding unclear","Direct interaction interface unmapped"]},{"year":2023,"claim":"Pathogenic DHX9 variants causally linking it to neurodevelopmental disorders and CMT defined genotype-specific mechanisms (mislocalization, altered ATPase, elevated R-loops/DSBs).","evidence":"Exome sequencing with family analysis, variant expression and localization, ATPase assays, R-loop and γH2AX measurement, Dhx9 knockout mice","pmids":["37467750"],"confidence":"High","gaps":["Cell-type basis of neuronal versus sensory phenotypes unclear","How distinct molecular defects map to distinct diseases not fully resolved"]},{"year":2023,"claim":"Defining DHX9-STAT1-RNAPII recruitment to ISG promoters established a MAVS-independent, interferon-downstream antiviral transcription role distinct from its dsRNA-sensor function.","evidence":"Cell-type-specific KO mice, double-KO epistasis with MAVS and STAT1, co-IP, ChIP at ISG promoters, viral infection","pmids":["36735791"],"confidence":"High","gaps":["Reconciling MAVS-dependent sensing with MAVS-independent transcription unclear","Promoter-level helicase substrate not defined"]},{"year":2024,"claim":"ATR-mediated S321 phosphorylation was shown to gate DHX9 association with R-loops and damage factors, providing a damage-responsive regulatory switch.","evidence":"Phospho-mapping MS, ATR inhibition, phosphomimetic/non-phosphorylatable mutants, co-IP, DRIP, in vitro DHX9-RPA binding, drug sensitivity","pmids":["37930853"],"confidence":"High","gaps":["Structural effect of S321 phosphorylation unknown","Kinetics relative to damage signaling unresolved"]},{"year":2024,"claim":"SUMO2 modification at K120 was shown to license SIM-dependent interactions with PARP1 and DDX21 required for genome stability, adding a second post-translational control of R-loop function.","evidence":"K120R mutagenesis, SUMO2 fusion rescue, co-IP with SIM-dependent partners, DRIP, γH2AX IF, viability assays","pmids":["39019926"],"confidence":"High","gaps":["SUMO E3 ligase not identified","Interplay between K120 SUMO and S321 phosphorylation untested"]},{"year":2024,"claim":"Genetic studies established DHX9 as a therapeutic target by showing its loss triggers dual cytoplasmic dsRNA innate immunity and R-loop-driven DNA damage, enhancing checkpoint-blockade response in SCLC and driving cGAS-STING inflammation in intestinal stem cells.","evidence":"CRISPR screen and KO with in vivo tumor models and immune profiling; conditional Dhx9 KO mice with DRIP and cGAS-STING readouts and colitis models","pmids":["38189443","38594251"],"confidence":"High","gaps":["Relative contribution of dsRNA versus R-loop arms to phenotypes unclear","Tissue-specific thresholds for DHX9 loss unknown"]},{"year":2024,"claim":"Discovery of DHX9-specific stress granules enriched in damaged intron RNA defined a distinct cytoplasmic dsRNA-handling compartment promoting survival after UV damage.","evidence":"FANCI damaged-RNA mapping, IF, SG-fraction RNA-seq, p62 knockout/knockdown, viability assays","pmids":["38503283"],"confidence":"High","gaps":["Trigger of DHX9 SG nucleation not fully defined","Relationship to nuclear DHX9 functions unclear"]},{"year":null,"claim":"How DHX9 switches between R-loop formation and resolution, and how its many post-translational modifications and partner proteins are integrated to direct it among genome-protective, transcriptional, translational, and antiviral roles, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model coordinating modification states with substrate choice","Structural basis for partner-directed targeting lacking","Determinants of nuclear versus cytoplasmic functional partitioning unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[5,9,16]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[1,5,8]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,4,45]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,4,7,32]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,8]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,9]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[30,29,36]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[29,30,41]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[10,41]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,22,26,27]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[11,24,38]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[13,37,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[30,29,16,36]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,7,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,29,26,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[41,26,31]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[24,27]}],"complexes":["RNA Polymerase II transcription complex","RISC"],"partners":["BRCA1","RPA","TDRD3","NUP98","STAT1","RELA","ADAR","AR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q08211","full_name":"ATP-dependent RNA helicase A","aliases":["DEAH box protein 9","DExH-box helicase 9","Leukophysin","LKP","Nuclear DNA helicase II","NDH II","RNA helicase A"],"length_aa":1270,"mass_kda":141.0,"function":"Multifunctional ATP-dependent nucleic acid helicase that unwinds DNA and RNA in a 3' to 5' direction and that plays important roles in many processes, such as DNA replication, transcriptional activation, post-transcriptional RNA regulation, mRNA translation and RNA-mediated gene silencing (PubMed:11416126, PubMed:12711669, PubMed:15355351, PubMed:16680162, PubMed:17531811, PubMed:20669935, PubMed:21561811, PubMed:24049074, PubMed:24990949, PubMed:25062910, PubMed:28221134, PubMed:9111062, PubMed:37467750). Requires a 3'-single-stranded tail as entry site for acid nuclei unwinding activities as well as the binding and hydrolyzing of any of the four ribo- or deoxyribo-nucleotide triphosphates (NTPs) (PubMed:1537828). Unwinds numerous nucleic acid substrates such as double-stranded (ds) DNA and RNA, DNA:RNA hybrids, DNA and RNA forks composed of either partially complementary DNA duplexes or DNA:RNA hybrids, respectively, and also DNA and RNA displacement loops (D- and R-loops), triplex-helical DNA (H-DNA) structure and DNA and RNA-based G-quadruplexes (PubMed:20669935, PubMed:21561811, PubMed:24049074). Binds dsDNA, single-stranded DNA (ssDNA), dsRNA, ssRNA and poly(A)-containing RNA (PubMed:10198287, PubMed:9111062). Also binds to circular dsDNA or dsRNA of either linear and/or circular forms and stimulates the relaxation of supercoiled DNAs catalyzed by topoisomerase TOP2A (PubMed:12711669). Plays a role in DNA replication at origins of replication and cell cycle progression (PubMed:24990949). Plays a role as a transcriptional coactivator acting as a bridging factor between polymerase II holoenzyme and transcription factors or cofactors, such as BRCA1, CREBBP, RELA and SMN1 (PubMed:11038348, PubMed:11149922, PubMed:11416126, PubMed:15355351, PubMed:28221134, PubMed:9323138, PubMed:9662397). Binds to the CDKN2A promoter (PubMed:11038348). Plays several roles in post-transcriptional regulation of gene expression (PubMed:28221134, PubMed:28355180). In cooperation with NUP98, promotes pre-mRNA alternative splicing activities of a subset of genes (PubMed:11402034, PubMed:16680162, PubMed:28221134, PubMed:28355180). As component of a large PER complex, is involved in the negative regulation of 3' transcriptional termination of circadian target genes such as PER1 and NR1D1 and the control of the circadian rhythms (By similarity). Also acts as a nuclear resolvase that is able to bind and neutralize harmful massive secondary double-stranded RNA structures formed by inverted-repeat Alu retrotransposon elements that are inserted and transcribed as parts of genes during the process of gene transposition (PubMed:28355180). Involved in the positive regulation of nuclear export of constitutive transport element (CTE)-containing unspliced mRNA (PubMed:10924507, PubMed:11402034, PubMed:9162007). Component of the coding region determinant (CRD)-mediated complex that promotes cytoplasmic MYC mRNA stability (PubMed:19029303). Plays a role in mRNA translation (PubMed:28355180). Positively regulates translation of selected mRNAs through its binding to post-transcriptional control element (PCE) in the 5'-untranslated region (UTR) (PubMed:16680162). Involved with LARP6 in the translation stimulation of type I collagen mRNAs for CO1A1 and CO1A2 through binding of a specific stem-loop structure in their 5'-UTRs (PubMed:22190748). Stimulates LIN28A-dependent mRNA translation probably by facilitating ribonucleoprotein remodeling during the process of translation (PubMed:21247876). Plays also a role as a small interfering (siRNA)-loading factor involved in the RNA-induced silencing complex (RISC) loading complex (RLC) assembly, and hence functions in the RISC-mediated gene silencing process (PubMed:17531811). Binds preferentially to short double-stranded RNA, such as those produced during rotavirus intestinal infection (PubMed:28636595). This interaction may mediate NLRP9 inflammasome activation and trigger inflammatory response, including IL18 release and pyroptosis (PubMed:28636595). Finally, mediates the attachment of heterogeneous nuclear ribonucleoproteins (hnRNPs) to actin filaments in the nucleus (PubMed:11687588) (Microbial infection) Plays a role in HIV-1 replication and virion infectivity (PubMed:11096080, PubMed:19229320, PubMed:25149208, PubMed:27107641). Enhances HIV-1 transcription by facilitating the binding of RNA polymerase II holoenzyme to the proviral DNA (PubMed:11096080, PubMed:25149208). Binds (via DRBM domain 2) to the HIV-1 TAR RNA and stimulates HIV-1 transcription of transactivation response element (TAR)-containing mRNAs (PubMed:11096080, PubMed:9892698). Involved also in HIV-1 mRNA splicing and transport (PubMed:25149208). Positively regulates HIV-1 gag mRNA translation, through its binding to post-transcriptional control element (PCE) in the 5'-untranslated region (UTR) (PubMed:16680162). Binds (via DRBM domains) to a HIV-1 double-stranded RNA region of the primer binding site (PBS)-segment of the 5'-UTR, and hence stimulates DHX9 incorporation into virions and virion infectivity (PubMed:27107641). Also plays a role as a cytosolic viral MyD88-dependent DNA and RNA sensors in plasmacytoid dendritic cells (pDCs), and hence induce antiviral innate immune responses (PubMed:20696886, PubMed:21957149). Binds (via the OB-fold region) to viral single-stranded DNA unmethylated C-phosphate-G (CpG) oligonucleotide (PubMed:20696886)","subcellular_location":"Nucleus; Nucleus, nucleoplasm; Nucleus, nucleolus; Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q08211/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DHX9","classification":"Common 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Theoretical and applied genetics. 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Remodeling.","date":"2020","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/32087197","citation_count":16,"is_preprint":false},{"pmid":"36409901","id":"PMC_36409901","title":"Regulation of the DEAH/RHA helicase Prp43 by the G-patch factor Pfa1.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36409901","citation_count":15,"is_preprint":false},{"pmid":"31141705","id":"PMC_31141705","title":"Molecular characterization and expression of the teleost cytosolic DNA sensor genes cGAS, LSm14A, DHX9, and DHX36 in Japanese medaka, Oryzias latipes.","date":"2019","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31141705","citation_count":15,"is_preprint":false},{"pmid":"26382053","id":"PMC_26382053","title":"Evolution of the DEAD box helicase family in chicken: chickens have no DHX9 ortholog.","date":"2015","source":"Microbiology and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26382053","citation_count":15,"is_preprint":false},{"pmid":"35590370","id":"PMC_35590370","title":"The DNA/RNA helicase DHX9 contributes to the transcriptional program of the androgen receptor in prostate cancer.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35590370","citation_count":14,"is_preprint":false},{"pmid":"38874176","id":"PMC_38874176","title":"AURKB targets DHX9 to promote hepatocellular carcinoma progression via PI3K/AKT/mTOR pathway.","date":"2024","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/38874176","citation_count":14,"is_preprint":false},{"pmid":"32761833","id":"PMC_32761833","title":"C1orf109L binding DHX9 promotes DNA damage depended on the R-loop accumulation and enhances camptothecin chemosensitivity.","date":"2020","source":"Cell 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I. Genetic analysis of the Rha phenotype.","date":"1985","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/3155885","citation_count":13,"is_preprint":false},{"pmid":"38041141","id":"PMC_38041141","title":"DHRS4-AS1 regulate gastric cancer apoptosis and cell proliferation by destabilizing DHX9 and inhibited the association between DHX9 and ILF3.","date":"2023","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/38041141","citation_count":12,"is_preprint":false},{"pmid":"3718662","id":"PMC_3718662","title":"Behavioral characteristics of Roman high avoidance rats homozygous for diabetes insipidus (RHA: di/di).","date":"1986","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/3718662","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49482,"output_tokens":11464,"usd":0.160203,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22768,"output_tokens":7220,"usd":0.14717,"stage2_stop_reason":"end_turn"},"total_usd":0.307373,"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\": 2017,\n      \"finding\": \"DHX9 binds specifically to inverted-repeat Alu elements transcribed as parts of genes; loss of DHX9 increases circular RNA production, causes translational repression of reporters containing inverted-repeat Alu elements, and produces transcriptional rewiring. DHX9 interacts with the interferon-inducible ADAR isoform p150 (but not p110) in an RNA-independent manner. Co-depletion of ADAR and DHX9 augments dsRNA accumulation and circular RNA production, revealing a functional link between the two enzymes.\",\n      \"method\": \"Biochemical purification, RNA immunoprecipitation, reporter assays, siRNA knockdown, circular RNA quantification, co-IP\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical purification, reporter assays, co-IP, RNA-seq) in a single rigorous study with clear mechanistic readouts\",\n      \"pmids\": [\"28355180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DHX9 preferentially unwinds RNA-containing displacement loops (R-loops) and DNA/RNA-based G-quadruplexes over simple DNA-DNA duplexes in vitro, suggesting these structures are biologically relevant substrates.\",\n      \"method\": \"In vitro helicase assays using defined nucleic acid substrates (partial duplexes, D-loops, R-loops, G-quadruplexes)\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple defined substrates, single lab, multiple orthogonal substrate comparisons\",\n      \"pmids\": [\"21561811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DHX9 functions as a dsRNA sensor in myeloid dendritic cells, binding polyinosine-polycytidylic acid via its dsRNA-binding motifs and interacting with the adaptor IPS-1 (MAVS) via DHX9's HelicC-HA2-DUF domain and IPS-1's CARD domain to activate NF-κB and IRF3 signaling in response to dsRNA.\",\n      \"method\": \"siRNA knockdown, dsRNA binding assays, co-immunoprecipitation with domain mapping, cytokine production assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping, functional knockdown with defined cytokine readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21957149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DHX9 (RNA helicase A) promotes the formation of R-loops in cells with impaired splicing through prolonged association with RNA Polymerase II, producing DNA-RNA hybrids that trap RNA Pol II on chromatin and can block DNA replication.\",\n      \"method\": \"R-loop immunofluorescence (S9.6 antibody), chromatin immunoprecipitation, DRIP-seq, proximity ligation assay, siRNA knockdown of splicing factors\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, DRIP-seq, and proximity ligation combined in single study with defined mechanistic pathway; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30341290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DHX9 and DHX36 helicase depletion promotes translation of rG4-associated upstream open reading frames (uORFs) while reducing translation of downstream coding regions; transcriptome-wide binding analysis shows DHX9 directly interacts with rG4 substrates in 5'-UTRs to regulate translation.\",\n      \"method\": \"Ribosome profiling (Ribo-seq), CLIP-seq for DHX9 binding site identification, siRNA knockdown, luciferase reporter assays\",\n      \"journal\": \"Genome biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transcriptome-wide ribosome profiling plus direct binding site identification (CLIP-seq) plus functional reporters, multiple orthogonal methods\",\n      \"pmids\": [\"30591072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DHX9 unwinds triple-helical DNA structures (H-DNA/intramolecular triplexes) in vitro with 3'→5' polarity with respect to the displaced third strand, requiring a 3'-single-stranded overhang and ATP hydrolysis; DHX9 co-immunoprecipitates with triplex DNA structures in mammalian cells.\",\n      \"method\": \"In vitro helicase assay with triplex substrates, co-immunoprecipitation with triplex DNA, ATP hydrolysis assays, kinetic analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with defined substrates plus mutational/substrate-specificity analysis plus cellular co-IP, single lab\",\n      \"pmids\": [\"20669935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DHX9 stimulates WRN helicase unwinding of RNA-containing Okazaki fragment-like substrates and RNA-containing 'chicken-foot' structures in vitro, suggesting cooperative action at replication forks; DHX9 and WRN engage in direct protein-protein interaction.\",\n      \"method\": \"In vitro helicase assays with synthetic substrates, protein-protein interaction assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with defined substrates, single lab, no in vivo functional validation of the cooperative mechanism\",\n      \"pmids\": [\"20385589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DHX9 is required for RISC assembly via its dsRNA-binding domains (dsRBD1 and dsRBD2); crystal structures of dsRBD1 and dsRBD2 in complex with dsRNA reveal that dsRBD1 has higher siRNA-binding affinity and a crystallographic dsRBD1 pair cooperatively recognizes dsRNA. Both dsRBDs are required for RISC association mediated by dsRNA.\",\n      \"method\": \"Crystal structure determination, isothermal titration calorimetry (ITC), co-immunoprecipitation with mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures plus ITC thermodynamics plus mutagenesis-validated co-IP, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"23361462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DHX9 depletion increases mutagenesis at H-DNA structures in human cells, predominantly causing deletions; DHX9 associates with H-DNA in supercoiled plasmids and is enriched at H-DNA regions in chromatin by ChIP, implicating DHX9 in processing intramolecular triplex DNA in vivo.\",\n      \"method\": \"siRNA knockdown mutation-reporter assay, in vitro binding assay, chromatin immunoprecipitation (ChIP) in U2OS cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutation-reporter assay plus ChIP plus in vitro binding, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"24049074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the conserved helicase domain 1 (DEIH motif) of human DHX9 reveals a RecA-like core more similar to viral NS3 helicases than DEAD-box proteins; DHX9 lacks base-selective contacts and forms an unspecific stacking interaction with the nucleotide base, allowing hydrolysis of ATP, GTP, CTP, and UTP.\",\n      \"method\": \"X-ray crystallography, NTPase biochemical assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with biochemical validation of NTPase activity, multiple NTP substrates tested\",\n      \"pmids\": [\"20510246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DHX9 binds to IGS-rRNA at rRNA genes upon embryonic stem cell (ESC) differentiation, processes IGS-rRNA into pRNA, and thereby guides the repressor TIP5 to establish heterochromatin at rRNA genes; DHX9 depletion prevents ESC differentiation, a phenotype rescued by addition of pRNA but not IGS-rRNA or TIP5-binding-deficient pRNA mutants.\",\n      \"method\": \"RNA immunoprecipitation, ChIP, siRNA knockdown, differentiation assays, rescue experiments with RNA addition\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RIP, ChIP, functional rescue with defined RNA species, KD phenotype), clear epistatic ordering\",\n      \"pmids\": [\"28588071\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DHX9 promotes BRCA1 recruitment to RNA at sites of DNA damage as part of the RNA Polymerase II transcription complex, facilitating DNA end resection and homologous recombination (HR). DHX9-deficient cells fail to recruit RPA and RAD51 to DSBs, are defective in HR, hypersensitive to camptothecin and Olaparib, and show impaired ATR-mediated damage signaling and replication restart.\",\n      \"method\": \"siRNA knockdown, immunofluorescence for RPA/RAD51 foci, co-immunoprecipitation, HR reporter assay, drug sensitivity assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IP, foci assays, HR reporter, drug sensitivity), pathway placement via epistasis, single lab\",\n      \"pmids\": [\"34226554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TDRD3 directly interacts with DHX9 via its Tudor domain, recruits DHX9 to target gene promoters to resolve R-loops in a helicase-activity-dependent manner, and stimulates DHX9 helicase activity via its OB-fold domain that likely binds the ssDNA in the R-loop.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, DRIP (DNA-RNA immunoprecipitation), helicase activity assays, domain-mapping mutagenesis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain mapping, ChIP, DRIP, in vitro helicase stimulation assay, multiple orthogonal methods\",\n      \"pmids\": [\"34329467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Suppression of DHX9 in primary human diploid fibroblasts induces premature senescence in a p53-dependent manner; DHX9 associates with origins of replication by ChIP, and its suppression reduces nascent DNA synthesis, demonstrating an essential role in DNA replication and cell cycle progression.\",\n      \"method\": \"siRNA/shRNA knockdown, senescence-associated β-galactosidase assay, ChIP at replication origins, nascent DNA labeling, gene expression profiling\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with defined cellular phenotype, ChIP, replication assay, p53 pathway validation; multiple orthogonal methods, single lab\",\n      \"pmids\": [\"24990949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DHX9 functions as a bidirectional regulator of A-to-I RNA editing in cancer cells, at least partially dependent on its helicase activity: DHX9 silencing preferentially represses ADAR1-specific editing while augmenting ADAR2-specific substrate editing.\",\n      \"method\": \"siRNA knockdown, transcriptome-wide RNA editing analysis, helicase-dead mutant expression\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — transcriptome-wide editing analysis plus helicase-dead mutant, but single lab and mechanistic link to ADAR specificity not fully resolved\",\n      \"pmids\": [\"29796672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DHX9 forms a complex with RNA Polymerase II and EWS-FLI1 to enhance transcription in Ewing sarcoma cells; UV irradiation causes enhanced RNAPII phosphorylation and decreased processivity, leading to alternative splicing inclusion of DHX9 exon 6A that targets DHX9 mRNA to NMD-mediated decay, reducing DHX9 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, minigene splicing assays, RT-PCR for alternative isoforms, UV irradiation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, splicing mechanism validated by minigene, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"26450900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human Nup98 binds to DHX9 via its FG/GLFG repeat region interacting with N- and C-terminal regions of DHX9 in an RNA-facilitated manner; Nup98 binding stimulates DHX9 ATPase activity and supports DHX9-stimulated transcription; Nup98 and DHX9 bind interdependently to similar gene loci.\",\n      \"method\": \"In vitro binding assays, ATPase activity assays, transcriptional reporter assay, ChIP-seq, co-immunoprecipitation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ATPase stimulation assay plus ChIP-seq plus reporter assay plus binding domain mapping; multiple orthogonal methods\",\n      \"pmids\": [\"28221134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Myxoma virus M029 protein interacts with DHX9/RHA in a dsRNA-independent manner in infected cells; M029 not only inhibits PKR but also conscripts DHX9 as a pro-viral effector to promote viral replication specifically in myeloid THP1 cells, as PKR depletion rescue of M029-minus viruses is reversed by DHX9 knockdown.\",\n      \"method\": \"Proteomic co-immunoprecipitation, siRNA knockdown of DHX9, virus replication assays, epistasis (PKR KD + DHX9 KD double knockdown)\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double KD) plus co-IP proteomics, single lab\",\n      \"pmids\": [\"23853588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRRSV nucleocapsid (N) protein interacts with cellular DHX9 and redistributes it from the nucleus to the cytoplasm; knockdown of DHX9 increases production of short subgenomic mRNAs while DHX9 overexpression promotes synthesis of longer subgenomic mRNAs and genomic RNA, suggesting DHX9 acts as an antiattenuation factor for continuous elongation during viral RNA synthesis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, viral RNA quantification by RT-qPCR, immunofluorescence for localization\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, functional KD and OE with defined viral RNA readouts, localization imaging; single lab\",\n      \"pmids\": [\"27009951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DHX9/RHA binds to the double-stranded PBS-segment of the HIV-1 5'-UTR dimer; ITC shows one RHA molecule binds per RNA strand independently of nucleocapsid protein; NMR with deuterium labeling defines the structural basis of this interaction; disruption of this binding (single A-to-C substitution) attenuates virion infectivity.\",\n      \"method\": \"Isothermal titration calorimetry (ITC), NMR spectroscopy, cell-based viral infectivity assays, mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ITC thermodynamics plus NMR structure plus functional mutagenesis and infectivity assay; multiple orthogonal Tier 1 methods\",\n      \"pmids\": [\"27107641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Virion-associated DHX9/RHA enhances the processivity of HIV-1 reverse transcriptase (RT) during elongation phase of (-)cDNA synthesis; pre-steady-state and steady-state kinetics show RHA has little impact on single-nucleotide incorporation rate but increases RT processivity, as demonstrated by primer extension in the presence of trap dsDNA.\",\n      \"method\": \"In vitro reverse transcription reconstitution, pre-steady-state and steady-state kinetic assays, primer extension with trap assay, quantification of reverse-transcription intermediates in infected T cells\",\n      \"journal\": \"Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with kinetic analysis plus cellular RT intermediate quantification; multiple orthogonal methods\",\n      \"pmids\": [\"31175158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DHX9 is recruited to CHIKV replication complexes at the plasma membrane via interaction with nsP3's C-terminal hypervariable domain; during early infection DHX9 negatively controls viral RNA synthesis but is required for optimal translation of mature nonstructural proteins; at later stages DHX9 is degraded via the proteasome.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence for colocalization, viral RNA quantification, proteasome inhibitor experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain identification, KD with defined viral RNA/protein readouts, localization imaging; single lab\",\n      \"pmids\": [\"30463980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"During FMDV infection, JMJD6 arginine demethylase physically interacts with DHX9 (preferring JMJD6 monomers) and demethylates RHA arginine residues at its C-terminus; this demethylation promotes DHX9 redistribution from nucleus to cytoplasm and facilitates viral protein synthesis and virus replication.\",\n      \"method\": \"Reciprocal co-immunoprecipitation, NOG inhibitor of JmjC demethylases, modified biochemical demethylation assay, immunofluorescence for subcellular localization\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, biochemical demethylation assay, pharmacological inhibition with NOG; single lab\",\n      \"pmids\": [\"24606677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DHX9/RHA is SUMOylated by Ubc9 (E2 SUMO ligase); the N-terminal domain (residues 1–137) of RHA is sufficient for Ubc9 interaction; Ubc9 interaction activates RHA transcriptional activity in a CREB-mediated reporter assay, and Ubc9 catalytic activity is dispensable for the transcription activation function.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping truncation mutants, in vitro and in vivo SUMO conjugation assay, transcriptional reporter assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, in vitro SUMO conjugation, functional reporter assay; single lab, multiple methods\",\n      \"pmids\": [\"15312759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATR kinase phosphorylates DHX9 at serine 321 (S321) upon DNA damage; this phosphorylation promotes DHX9 interaction with γH2AX, BRCA1, and RPA, and is required for DHX9 association with R-loops under genotoxic stress. Non-phosphorylatable DHX9-S321A causes R-loop accumulation and hypersensitivity to genotoxic agents; phosphomimetic DHX9-S321D prevents R-loop accumulation and confers resistance. In vitro binding confirms direct DHX9–RPA interaction.\",\n      \"method\": \"Phospho-mapping mass spectrometry, ATR inhibitor treatment, phosphomimetic/non-phosphorylatable mutants, co-immunoprecipitation, DRIP assay, in vitro binding assay, drug sensitivity assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-specific mutagenesis of phosphorylation site with functional phenotype, in vitro binding, DRIP, co-IP; multiple orthogonal methods\",\n      \"pmids\": [\"37930853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DHX9 SUMOylation at lysine 120 (K120) is required for genome stability; SUMO2 modification at K120 enables DHX9 to interact with R-loop-associated proteins PARP1 and DDX21 via SUMO-interacting motifs. The K120R mutant (non-SUMOylatable) shows R-loop accumulation, increased DNA damage, and cell death; fusing SUMO2 to K120R rescues these defects.\",\n      \"method\": \"Site-directed mutagenesis (K120R), SUMO2 fusion rescue construct, co-immunoprecipitation, DRIP assay, γH2AX immunofluorescence, cell viability assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — defined mutagenesis of modification site, SUMO2 fusion rescue, co-IP with SIM-dependent partners, DRIP; multiple orthogonal methods\",\n      \"pmids\": [\"39019926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DHX9 depletion in SCLC leads to cytoplasmic dsRNA accumulation triggering tumor-intrinsic innate immunity, and simultaneously causes aberrant R-loop accumulation leading to DNA damage-derived cytoplasmic DNA and replication stress; in vivo, DHX9 deletion reduces tumor growth and enhances immunogenic tumor microenvironment, improving response to immune-checkpoint blockade.\",\n      \"method\": \"CRISPR-based screen, CRISPR knockout, immunofluorescence for dsRNA and R-loops, DNA damage markers, in vivo tumor models, immune profiling\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen plus in vivo tumor models plus mechanistic molecular readouts (dsRNA, R-loops, DNA damage), replicated across multiple approaches\",\n      \"pmids\": [\"38189443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DHX9 forms stress granules (SGs) distinct from classical SGs upon UV irradiation; DHX9 SGs are enriched in damaged intron RNA rather than mature mRNA. UV-induced RNA crosslinking impedes intron splicing and decay, triggering DHX9 SGs in daughter cells. DHX9 modulates dsRNA abundance within SGs and promotes cell survival; autophagy receptor p62 is required for DHX9 SG disassembly.\",\n      \"method\": \"FANCI technology for damaged RNA identification, immunofluorescence, RNA sequencing of SG fractions, p62 knockout/knockdown, cell viability assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — novel technology (FANCI) plus multiple imaging and sequencing approaches, clear mechanistic distinctions from classical SGs, cell viability functional readout\",\n      \"pmids\": [\"38503283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DHX9 deficiency in intestinal stem cells (ISCs) causes abnormal R-loop accumulation leading to genomic instability and cGAS-STING-mediated inflammatory response, impairing ISC function; conditional Dhx9 knockout in intestinal epithelium increases susceptibility to experimental colitis with reduction in ISC and Paneth cell numbers.\",\n      \"method\": \"Conditional ISC-specific and Paneth cell-specific Dhx9 knockout mice, DRIP for R-loops, cGAS-STING pathway marker analysis, histology, colitis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific in vivo knockout with multiple pathway readouts (R-loops, cGAS-STING, inflammation), replicated in multiple conditional KO lines\",\n      \"pmids\": [\"38594251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nuclear DHX9 directly binds STAT1 and recruits RNA Pol II to interferon-stimulated gene (ISG) promoters to participate in STAT1-mediated ISG transcription; myeloid- or hepatocyte-specific DHX9 knockout mice are more susceptible to RNA virus infections, and this antiviral role is downstream of type I interferon, dependent on STAT1 (not MAVS).\",\n      \"method\": \"Myeloid- and hepatocyte-specific DHX9 knockout mice, double-KO with MAVS or STAT1, co-immunoprecipitation, ChIP for Pol II at ISG promoters, viral infection models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo cell-type-specific KO with double-KO epistasis, co-IP, ChIP; pathway placement defined by genetic epistasis with MAVS and STAT1\",\n      \"pmids\": [\"36735791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DHX9 interacts with p65 (NF-κB subunit) and RNA Polymerase II in chromatin at NF-κB binding sites; nuclear DHX9 is essential for recruitment of RNAPII (but not p65) to NF-κB target gene promoters, requiring its ATPase/helicase activity; macrophage- and fibroblast-specific DHX9 knockout/knockdown impairs antiviral innate immunity against DNA viruses.\",\n      \"method\": \"Macrophage-specific KO, fibroblast-specific KD, co-immunoprecipitation of multiprotein complex, ChIP for p65 and RNAPII at NF-κB promoters, helicase-dead mutant, viral replication assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO, ChIP with RNAPII and p65, helicase-dead mutant epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"30137501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DHX9 interacts with p65 and RNAPII to enhance p65 phosphorylation and nuclear translocation, facilitating NF-κB-mediated transcription of downstream targets (Survivin, Snail) to promote colorectal cancer malignant phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, overexpression, xenograft and hepatic metastasis mouse models\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP, in vivo models; single lab; overlaps with findings in PMID 30137501\",\n      \"pmids\": [\"34773477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DHX9 binds the 3'-UTR of CDK6 mRNA and post-transcriptionally suppresses CDK6 expression; lnc-UCID (lncRNA) interacts with DHX9 via its 850-1030 nt domain and sequesters DHX9 from CDK6-3'UTR, thereby enhancing CDK6 expression and promoting G1/S transition.\",\n      \"method\": \"RNA immunoprecipitation, RNA pulldown, co-immunoprecipitation, luciferase reporter of CDK6-3'UTR, siRNA knockdown, gain/loss-of-function studies, xenograft models\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and RNA pulldown plus functional CDK6-3'UTR reporter, competitive binding mechanism validated; single lab\",\n      \"pmids\": [\"30865310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DHX9 is associated with HBV viral RNAs; DHX9 knockdown increases HBV-derived circular RNA production while decreasing viral protein levels (without affecting HBV DNA levels), demonstrating DHX9 is a novel regulator of viral circular RNA biogenesis.\",\n      \"method\": \"Co-immunoprecipitation/RNA binding assay, siRNA knockdown, circular RNA quantification, viral protein and DNA assays in HBV-producing cell lines and primary hepatocytes\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA binding demonstrated, functional KD with defined molecular readouts in multiple cell systems; single lab\",\n      \"pmids\": [\"29765512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DHX9 interacts with the EBV SM protein (co-immunoprecipitation, nuclear co-localization) and restricts EBV lytic replication; DHX9 depletion increases EBV late gene expression and virion production; DHX9 enhances innate antiviral pathways (ISGs), and SM inhibits DHX9's transcription-activating function through cAMP response elements (CREs).\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, immunofluorescence, siRNA knockdown, viral gene expression and titer assays, CRE reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP (mass spec + co-IP), KD functional assays, CRE reporter; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30541834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DHX9 induces alternative splicing of KLF5 mRNA by bridging YB-1 protein in vascular smooth muscle cells; smooth muscle cell-specific DHX9 conditional knockout alters transcriptional and alternative splicing profiles of smooth muscle cell phenotype-related genes and exacerbates aortic dissection.\",\n      \"method\": \"Vascular smooth muscle cell-specific DHX9 conditional knockout mice, RNA-seq, alternative splicing analysis, co-immunoprecipitation (DHX9-YB-1 interaction), aortic dissection model\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with RNA-seq plus co-IP for bridging mechanism; single lab\",\n      \"pmids\": [\"31116584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DHX9 interacts with Androgen Receptor (AR) in prostate cancer cells; AR binds the DHX9 promoter to induce DHX9 expression; DHX9 depletion reduces AR recruitment to target gene promoters and AR-driven transcription in response to DHT; enzalutamide-mediated AR inhibition represses DHX9 expression, establishing a DHX9/AR positive feedback axis.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, RNA-seq, promoter reporter assay, siRNA knockdown, cell proliferation and migration assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ChIP of AR at DHX9 promoter, RNA-seq, pharmacological validation; single lab\",\n      \"pmids\": [\"35590370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pol η (DNA polymerase eta) interacts with DHX9 (identified by proximity labeling and affinity pulldown-MS); Pol η promotes DHX9 recruitment to G4-structure loci in chromatin; deficiency in either Pol η or DHX9 impairs replication across G4 regions, indicating cooperative action at G4 sites during replication.\",\n      \"method\": \"Proximity labeling (BioID), affinity pulldown with LC-MS/MS, ChIP-seq, co-immunoprecipitation, replication assay at G4 loci, siRNA knockdown\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent interaction discovery methods (proximity labeling + pulldown-MS) plus ChIP-seq plus replication assay; single lab\",\n      \"pmids\": [\"35905379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"USP42 interacts with DHX9 and promotes R-loop resolution at DNA double-strand breaks (DSBs); USP42 localization to nuclear speckles is required for efficient HR; DHX9's DNA-RNA helicase activity is required for DSB-induced R-loop resolution and BRCA1 recruitment.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, HR reporter assay, DRIP for R-loops, BRCA1 foci immunofluorescence\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, functional HR assay, DRIP, BRCA1 recruitment assay; single lab\",\n      \"pmids\": [\"32541651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AKT1 kinase domain directly interacts with DHX9 and facilitates DHX9 recruitment to R-loops; AKT inhibition reduces DHX9 association with R-loops and increases ATRi-induced R-loop-mediated replication stress; the interaction is direct as shown by in vitro binding analysis.\",\n      \"method\": \"Quantitative high-throughput drug combination screen, co-immunoprecipitation, in vitro binding assay, DRIP for R-loops, replication stress markers\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus co-IP plus DRIP, pharmacological modulation; single lab\",\n      \"pmids\": [\"38241710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Oxaliplatin induces PI3KK-mediated phosphorylation of DHX9 at two sites near substrate-binding domains; non-phosphorylatable DHX9 mutants or PI3KK inhibitor blockage decreases oxaliplatin-induced circCCDC66 circular RNA expression and impairs development of chemoresistance.\",\n      \"method\": \"Site-directed mutagenesis (non-phosphorylatable DHX9 mutants), PI3KK inhibitors, circular RNA quantification, drug resistance assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of phosphorylation sites with functional readout (circRNA and drug resistance); single lab\",\n      \"pmids\": [\"32187976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DHX9 pathogenic variants cause neurodevelopmental disorders and Charcot-Marie-Tooth disease; NLS missense variants cause abnormal cytoplasmic DHX9 accumulation (loss of nuclear localization), CMT2-associated variants cause aberrant nucleolar DHX9 accumulation, and an NDD variant (p.Arg141Gln) increases R-loop levels and DNA double-strand breaks without altering localization. Two variants (p.Gly411Glu, p.Arg761Gln) alter DHX9 ATPase activity. Dhx9-/- mice show hypoactivity, tremor, and sensorineural hearing loss.\",\n      \"method\": \"Exome sequencing with family analysis, human cell line DHX9 variant expression (localization by immunofluorescence), patient fibroblast localization, ATPase activity assays, R-loop measurement (S9.6), γH2AX foci, Dhx9 knockout mice\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (ATPase assay, cell imaging, R-loop quantification, mouse KO model), variant-specific mechanistic phenotyping, 20 patients with genotype-phenotype correlations\",\n      \"pmids\": [\"37467750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MDM2 E3 ubiquitin ligase interacts with DHX9 and mediates its ubiquitin-proteasome-dependent degradation; lnc-CCDST lncRNA binds DHX9 and serves as a scaffold to facilitate the DHX9–MDM2 interaction, promoting DHX9 degradation and suppressing cervical cancer motility and angiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, in vitro and in vivo migration/invasion/angiogenesis assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, scaffold mechanism via lncRNA; single lab\",\n      \"pmids\": [\"30518908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPOP E3 ubiquitin ligase binds DHX9 via a canonical SPOP-binding motif in DHX9 and induces its ubiquitination and proteasomal degradation; SPOP depletion increases DHX9 levels and promotes choriocarcinoma migration and invasion; DHX9 siRNA partially rescues the pro-migratory effect of SPOP knockdown.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, binding motif identification, migration/invasion assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, ubiquitination assay, SPOP-binding motif mutation, functional rescue; single lab\",\n      \"pmids\": [\"32905556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DHX9 interacts with APOBEC3B (A3B) in the presence of HBV; DHX9 does not affect A3B deaminase activity but inhibits A3B binding to HBV pregenomic RNA (pgRNA), thereby attenuating A3B's anti-HBV effect.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry, in vitro deaminase assay, pgRNA binding assay, HBV DNA replication quantification\",\n      \"journal\": \"Emerging microbes & infections\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with MS, in vitro binding assay, functional deaminase and HBV replication readouts; single lab\",\n      \"pmids\": [\"32056513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DHX9 unwinds inhibitory RNA G-quadruplex (rG4) structures near the translation initiation site of PCMT1 mRNA; circCLASP2 acts as a molecular scaffold bringing DHX9 to PCMT1 mRNA, increasing PCMT1 translation and promoting cytoskeletal changes in nasopharyngeal carcinoma.\",\n      \"method\": \"RNA immunoprecipitation, RNA pulldown, ribosomal gradient sedimentation, dual-luciferase reporter, immunofluorescence, in vitro and in vivo NPC assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP, RNA pulldown, ribosome profiling, rG4 reporter assay; single lab\",\n      \"pmids\": [\"40050914\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DHX9 is an abundant nuclear DExH-box RNA/DNA helicase that maintains genome stability and regulates gene expression by unwinding diverse non-canonical nucleic acid structures (R-loops, G-quadruplexes, inverted-repeat Alu dsRNA, intramolecular triplexes/H-DNA) in a 3'→5', ATP-dependent manner; it associates with RNA Polymerase II and transcription factors (including NF-κB p65, STAT1, and AR) to co-activate gene transcription, facilitates RISC assembly and RNA editing via its dsRNA-binding domains, acts as an innate immune dsRNA sensor signaling through IPS-1/MAVS, promotes homologous recombination by recruiting BRCA1 to RNA at damage sites, and is regulated by post-translational modifications including ATR-mediated S321 phosphorylation, SUMOylation at K120, arginine demethylation by JMJD6, and ubiquitin-mediated degradation by MDM2, SPOP, and PRPF19.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DHX9 is an abundant nuclear DExH-box helicase that maintains genome stability and shapes gene expression by recognizing and unwinding diverse non-canonical nucleic acid structures, including R-loops, DNA/RNA G-quadruplexes, intramolecular triplex H-DNA, and inverted-repeat Alu dsRNA [#1, #5, #0]. Its catalytic core is a RecA-like helicase domain structurally closer to viral NS3 helicases than to DEAD-box proteins, lacking base-selective contacts so that it hydrolyzes ATP, GTP, CTP, and UTP, and it unwinds substrates with 3'\\u21925' polarity in an ATP-dependent manner [#9, #5]. At the genome level, DHX9 resolves transcription-associated R-loops and processes triplex DNA to suppress mutagenesis and replication stress, and its loss drives premature senescence, aberrant R-loop accumulation, DNA double-strand breaks, and cGAS-STING- or dsRNA-triggered innate immune activation [#3, #8, #13, #28, #26]. It promotes homologous recombination by resolving R-loops at double-strand breaks and recruiting BRCA1, RPA, and RAD51, an activity coordinated by partners such as TDRD3, USP42, and Pol\\u03b7, and gated by ATR-mediated S321 phosphorylation and SUMO2 modification at K120 that license its association with R-loop-bound factors including \\u03b3H2AX, RPA, PARP1, and DDX21 [#11, #12, #38, #37, #24, #25]. As a transcriptional co-activator, DHX9 associates with RNA Polymerase II and bridges it to sequence-specific factors\\u2014NF-\\u03baB p65, STAT1, and the androgen receptor\\u2014and to Nup98, with its ATPase/helicase activity required for RNAPII recruitment to target promoters [#30, #29, #36, #16]. Through its dsRNA-binding domains it controls post-transcriptional outcomes: it is required for RISC assembly, regulates A-to-I editing bidirectionally with ADAR, suppresses circular RNA biogenesis from inverted-repeat Alu elements, and unwinds rG4 structures in 5'-UTRs to govern translation [#7, #14, #0, #4]. DHX9 additionally functions in innate antiviral immunity as a dsRNA sensor signaling through IPS-1/MAVS [#2], and is exploited by numerous viruses as a host factor. Pathogenic DHX9 variants cause neurodevelopmental disorders and Charcot-Marie-Tooth disease, with distinct variants causing mislocalization, altered ATPase activity, or elevated R-loops and DNA damage [#41].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing the structural and biochemical basis of DHX9 catalysis answered how this helicase engages nucleotides and nucleic acid substrates, distinguishing it mechanistically from DEAD-box enzymes.\",\n      \"evidence\": \"X-ray crystallography of helicase domain 1 plus NTPase assays, and in vitro triplex helicase assays with kinetic analysis\",\n      \"pmids\": [\"20510246\", \"20669935\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure with substrate engaged\", \"Mechanism of substrate-structure selectivity not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating cooperative unwinding with WRN at RNA-containing replication intermediates placed DHX9 at the replication fork, though without in vivo validation.\",\n      \"evidence\": \"In vitro helicase assays with Okazaki-fragment-like and chicken-foot substrates plus protein-protein interaction assays\",\n      \"pmids\": [\"20385589\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo confirmation of cooperative mechanism\", \"Direct interaction interface not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining R-loops and G-quadruplexes as preferred substrates over simple duplexes identified the physiologically relevant structures DHX9 acts on.\",\n      \"evidence\": \"In vitro helicase assays on defined partial duplex, D-loop, R-loop, and G-quadruplex substrates\",\n      \"pmids\": [\"21561811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular substrate preference not directly tested in this study\", \"No genome-wide substrate map\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying DHX9 as a dsRNA sensor signaling through IPS-1/MAVS established a role in innate immune detection of viral RNA, defining the domain interfaces involved.\",\n      \"evidence\": \"siRNA knockdown, dsRNA binding assays, co-IP with HelicC-HA2-DUF/CARD domain mapping, cytokine readouts in dendritic cells\",\n      \"pmids\": [\"21957149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution versus canonical RNA sensors unclear\", \"In vivo requirement not established here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Structural and functional dissection of the dsRNA-binding domains showed how DHX9 is incorporated into RISC, linking its dsRNA recognition to gene silencing.\",\n      \"evidence\": \"Crystal structures of dsRBD1/dsRBD2 with dsRNA, ITC, mutagenesis-validated co-IP\",\n      \"pmids\": [\"23361462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling between dsRBD binding and helicase core not resolved\", \"Step in RISC assembly not pinpointed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that DHX9 depletion increases H-DNA-induced mutagenesis demonstrated an in vivo genome-protective role at triplex-forming sequences.\",\n      \"evidence\": \"siRNA mutation-reporter assay, in vitro binding, ChIP at H-DNA regions in U2OS cells\",\n      \"pmids\": [\"24049074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism converting unresolved triplex to deletions unclear\", \"Downstream repair factors not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linking DHX9 to p53-dependent senescence and origin firing established its essentiality for DNA replication and proliferation.\",\n      \"evidence\": \"siRNA/shRNA knockdown, SA-\\u03b2-gal assay, ChIP at replication origins, nascent DNA labeling in human fibroblasts\",\n      \"pmids\": [\"24990949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular role at origins not defined\", \"Connection to R-loop resolution at origins untested here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealing DHX9 control of inverted-repeat Alu dsRNA and circular RNA production, with an RNA-independent ADAR1-p150 interaction, connected dsRNA structure resolution to circRNA biogenesis and editing.\",\n      \"evidence\": \"Biochemical purification, RIP, reporter assays, circRNA quantification, ADAR/DHX9 co-depletion and co-IP\",\n      \"pmids\": [\"28355180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism on Alu dsRNA in cells not directly shown\", \"Functional consequence of ADAR1-p150 interaction incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining DHX9 processing of IGS-rRNA into pRNA to guide TIP5 placed DHX9 in heterochromatin establishment and stem cell differentiation.\",\n      \"evidence\": \"RIP, ChIP, knockdown with rescue by defined RNA species, ESC differentiation assays\",\n      \"pmids\": [\"28588071\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether helicase activity per se generates pRNA not isolated\", \"Generality across rRNA loci unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying Nup98 as a stimulator of DHX9 ATPase and co-occupant of gene loci connected nucleoporin function to DHX9-dependent transcription.\",\n      \"evidence\": \"In vitro binding and ATPase assays, ChIP-seq, transcriptional reporter, co-IP\",\n      \"pmids\": [\"28221134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ATPase stimulation not structurally defined\", \"Subnuclear site of action unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing DHX9-driven R-loop formation through prolonged RNAPII association upon splicing impairment defined a context where DHX9 generates rather than resolves hybrids that trap Pol II and block replication.\",\n      \"evidence\": \"S9.6 IF, ChIP, DRIP-seq, proximity ligation, splicing-factor knockdown\",\n      \"pmids\": [\"30341290\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling R-loop-forming versus R-loop-resolving roles unresolved\", \"Determinants of switch between activities unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Transcriptome-wide profiling showed DHX9 binds 5'-UTR rG4 substrates to regulate uORF and downstream translation, extending its role to translational control.\",\n      \"evidence\": \"Ribo-seq, CLIP-seq, knockdown, luciferase reporters\",\n      \"pmids\": [\"30591072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Division of labor with DHX36 not fully separated\", \"In vivo translational impact untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing the DHX9-p65-RNAPII axis showed DHX9 is required for RNAPII recruitment to NF-\\u03baB promoters via its helicase activity and contributes to antiviral immunity against DNA viruses.\",\n      \"evidence\": \"Macrophage-specific KO, fibroblast KD, multiprotein co-IP, ChIP for p65/RNAPII, helicase-dead mutant, viral assays\",\n      \"pmids\": [\"30137501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How helicase activity enables Pol II loading mechanistically unclear\", \"Promoter structures unwound not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Bidirectional regulation of A-to-I editing demonstrated DHX9 differentially modulates ADAR1 versus ADAR2 substrate editing, partly via helicase activity.\",\n      \"evidence\": \"siRNA knockdown, transcriptome-wide editing analysis, helicase-dead mutant in cancer cells\",\n      \"pmids\": [\"29796672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of ADAR isoform specificity unresolved\", \"Single lab without structural support\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining DHX9-mediated BRCA1 recruitment to RNA at damage sites placed DHX9 mechanistically within homologous recombination and end resection.\",\n      \"evidence\": \"Knockdown, RPA/RAD51 foci, co-IP, HR reporter, camptothecin/Olaparib sensitivity\",\n      \"pmids\": [\"34226554\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical role in resection not reconstituted\", \"RNA species recruiting BRCA1 not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying TDRD3 as a recruiter and stimulator of DHX9 helicase activity at promoters established a mechanism for targeted R-loop resolution.\",\n      \"evidence\": \"Reciprocal co-IP with domain mapping, ChIP, DRIP, in vitro helicase stimulation\",\n      \"pmids\": [\"34329467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promoter selectivity determinants unclear\", \"Interplay with other R-loop resolvers not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"USP42 was shown to partner DHX9 for R-loop resolution at DSBs and HR, reinforcing the helicase-dependent R-loop/BRCA1 axis.\",\n      \"evidence\": \"Co-IP, knockdown, HR reporter, DRIP, BRCA1 foci\",\n      \"pmids\": [\"32541651\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether USP42 deubiquitinates DHX9 not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Pol\\u03b7 was identified as recruiting DHX9 to G4 loci, defining cooperative action enabling replication through G-quadruplex regions.\",\n      \"evidence\": \"BioID, affinity pulldown-MS, ChIP-seq, co-IP, replication assay at G4 loci\",\n      \"pmids\": [\"35905379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Order of recruitment versus unwinding unclear\", \"Direct interaction interface unmapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Pathogenic DHX9 variants causally linking it to neurodevelopmental disorders and CMT defined genotype-specific mechanisms (mislocalization, altered ATPase, elevated R-loops/DSBs).\",\n      \"evidence\": \"Exome sequencing with family analysis, variant expression and localization, ATPase assays, R-loop and \\u03b3H2AX measurement, Dhx9 knockout mice\",\n      \"pmids\": [\"37467750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type basis of neuronal versus sensory phenotypes unclear\", \"How distinct molecular defects map to distinct diseases not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining DHX9-STAT1-RNAPII recruitment to ISG promoters established a MAVS-independent, interferon-downstream antiviral transcription role distinct from its dsRNA-sensor function.\",\n      \"evidence\": \"Cell-type-specific KO mice, double-KO epistasis with MAVS and STAT1, co-IP, ChIP at ISG promoters, viral infection\",\n      \"pmids\": [\"36735791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling MAVS-dependent sensing with MAVS-independent transcription unclear\", \"Promoter-level helicase substrate not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ATR-mediated S321 phosphorylation was shown to gate DHX9 association with R-loops and damage factors, providing a damage-responsive regulatory switch.\",\n      \"evidence\": \"Phospho-mapping MS, ATR inhibition, phosphomimetic/non-phosphorylatable mutants, co-IP, DRIP, in vitro DHX9-RPA binding, drug sensitivity\",\n      \"pmids\": [\"37930853\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural effect of S321 phosphorylation unknown\", \"Kinetics relative to damage signaling unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SUMO2 modification at K120 was shown to license SIM-dependent interactions with PARP1 and DDX21 required for genome stability, adding a second post-translational control of R-loop function.\",\n      \"evidence\": \"K120R mutagenesis, SUMO2 fusion rescue, co-IP with SIM-dependent partners, DRIP, \\u03b3H2AX IF, viability assays\",\n      \"pmids\": [\"39019926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUMO E3 ligase not identified\", \"Interplay between K120 SUMO and S321 phosphorylation untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genetic studies established DHX9 as a therapeutic target by showing its loss triggers dual cytoplasmic dsRNA innate immunity and R-loop-driven DNA damage, enhancing checkpoint-blockade response in SCLC and driving cGAS-STING inflammation in intestinal stem cells.\",\n      \"evidence\": \"CRISPR screen and KO with in vivo tumor models and immune profiling; conditional Dhx9 KO mice with DRIP and cGAS-STING readouts and colitis models\",\n      \"pmids\": [\"38189443\", \"38594251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of dsRNA versus R-loop arms to phenotypes unclear\", \"Tissue-specific thresholds for DHX9 loss unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery of DHX9-specific stress granules enriched in damaged intron RNA defined a distinct cytoplasmic dsRNA-handling compartment promoting survival after UV damage.\",\n      \"evidence\": \"FANCI damaged-RNA mapping, IF, SG-fraction RNA-seq, p62 knockout/knockdown, viability assays\",\n      \"pmids\": [\"38503283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger of DHX9 SG nucleation not fully defined\", \"Relationship to nuclear DHX9 functions unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DHX9 switches between R-loop formation and resolution, and how its many post-translational modifications and partner proteins are integrated to direct it among genome-protective, transcriptional, translational, and antiviral roles, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model coordinating modification states with substrate choice\", \"Structural basis for partner-directed targeting lacking\", \"Determinants of nuclear versus cytoplasmic functional partitioning unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [5, 9, 16]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [1, 5, 8]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 4, 45]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 4, 7, 32]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [30, 29, 36]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [29, 30, 41]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [10, 41]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 22, 26, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [11, 24, 38]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [13, 37, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [30, 29, 16, 36]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 7, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 29, 26, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [41, 26, 31]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [24, 27]}\n    ],\n    \"complexes\": [\n      \"RNA Polymerase II transcription complex\",\n      \"RISC\"\n    ],\n    \"partners\": [\n      \"BRCA1\",\n      \"RPA\",\n      \"TDRD3\",\n      \"NUP98\",\n      \"STAT1\",\n      \"RELA\",\n      \"ADAR\",\n      \"AR\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}