{"gene":"DDX17","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":1996,"finding":"DDX17 (p72) is a nuclear DEAD-box protein that exhibits ATPase activity in the presence of RNA; immunocytochemistry showed it co-localizes with p68 in the nucleus of HeLa cells, consistent with a nuclear function.","method":"Recombinant protein purification, ATPase assay, immunocytochemistry","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — in vitro ATPase assay and direct localization, single study, no functional mutagenesis","pmids":["8871553"],"is_preprint":false},{"year":2001,"finding":"DDX17 (p72) possesses both RNA helicase (unwinding) and RNA annealing activities, and can catalyze ATP-dependent rearrangement of stable RNA secondary structures via branch migration intermediates, analogous to certain DNA helicases.","method":"In vitro biochemical assays with recombinant p72 protein; RNA unwinding and annealing assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro helicase and annealing assays, two activities characterized, single lab but rigorous biochemical demonstration","pmids":["11353078"],"is_preprint":false},{"year":2001,"finding":"The p72 mRNA contains a 5'-UTR with an upstream non-AUG codon that drives alternative translation to produce an 82 kDa isoform (p82) with RNA helicase activity nearly identical to p72; p82 is a naturally expressed protein in HeLa cells.","method":"5' UTR mapping, in vitro translation, immunological characterization, purification and helicase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — alternative translation mechanism established by molecular mapping and biochemical validation, single lab with multiple orthogonal methods","pmids":["11675387"],"is_preprint":false},{"year":2002,"finding":"DDX17 (p72) specifically promotes inclusion of CD44 alternative exons containing AC-rich exon enhancer elements; this requires both the helicase ATP-binding activity and the C-terminal region of p72. The related protein p68 does not share this splicing activity. p72 associates with pre-mRNA complexes in vitro.","method":"Transient transfection of minigenes, ATPase-site mutants, deletion mutants, in vitro splicing extracts, co-immunoprecipitation with pre-mRNA","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — functional mutagenesis (ATP-binding and C-terminal deletion) plus in vitro extract assay, single lab with multiple orthogonal methods","pmids":["12138182"],"is_preprint":false},{"year":2003,"finding":"DDX17 (p72) and p68 interact with each other and self-associate; they preferentially exist as heterodimers in cells. p68 also interacts with NFAR-2. Gel filtration indicates p68/p72 exist in complexes of ~150–400 kDa, with a subset of p68 in very large complexes (>2 MDa).","method":"Yeast two-hybrid, co-immunoprecipitation, gel filtration chromatography","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal co-IP and yeast two-hybrid, single lab, two orthogonal methods","pmids":["12595555"],"is_preprint":false},{"year":2004,"finding":"DDX17 (p72) and p68 associate with histone deacetylase 1 (HDAC1) and repress transcription in a promoter-specific manner when targeted to constitutive promoters.","method":"Co-immunoprecipitation, reporter gene transcription repression assays","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct Co-IP interaction and functional reporter assay, single lab, two orthogonal methods","pmids":["15298701"],"is_preprint":false},{"year":2006,"finding":"DDX17 (p72) and p68 are MyoD-associated proteins that co-activate MyoD-dependent muscle gene expression; knockdown of p68/p72 impairs recruitment of TBP, RNA polymerase II, and Brg-1 (SWI/SNF ATPase subunit) to muscle gene promoters, and blocks chromatin remodeling and skeletal muscle differentiation. The noncoding RNA SRA also co-immunoprecipitates with MyoD.","method":"Co-immunoprecipitation, RNA interference, chromatin immunoprecipitation, differentiation assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, RNAi loss-of-function with defined transcriptional phenotype, ChIP, replicated with multiple methods","pmids":["17011493"],"is_preprint":false},{"year":2007,"finding":"DDX17 (p72) and p68 form complexes with beta-catenin and promote beta-catenin-dependent transcription of target genes (c-Myc, cyclin D1, c-jun, fra-1); simultaneous knockdown reduces beta-catenin target gene expression, enhances p21 expression, inhibits proliferation, and reduces tumor formation in vivo.","method":"Co-immunoprecipitation, siRNA knockdown, reporter gene assays, xenograft tumor assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional knockdown with defined transcriptional readout, single lab, multiple orthogonal approaches","pmids":["17699760"],"is_preprint":false},{"year":2007,"finding":"DDX17 (p72) RNA helicase forms complexes with the coactivators p300/CBP via its N-terminal 63 amino acids, and also binds P/CAF; these three proteins synergize to activate the Mdm2 promoter. Knockdown of p72 reduces Mdm2 transcription in a p53-dependent and -independent manner.","method":"Co-immunoprecipitation, in vitro binding assays, reporter gene assays, siRNA knockdown","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP (in vitro and in vivo), N-terminal domain mapping, functional reporter assay, single lab","pmids":["17226766"],"is_preprint":false},{"year":2007,"finding":"p68 negatively controls p72/p82 gene expression (but not vice versa). Co-silencing of both p68 and p72/p82 causes perturbation of nucleolar structure and cell death; the nucleolytic cleavage of 32S pre-rRNA is reduced, consistent with a role in structural rearrangement of the pre-60S ribosomal subunit. The redundant function maps to RNA rearrangement (not unwinding) activity.","method":"siRNA knockdown, mutant studies distinguishing rearrangement vs. unwinding activity, nucleolar morphology, pre-rRNA processing assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutant analysis distinguishing biochemical activities, knockdown with specific rRNA processing readout, single lab","pmids":["17485482"],"is_preprint":false},{"year":2008,"finding":"DDX17 (p72), but not the highly similar p68, is identified as a ZAP (zinc-finger antiviral protein)-interacting protein. ZAP binds via its N-terminal domain; both N- and C-terminal domains of p72 bind ZAP. p72 RNA helicase activity is required for promoting ZAP-mediated viral RNA degradation. Overexpression of the p72 C-terminal domain reduces ZAP activity; full-length p72 enhances it. Knockdown of p72 reduces ZAP activity but does not affect tristetraprolin-mediated RNA degradation.","method":"Co-immunoprecipitation, domain mapping, RNAi knockdown, viral RNA degradation assays, helicase-dead mutant","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain mapping, helicase-activity mutant, gain/loss-of-function, multiple orthogonal methods, single lab","pmids":["18334637"],"is_preprint":false},{"year":2009,"finding":"siRNA-mediated knockdown of DDX17 (p72), but not p68, significantly inhibits oestrogen-dependent transcription of endogenous ERα-responsive genes and oestrogen-dependent proliferation of MCF-7 and ZR75-1 breast cancer cells, demonstrating a non-redundant role for p72 in ERα co-activation.","method":"siRNA knockdown, RT-PCR of endogenous ERα target genes, cell proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined transcriptional and cellular phenotype, isoform-specific comparison, single lab","pmids":["19718048"],"is_preprint":false},{"year":2010,"finding":"DDX17 (p72) and p68 are sumoylated at a single, homologous consensus SUMO site; sumoylation significantly increases protein stability of both proteins. Preventing sumoylation of p72 increases its ability to transactivate estrogen receptor and p53, while sumoylation promotes interaction of p68/p72 with HDAC1 (but not HDAC2/3, p300, or estrogen receptor). p68 but not p72 is polyubiquitylated, and mutation of the sumoylation site increases p68 polyubiquitylation, suggesting SUMO competes with ubiquitin-mediated proteasomal degradation for p68.","method":"Sumoylation site mutagenesis, protein stability assays, co-immunoprecipitation, transcriptional reporter assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-directed mutagenesis of PTM site, multiple functional readouts, protein stability and interaction studies, single lab with multiple orthogonal methods","pmids":["19995069"],"is_preprint":false},{"year":2010,"finding":"DDX17 (p72) and p68 are substrates for acetylation by the acetyltransferase p300 in vitro and in vivo. Mutation of acetylation sites affects binding to HDACs (but not to p300 or estrogen receptor). Acetylation increases protein stability and coactivation of estrogen receptor. Acetylation of p72 (but not p68) also enhances p53-dependent MDM2 promoter activation. Blocking p72 acetylation causes cell cycle arrest and apoptosis.","method":"In vitro acetylation assay, acetylation-site mutagenesis, co-immunoprecipitation, reporter gene assays, cell cycle/apoptosis analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro and in vivo acetylation validated, mutagenesis, multiple functional readouts, single lab","pmids":["20663877"],"is_preprint":false},{"year":2012,"finding":"DDX5 and DDX17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. In parallel, DDX5/DDX17 promote inclusion of NFAT5 exon 5 (which contains a premature stop codon), coupling transcriptional activation to NMD-mediated reduction of NFAT5 protein levels — a dual regulatory role.","method":"Co-immunoprecipitation, reporter gene assays, siRNA knockdown, alternative splicing assays, migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — RNAi loss-of-function with defined transcriptional and splicing phenotype, functional migration assay, single lab","pmids":["22266867"],"is_preprint":false},{"year":2013,"finding":"p68 (Ddx5) binds Upf3 protein of the NMD machinery; this interaction interferes with EJC binding. Ddx5 activates NMD of Ddx17/p72 mRNA (and Smg5 mRNA) in an ATP-binding-dependent manner requiring the 3'-UTR of target mRNAs, thereby establishing a regulatory loop controlling p72 expression levels.","method":"Co-immunoprecipitation, NMD reporter assays, ATPase mutant studies, 3'-UTR deletion analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ATPase mutant, 3'-UTR requirement defined, single lab","pmids":["23788676"],"is_preprint":false},{"year":2013,"finding":"DDX17 promotes production of infectious HIV-1 particles; its helicase activity is required. A DQAD helicase-dead mutant reduces packaging of viral genomic RNA and diminishes HIV-1 Gag-Pol frameshift, demonstrating that DDX17 modulates HIV-1 RNA metabolism to support infectious particle production.","method":"Overexpression of helicase-dead mutant (DQAD), viral RNA packaging assay, frameshifting assay","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant defines helicase activity requirement, multiple RNA-level readouts, single lab","pmids":["23769241"],"is_preprint":false},{"year":2014,"finding":"DDX17 cooperates with hnRNP H/F splicing factors to define epithelial- and myoblast-specific splicing subprograms. Downregulation of DDX5/DDX17 protein during myogenesis and EMT is mediated by differentiation-induced miRNAs whose biogenesis itself depends on DDX5/DDX17. DDX5/DDX17 also function as coregulators of master transcriptional regulators of differentiation.","method":"siRNA knockdown, RNA-seq, CLIP-seq, miRNA profiling, alternative splicing assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi, transcriptome-wide splicing analysis, miRNA profiling, CLIP-seq, multiple biological contexts tested, single lab but multiple orthogonal approaches","pmids":["24910439"],"is_preprint":false},{"year":2014,"finding":"DDX17 binds the stem loops of host pri-miRNA to facilitate their processing by Drosha (nuclear function), and also directly binds a specific stem loop in bunyaviral (RVFV) RNA to restrict infection (cytoplasmic function). Loss of DDX17 (but not the related DDX5) specifically increases RVFV replication. This dual stem-loop recognition underlies both roles.","method":"RNAi screening, CLIP-seq, genetic depletion in Drosophila and human cells, viral replication assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — CLIP-seq for direct RNA binding, depletion in two organisms, DDX5 specificity control, multiple orthogonal methods","pmids":["25126784"],"is_preprint":false},{"year":2015,"finding":"DDX17 (p72) physically interacts with Sox2 via co-immunoprecipitation, and this interaction is preferentially restricted to Sox2-reporter-responsive (stem-like) breast cancer cells where DDX17 is nuclear. DDX17 knockdown reduces Sox2-SRR2 promoter binding and Sox2-dependent target gene expression (MUC15, CCND1, CD133), as well as colony and mammosphere formation in stem-like cells.","method":"LC-MS (initial identification), co-immunoprecipitation, siRNA knockdown, ChIP-PCR, reporter assays, colony/mammosphere assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP confirmed, ChIP, functional knockdown, but single lab","pmids":["26569340"],"is_preprint":false},{"year":2017,"finding":"DDX17 promotes gefitinib resistance in NSCLC cells by dissociating the E-cadherin/β-catenin complex, causing β-catenin nuclear translocation and transcription of β-catenin target genes. DDX17 undergoes nucleocytoplasmic shuttling via nuclear localization signals (NLS) and nuclear export signals (NES) through an exportin/importin-dependent pathway; disrupting this shuttling impairs β-catenin activation and acquired resistance.","method":"Co-immunoprecipitation, NLS/NES sequence identification, nuclear/cytoplasmic fractionation, β-catenin reporter assays, drug resistance assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP, subcellular fractionation, functional resistance assay, NLS/NES defined, single lab","pmids":["28259822"],"is_preprint":false},{"year":2018,"finding":"DDX17 controls REST-dependent transcriptional repression of neuronal genes by associating with REST and promoting its binding to a subset of REST-target gene promoters. During neuronal differentiation, DDX17 downregulation contributes to REST complex release and neuronal gene activation. DDX17 and DDX5 also regulate processing of proneural miRNAs (including miR-26a/b) that target the REST complex; an intronic regulatory region negatively impacts miR-26a2 processing and splicing in a DDX17-dependent manner.","method":"Co-immunoprecipitation, ChIP, siRNA knockdown, miRNA processing assays, luciferase reporter assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, miRNA processing functional assays, single lab with multiple methods","pmids":["29931089"],"is_preprint":false},{"year":2018,"finding":"DDX17 controls HIV-1 splicing specifically at the A4/A5 splice acceptor cluster (but not A1), independently of DDX5. In the absence of DDX17, viral envelope protein production and other accessory proteins are severely reduced. DDX17 interacts with splicing factors SRSF1/SF2 and U2AF65/35. Specific RNA-binding motifs (not the Walker A, Walker B/DEAD, Q motif, or glycine doublet) are essential for this splicing function.","method":"siRNA knockdown, splicing assays, motif-deletion mutagenesis, co-immunoprecipitation with splicing factors","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — domain mutagenesis, Co-IP with splicing factors, specific isoform comparison (DDX5 vs DDX17), multiple mechanistic readouts, single lab","pmids":["30131116"],"is_preprint":false},{"year":2019,"finding":"Under hypoxia, the E3 ubiquitin ligase HectH9 mediates K63-linked polyubiquitination of DDX17. Polyubiquitinated DDX17 dissociates from the Drosha-DGCR8 complex (reducing biogenesis of anti-stemness miRNAs) and associates with p300-YAP, leading to H3K56 acetylation at stemness-related gene promoters and their transcriptional activation, promoting cancer stem-like properties.","method":"Ubiquitination assays (K63-linkage specific), Co-IP, Drosha complex pulldown, ChIP (H3K56ac), miRNA profiling, tumor-initiating capacity assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — specific K63-ubiquitination mapped, complex dissociation demonstrated, ChIP for histone modification, multiple functional readouts, single lab","pmids":["30877109"],"is_preprint":false},{"year":2019,"finding":"Crystal structures of the DDX17 core catalytic domain revealed sequence-specific RNA recognition; the catalytic core binds and remodels a specific region of primary miRNA 3' to the mature sequence, enhancing Drosha processing. An intramolecular interaction between the DDX17 N-terminal tail and the DEAD domain acts as an autoregulatory mechanism controlling ATPase activity.","method":"X-ray crystallography, biochemical RNA-binding and ATPase assays, pri-miRNA processing assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional biochemical validation, intramolecular regulatory mechanism defined, single lab with multiple orthogonal methods","pmids":["31851931"],"is_preprint":false},{"year":2019,"finding":"DDX17 physically interacts with Klf4 (demonstrated by co-IP and GST pull-down); DDX17 inhibits Klf4 transcriptional activity at target gene promoters (E-cadherin, MMP2) and prevents Klf4 from binding the MMP2 promoter. The interaction requires the zinc-finger domain of Klf4.","method":"Co-immunoprecipitation, GST pull-down, luciferase reporter assay, ChIP (Klf4 promoter binding), Klf4 domain deletion","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal Co-IP and pull-down, functional reporter and ChIP, domain requirement defined, single lab","pmids":["31653828"],"is_preprint":false},{"year":2020,"finding":"DDX17 directly binds RVFV non-coding RNAs (intergenic region, IGR, and 5' NCR) with Kd values of 5.77 µM and 9.85 µM respectively (measured by microscale thermophoresis), and the helicase domain (DDX17135-555) can unwind both RNAs in vitro.","method":"Microscale thermophoresis, SAXS, analytical ultracentrifugation, helicase unwinding assay","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding quantification, SAXS structural analysis, in vitro helicase activity measured, multiple biophysical methods, single lab","pmids":["33374561"],"is_preprint":false},{"year":2021,"finding":"DDX17 is identified as the sensor of endogenous SINE RNAs (retrotransposon RNAs) that activates the NLRC4 inflammasome independently of NAIPs. DDX17 licenses assembly of an inflammasome comprising NLRC4, NLRP3, and ASC, driving caspase-1 activation and cytokine (IL-18) release. Inhibiting DDX17-mediated NLRC4 activation reduced IL-18 in SLE patient PBMCs and prevented retinal degeneration in an AMD animal model.","method":"siRNA knockdown, co-immunoprecipitation, caspase-1 activation assay, cytokine release assay, in vivo retinal degeneration model","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct SINE RNA sensing mechanism, inflammasome assembly by Co-IP, loss-of-function in patient cells and animal model, multiple orthogonal methods","pmids":["34860583"],"is_preprint":false},{"year":2021,"finding":"DDX17 inhibits HBV replication primarily by blocking cytoplasmic encapsidation of pregenomic RNA (pgRNA). DDX17 competes with HBV polymerase to bind the 5' epsilon stem-loop of pgRNA. Immunofluorescence showed DDX17 translocates from nucleus to cytoplasm in the presence of HBV RNA. This antiviral function is helicase-activity dependent.","method":"RNA immunoprecipitation, EMSA (electrophoretic mobility shift assay), immunofluorescence, encapsidation assay, helicase-dead mutant","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct RNA binding by RIP and EMSA, competition assay with viral polymerase, helicase mutant requirement, subcellular localization linked to function","pmids":["34287051"],"is_preprint":false},{"year":2021,"finding":"Mutant FUS recruits nuclear DDX17 into cytoplasmic stress granules and physically interacts with DDX17 through the RGG1 domain of FUS. Ectopic expression of DDX17 reduces cytoplasmic mislocalization of mutant FUS and suppresses FUS-mediated neurodegeneration in vivo. DDX17 functions as a regulator of the DNA damage response and its upregulation repairs defective DDR caused by mutant FUS.","method":"Co-immunoprecipitation (RGG1 domain), immunofluorescence (stress granule localization), overexpression rescue in vivo (Drosophila), DNA damage assays","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, functional rescue in vivo, localization studies, single lab","pmids":["34061233"],"is_preprint":false},{"year":2021,"finding":"DDX17 regulates alternative splicing of PXN-AS1 by inducing intron 3 retention, producing transcript PXN-AS1-IR3 that recruits TEX10 and p300 to the MYC enhancer to activate MYC transcription and downstream metastasis-associated genes. DDX17 knockout in a mouse model inhibits HCC metastasis.","method":"RNA-seq, splicing assays, Co-IP (TEX10/p300 complex), ChIP (MYC enhancer), DDX17 knockout mouse model","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanism involves splicing event producing specific isoform, complex demonstrated by Co-IP, ChIP for MYC enhancer binding, in vivo model, single lab","pmids":["34626132"],"is_preprint":false},{"year":2022,"finding":"DDX17 helicase unwinds R-loops in vitro and promotes MUS81-dependent restart of R-loop-stalled replication forks in human cells. Loss of DDX17 causes R-loop accumulation, anaphase bridges, and micronuclei. DDX17 associates with R-loops and facilitates their formation (specifically at loci with low pre-existing hybrid levels) to allow propagation of DSB ubiquitin cascade responses.","method":"In vitro R-loop unwinding assay, S9.6 immunofluorescence (R-loop detection), genome-wide R-loop mapping (DRIP-seq), DNA fiber assay (fork restart), helicase mutant","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro helicase activity on R-loops, genome-wide R-loop mapping, fork restart assay, helicase mutant, single lab with multiple orthogonal methods","pmids":["36453994"],"is_preprint":false},{"year":2022,"finding":"DDX17 is required for efficient DSB repair; it is recruited early in the DSB ubiquitin cascade and promotes formation of DNA:RNA hybrids (R-loops) at DSB sites specifically at loci with low pre-existing hybrids. Loss of DDX17 impairs cell survival and DNA repair in response to DSB-inducing agents.","method":"Proteomic meta-analysis, siRNA knockdown, γH2AX foci assay, R-loop mapping (DRIP), DSB repair factor recruitment assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with DSB repair phenotype, DRIP mapping, recruitment assay, single lab","pmids":["36200807"],"is_preprint":false},{"year":2022,"finding":"DDX17 acts as a transcriptional regulator that interacts with Y-box binding protein 1 (YB1) in the nucleus, driving YB1 binding to the EGFR promoter to activate EGFR transcription and downstream MEK/pERK signaling. MTDH stabilizes DDX17 by inhibiting its ubiquitination.","method":"Co-immunoprecipitation, ChIP-seq, promoter reporter assay, ubiquitination assay, in vitro and in vivo functional studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, promoter assay, ubiquitination mechanism defined, single lab","pmids":["36385375"],"is_preprint":false},{"year":2022,"finding":"THOC5 interacts with DDX17 (and DDX5) specifically in slow RNA polymerase II cells; this chromatin-associated complex also includes CDK12 and THOC6, and is involved in regulating R-loop structures and transcription elongation rate.","method":"Co-immunoprecipitation, THOC5 depletion, transcription elongation measurement, R-loop analysis","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP in specific cellular context, depletion phenotype, single lab","pmids":["36590164"],"is_preprint":false},{"year":2022,"finding":"JICD1 (JAG1 intracellular domain) forms a transcriptional complex with DDX17, SMAD3, and TGIF2 to drive SOX2 expression and cancer stem-like transformation of astrocytes. ChIP-seq confirmed complex binding at the SOX2 locus.","method":"Proteomics, co-immunoprecipitation, ChIP-seq, reporter assays, functional transformation assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP-seq, functional assays in same study, single lab","pmids":["36417870"],"is_preprint":false},{"year":2024,"finding":"DDX17 binds the transcriptional repressor BCL6 and inhibits expression of DRP1 (a mitochondrial fission protein). When DDX17 is reduced (as in heart failure), BCL6 repression is attenuated, DRP1 expression increases, mitochondrial fission is enhanced, and autophagy flux is blocked, leading to cardiomyocyte apoptosis and progressive cardiac dysfunction. Cardiomyocyte-specific Ddx17 knockout mice develop heart failure, while DDX17 restoration protects cardiac function.","method":"Co-immunoprecipitation (DDX17-BCL6), cardiomyocyte-specific KO and transgenic mice, mitochondrial morphology assays, autophagic flux assays, DRP1 expression analysis","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, KO and transgenic mouse models, multiple mechanistic readouts (BCL6, DRP1, mitochondrial fission, autophagy), single lab with multiple orthogonal approaches","pmids":["38782919"],"is_preprint":false}],"current_model":"DDX17 (p72) is a nuclear DEAD-box RNA helicase with ATPase-driven RNA unwinding, annealing, and rearrangement activities that underlie its roles in alternative splicing (via cooperation with hnRNP H/F and U2AF/SRSF1), pri-miRNA processing (through sequence-specific stem-loop recognition and enhancement of Drosha cleavage, regulated by an intramolecular N-tail/DEAD-domain autoregulatory interaction), ribosome biogenesis (32S pre-rRNA processing), and R-loop resolution at stalled replication forks; it also functions as a transcriptional co-regulator—forming complexes with ERα, MyoD, p53/MDM2, β-catenin, NFAT5, REST, SOX2, Klf4, YB1, BCL6, and coactivators p300/CBP/P/CAF/HDAC1—with its activity tuned by SUMO-ylation, K63-linked polyubiquitination (by HectH9 under hypoxia), and acetylation by p300; in antiviral defense it directly senses structured viral and retrotransposon RNAs (RVFV stem loops, HBV pgRNA epsilon, SINE RNAs) and can activate the non-canonical NLRC4 inflammasome, while its nucleocytoplasmic shuttling (via defined NLS/NES sequences) links nuclear transcription/splicing functions to cytoplasmic roles in viral RNA metabolism and β-catenin signaling."},"narrative":{"mechanistic_narrative":"DDX17 (p72) is a nuclear DEAD-box RNA helicase whose ATP-dependent RNA unwinding, annealing, and structural rearrangement activities underpin a broad range of RNA-processing and gene-regulatory functions [PMID:11353078]. As an enzyme it binds RNA in an ATP-dependent manner, possesses both unwinding and annealing activities, and can catalyze branch-migration-type rearrangement of stable RNA secondary structures; an alternative non-AUG translation start produces a larger p82 isoform with comparable helicase activity [PMID:11353078, PMID:11675387]. In RNA metabolism it promotes alternative exon inclusion (e.g., AC-rich CD44 exons) in a manner requiring both ATP-binding and its C-terminal region, cooperates with hnRNP H/F and the splicing factors SRSF1 and U2AF to define cell-type-specific splicing programs, and contributes to ribosome biogenesis through structural rearrangement during 32S pre-rRNA processing [PMID:12138182, PMID:24910439, PMID:30131116, PMID:17485482]. DDX17 also acts in microRNA biogenesis by sequence-specifically recognizing and remodeling pri-miRNA stem-loops to enhance Drosha cleavage, an activity tuned by an autoregulatory intramolecular interaction between its N-terminal tail and the DEAD domain [PMID:31851931, PMID:25126784]. Beyond RNA processing, DDX17 functions as a transcriptional co-regulator, partnering with diverse factors including MyoD, β-catenin, ERα, p53/MDM2, REST, SOX2, Klf4, YB1, BCL6, NFAT5, and the coactivators p300/CBP/P/CAF and HDAC1 to activate or repress target genes and to drive differentiation, proliferation, and stem-like programs [PMID:17011493, PMID:17699760, PMID:19718048, PMID:17226766, PMID:29931089]. Its activity and stability are controlled by SUMOylation, p300-mediated acetylation, and HectH9-mediated K63-linked polyubiquitination under hypoxia, the latter switching DDX17 from a Drosha-associated miRNA-processing role to a p300-YAP-associated chromatin-activating role [PMID:19995069, PMID:20663877, PMID:30877109]. In the nucleus DDX17 resolves R-loops to promote MUS81-dependent restart of stalled replication forks and participates in the DNA double-strand-break response [PMID:36453994, PMID:36200807]. Through helicase-dependent recognition of structured viral and retrotransposon RNAs it acts in antiviral defense—restricting bunyaviral (RVFV) and hepatitis B virus replication and sensing endogenous SINE RNAs to license a non-canonical NLRC4 inflammasome—while its NLS/NES-dependent nucleocytoplasmic shuttling couples these cytoplasmic roles to nuclear transcription and splicing [PMID:25126784, PMID:34287051, PMID:34860583, PMID:28259822]. Cardiomyocyte-specific Ddx17 loss in mice causes heart failure via derepression of the mitochondrial fission gene DRP1 [PMID:38782919].","teleology":[{"year":1996,"claim":"Establishing DDX17 as a bona fide nuclear DEAD-box protein with RNA-stimulated ATPase activity placed it among catalytically active RNA helicases and predicted a nuclear RNA-processing function.","evidence":"Recombinant ATPase assay and immunocytochemistry co-localizing with p68 in HeLa nuclei","pmids":["8871553"],"confidence":"Medium","gaps":["No RNA substrate or unwinding activity demonstrated","No functional mutagenesis linking ATPase activity to a cellular role"]},{"year":2001,"claim":"Reconstituted biochemistry showed DDX17 is not merely an ATPase but a true helicase with both unwinding and annealing activities capable of RNA structural rearrangement, defining its core enzymatic repertoire; alternative non-AUG translation additionally produces an active p82 isoform.","evidence":"In vitro RNA unwinding/annealing/branch-migration assays with recombinant protein, plus 5'-UTR mapping and in vitro translation","pmids":["11353078","11675387"],"confidence":"High","gaps":["Cellular substrates of unwinding vs. annealing not identified","Distinct functions of p72 vs p82 isoforms unresolved"]},{"year":2002,"claim":"Linking DDX17's ATPase/helicase activity to CD44 alternative exon inclusion provided the first specific RNA-processing function and distinguished it from the paralog p68, showing isoform-specific roles.","evidence":"Minigene transfection, ATP-binding and C-terminal deletion mutants, in vitro splicing extracts, pre-mRNA Co-IP","pmids":["12138182"],"confidence":"High","gaps":["Direct binding to AC-rich enhancer not structurally defined","Generality across other exons untested at this stage"]},{"year":2003,"claim":"Demonstrating that DDX17 and p68 heterodimerize and assemble into larger complexes established the physical basis for their frequently shared, sometimes redundant functions.","evidence":"Yeast two-hybrid, reciprocal Co-IP, gel filtration sizing of complexes","pmids":["12595555"],"confidence":"Medium","gaps":["Stoichiometry and other subunits of the large complexes unknown","Functional consequence of heterodimerization not directly tested"]},{"year":2004,"claim":"Identifying HDAC1 association and promoter-targeted repression revealed that DDX17 functions in transcriptional regulation, not only RNA processing.","evidence":"Co-IP and reporter repression assays at constitutive promoters","pmids":["15298701"],"confidence":"Medium","gaps":["Endogenous target genes not defined","Mechanism coupling helicase activity to repression unclear"]},{"year":2006,"claim":"Defining DDX17/p68 as MyoD coactivators required for recruiting the basal machinery and the Brg-1 chromatin remodeler tied DDX17 to chromatin remodeling and developmental differentiation programs.","evidence":"Reciprocal Co-IP, RNAi loss-of-function, ChIP, myogenic differentiation assays; SRA ncRNA co-IP with MyoD","pmids":["17011493"],"confidence":"High","gaps":["Role of SRA RNA in DDX17 function not mechanistically resolved","Whether helicase activity is needed for coactivation untested here"]},{"year":2007,"claim":"Discovery of DDX17 in β-catenin and p53/MDM2-p300/CBP/P/CAF transcriptional complexes broadened its co-regulator role into oncogenic and tumor-suppressor pathways, with N-terminal mapping to coactivator binding.","evidence":"Co-IP, in vitro binding, N-terminal domain mapping, siRNA knockdown, reporter and xenograft assays","pmids":["17699760","17226766"],"confidence":"Medium","gaps":["Direct vs indirect contacts within multiprotein complexes unresolved","Contribution of helicase catalysis to transcriptional output unclear"]},{"year":2007,"claim":"Co-silencing experiments revealed a non-redundant requirement for DDX17/p68 RNA-rearrangement activity in 32S pre-rRNA processing, assigning a role in ribosome biogenesis.","evidence":"siRNA knockdown, rearrangement vs unwinding mutant analysis, nucleolar morphology and pre-rRNA processing assays","pmids":["17485482"],"confidence":"Medium","gaps":["Direct pre-rRNA substrate engagement not shown","Position within pre-60S assembly pathway not mapped"]},{"year":2009,"claim":"Isoform-specific knockdown established that DDX17, but not p68, is uniquely required for ERα-dependent transcription and estrogen-driven breast cancer cell proliferation.","evidence":"siRNA knockdown, endogenous ERα target gene RT-PCR, proliferation assays in MCF-7/ZR75-1","pmids":["19718048"],"confidence":"Medium","gaps":["Molecular basis of isoform specificity unexplained","Direct DDX17-ERα contact not mapped"]},{"year":2010,"claim":"Defining SUMOylation and p300 acetylation as stability- and activity-controlling modifications established a PTM layer governing DDX17's transcriptional coactivation and its HDAC interactions, with SUMO competing against ubiquitin-mediated degradation.","evidence":"Site-directed PTM mutagenesis, protein stability assays, Co-IP, transcriptional reporters, cell-cycle/apoptosis analysis","pmids":["19995069","20663877"],"confidence":"High","gaps":["Enzymes catalyzing DDX17 SUMOylation not identified","Crosstalk between SUMO, acetylation, and ubiquitin not integrated"]},{"year":2012,"claim":"Showing DDX5/DDX17 both transcriptionally activate NFAT5 and promote an NMD-coupled splicing event revealed a dual transcription-plus-splicing regulatory logic controlling target protein levels.","evidence":"Co-IP, reporter assays, siRNA knockdown, alternative splicing and migration assays","pmids":["22266867"],"confidence":"Medium","gaps":["Direct splicing substrate recognition not defined","Balance between activation and NMD-mediated reduction in vivo unclear"]},{"year":2013,"claim":"Identifying that p68/Ddx5 drives NMD of DDX17 mRNA via Upf3, and that DDX17 supports HIV-1 particle production, defined an autoregulatory expression loop and an early viral RNA-metabolism role.","evidence":"Co-IP, NMD reporter and 3'-UTR analysis, ATPase mutants; HIV-1 DQAD helicase-dead packaging and frameshift assays","pmids":["23788676","23769241"],"confidence":"Medium","gaps":["Physiological setting of the Ddx5-Ddx17 NMD loop untested","Direct viral RNA target of DDX17 in HIV-1 not mapped here"]},{"year":2014,"claim":"Transcriptome-wide analyses showed DDX17 cooperates with hnRNP H/F to define epithelial/myoblast splicing subprograms and that its own downregulation during differentiation is driven by miRNAs whose biogenesis it controls—revealing a feedback circuit linking splicing, miRNA processing, and differentiation; the same dual stem-loop recognition supports both pri-miRNA processing and direct antiviral RNA binding.","evidence":"siRNA, RNA-seq, CLIP-seq, miRNA profiling, splicing assays; CLIP-seq and viral replication assays in fly and human cells","pmids":["24910439","25126784"],"confidence":"High","gaps":["Sequence determinants of stem-loop selectivity not yet structurally defined","Coordination between nuclear and cytoplasmic RNA-binding pools unclear"]},{"year":2015,"claim":"Identifying a SOX2-DDX17 interaction restricted to stem-like breast cancer cells extended DDX17's co-regulator role to cancer stemness programs.","evidence":"LC-MS, Co-IP, siRNA, ChIP-PCR, reporter and mammosphere assays","pmids":["26569340"],"confidence":"Medium","gaps":["Why the interaction is context-restricted not explained","Direct vs bridged DDX17-SOX2 contact unresolved"]},{"year":2017,"claim":"Mapping functional NLS/NES sequences and an exportin/importin-dependent shuttling pathway explained how DDX17 couples nuclear functions to cytoplasmic β-catenin activation and drug resistance.","evidence":"Co-IP, NLS/NES identification, nuclear/cytoplasmic fractionation, β-catenin reporter and gefitinib-resistance assays","pmids":["28259822"],"confidence":"Medium","gaps":["Signals triggering shuttling not defined","Direct cytoplasmic action on E-cadherin/β-catenin complex not biochemically reconstituted"]},{"year":2018,"claim":"Defining DDX17-specific control of HIV-1 A4/A5 splice-acceptor usage via SRSF1 and U2AF, and dissecting REST-dependent neuronal gene repression coupled to proneural miRNA processing, demonstrated context-specific splicing/transcription mechanisms relying on specific RNA-binding motifs rather than canonical helicase motifs.","evidence":"siRNA, splicing assays, motif-deletion mutagenesis, Co-IP with splicing factors; ChIP and miRNA processing assays for REST","pmids":["30131116","29931089"],"confidence":"High","gaps":["Structural basis of motif-dependent splicing recognition undefined","Generality of REST-DDX17 control across neuronal genes incomplete"]},{"year":2019,"claim":"Crystal structures plus hypoxia-driven K63-ubiquitination by HectH9 explained, at atomic and signaling levels, how DDX17 sequence-specifically remodels pri-miRNA 3' regions and how a PTM switch toggles it between Drosha-associated miRNA processing and p300-YAP-associated chromatin activation of stemness genes.","evidence":"X-ray crystallography with RNA-binding/ATPase/processing assays; K63-linkage ubiquitination, complex pulldowns, H3K56ac ChIP, tumor-initiation assays; plus Klf4 interaction studies","pmids":["31851931","30877109","31653828"],"confidence":"High","gaps":["Full-length DDX17 structure with bound pri-miRNA not resolved","Deubiquitinase reversing the HectH9 switch unknown"]},{"year":2021,"claim":"Biophysical and functional studies established DDX17 as a direct sensor of structured RNAs in innate immunity and viral restriction—quantifying RVFV RNA binding, blocking HBV pgRNA encapsidation by competing with viral polymerase, and licensing a non-canonical NLRC4 inflammasome in response to SINE RNAs—while also showing it rescues mutant-FUS neurodegeneration via stress-granule recruitment and DDR support.","evidence":"MST/SAXS and in vitro unwinding (RVFV); RIP/EMSA, encapsidation and helicase-mutant assays (HBV); Co-IP, caspase-1/IL-18 assays and disease models (NLRC4); Co-IP and in vivo rescue (FUS)","pmids":["33374561","34287051","34860583","34061233"],"confidence":"High","gaps":["How DDX17 discriminates self from non-self structured RNAs is unresolved","Mechanism of NLRC4 licensing downstream of RNA sensing not fully defined"]},{"year":2022,"claim":"Demonstrating that DDX17 unwinds R-loops to enable MUS81-dependent fork restart and is recruited in the DSB ubiquitin cascade, while also engaging YB1/EGFR transcription, PXN-AS1 splicing-driven MYC activation, and THOC5/CDK12 elongation complexes, established central roles in genome stability and oncogenic gene expression.","evidence":"In vitro R-loop unwinding, DRIP-seq, DNA fiber and γH2AX assays, helicase mutants; Co-IP, ChIP-seq, splicing assays, and KO/transgenic mouse models","pmids":["36453994","36200807","36385375","36590164","36417870","34626132"],"confidence":"High","gaps":["How DDX17 both promotes and resolves R-loops at different loci is mechanistically unreconciled","Direct DNA/RNA substrate selection at DSB sites not defined"]},{"year":2024,"claim":"Cardiomyocyte-specific genetics linked DDX17 to organ physiology, showing that DDX17-BCL6 repression of DRP1 restrains mitochondrial fission and that DDX17 loss causes heart failure.","evidence":"Co-IP, cardiomyocyte-specific KO/transgenic mice, mitochondrial morphology and autophagic flux assays","pmids":["38782919"],"confidence":"High","gaps":["Whether helicase activity is required for BCL6-mediated DRP1 repression untested","Upstream signals reducing DDX17 in heart failure unknown"]},{"year":null,"claim":"It remains unresolved how DDX17's single enzymatic core is partitioned among its many functions—how RNA-binding specificity, PTMs, and shuttling jointly determine whether it acts as a splicing factor, miRNA-processing enzyme, R-loop helicase, RNA sensor, or transcriptional co-regulator at a given locus and time.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model linking PTM state to functional output","Substrate-selection rules distinguishing antiviral, processing, and genome-stability roles undefined","Structural basis for partner discrimination among transcription factors unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,9,26,31]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[18,24,26,28]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,7,21,33]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[27,18]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,20]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[20,28]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3,9,18,24]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7,33]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[31,32]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[27,18,28]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[23,30,36]}],"complexes":["Drosha-DGCR8 microprocessor","NLRC4-NLRP3-ASC inflammasome","THOC5-DDX5-DDX17-CDK12-THOC6 complex"],"partners":["DDX5","HDAC1","P300","SRSF1","U2AF2","CTNNB1","ESR1","BCL6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92841","full_name":"Probable ATP-dependent RNA helicase DDX17","aliases":["DEAD box protein 17","DEAD box protein p72","DEAD box protein p82","RNA-dependent helicase p72"],"length_aa":729,"mass_kda":80.3,"function":"As an RNA helicase, unwinds RNA and alters RNA structures through ATP binding and hydrolysis. Involved in multiple cellular processes, including pre-mRNA splicing, alternative splicing, ribosomal RNA processing and miRNA processing, as well as transcription regulation. Regulates the alternative splicing of exons exhibiting specific features (PubMed:12138182, PubMed:22266867, PubMed:23022728, PubMed:24910439). For instance, promotes the inclusion of AC-rich alternative exons in CD44 transcripts (PubMed:12138182). This function requires the RNA helicase activity (PubMed:12138182, PubMed:22266867, PubMed:23022728, PubMed:24910439). Affects NFAT5 and histone macro-H2A.1/MACROH2A1 alternative splicing in a CDK9-dependent manner (PubMed:22266867, PubMed:26209609). In NFAT5, promotes the introduction of alternative exon 4, which contains 2 stop codons and may target NFAT5 exon 4-containing transcripts to nonsense-mediated mRNA decay, leading to the down-regulation of NFAT5 protein (PubMed:22266867). Affects splicing of mediators of steroid hormone signaling pathway, including kinases that phosphorylates ESR1, such as CDK2, MAPK1 and GSK3B, and transcriptional regulators, such as CREBBP, MED1, NCOR1 and NCOR2. By affecting GSK3B splicing, participates in ESR1 and AR stabilization (PubMed:24275493). In myoblasts and epithelial cells, cooperates with HNRNPH1 to control the splicing of specific subsets of exons (PubMed:24910439). In addition to binding mature mRNAs, also interacts with certain pri-microRNAs, including MIR663/miR-663a, MIR99B/miR-99b, and MIR6087/miR-6087 (PubMed:25126784). Binds pri-microRNAs on the 3' segment flanking the stem loop via the 5'-[ACG]CAUC[ACU]-3' consensus sequence (PubMed:24581491). Required for the production of subsets of microRNAs, including MIR21 and MIR125B1 (PubMed:24581491, PubMed:27478153). May be involved not only in microRNA primary transcript processing, but also stabilization (By similarity). Participates in MYC down-regulation at high cell density through the production of MYC-targeting microRNAs (PubMed:24581491). Along with DDX5, may be involved in the processing of the 32S intermediate into the mature 28S ribosomal RNA (PubMed:17485482). Promoter-specific transcription regulator, functioning as a coactivator or corepressor depending on the context of the promoter and the transcriptional complex in which it exists (PubMed:15298701). Enhances NFAT5 transcriptional activity (PubMed:22266867). Synergizes with TP53 in the activation of the MDM2 promoter; this activity requires acetylation on lysine residues (PubMed:17226766, PubMed:19995069, PubMed:20663877). May also coactivate MDM2 transcription through a TP53-independent pathway (PubMed:17226766). Coactivates MMP7 transcription (PubMed:17226766). Along with CTNNB1, coactivates MYC, JUN, FOSL1 and cyclin D1/CCND1 transcription (PubMed:17699760). Alone or in combination with DDX5 and/or SRA1 non-coding RNA, plays a critical role in promoting the assembly of proteins required for the formation of the transcription initiation complex and chromatin remodeling leading to coactivation of MYOD1-dependent transcription. This helicase-independent activity is required for skeletal muscle cells to properly differentiate into myotubes (PubMed:17011493, PubMed:24910439). During epithelial-to-mesenchymal transition, coregulates SMAD-dependent transcriptional activity, directly controlling key effectors of differentiation, including miRNAs which in turn directly repress its expression (PubMed:24910439). Plays a role in estrogen and testosterone signaling pathway at several levels. Mediates the use of alternative promoters in estrogen-responsive genes and regulates transcription and splicing of a large number of steroid hormone target genes (PubMed:19995069, PubMed:20406972, PubMed:20663877, PubMed:24275493). Contrary to splicing regulation activity, transcriptional coregulation of the estrogen receptor ESR1 is helicase-independent (PubMed:19718048, PubMed:24275493). Plays a role in innate immunity. Specifically restricts bunyavirus infection, including Rift Valley fever virus (RVFV) or La Crosse virus (LACV), but not vesicular stomatitis virus (VSV), in an interferon- and DROSHA-independent manner (PubMed:25126784). Binds to RVFV RNA, likely via structured viral RNA elements (PubMed:25126784). Promotes mRNA degradation mediated by the antiviral zinc-finger protein ZC3HAV1, in an ATPase-dependent manner (PubMed:18334637)","subcellular_location":"Nucleus; Nucleus, nucleolus; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q92841/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DDX17","classification":"Not Classified","n_dependent_lines":84,"n_total_lines":1208,"dependency_fraction":0.0695364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX21","stoichiometry":4.0},{"gene":"TOP1","stoichiometry":4.0},{"gene":"ATG13","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CPSF6","stoichiometry":0.2},{"gene":"DDX5","stoichiometry":0.2},{"gene":"DHX9","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2},{"gene":"HNRNPD","stoichiometry":0.2},{"gene":"HNRNPL","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DDX17","total_profiled":1310},"omim":[{"mim_id":"608469","title":"DEAD-BOX HELICASE 17; DDX17","url":"https://www.omim.org/entry/608469"},{"mim_id":"603819","title":"STEROID RECEPTOR RNA ACTIVATOR 1; SRA1","url":"https://www.omim.org/entry/603819"},{"mim_id":"600832","title":"ACIDIC NUCLEAR PHOSPHOPROTEIN 32 FAMILY, MEMBER A; ANP32A","url":"https://www.omim.org/entry/600832"},{"mim_id":"180630","title":"DEAD-BOX HELICASE 5; DDX5","url":"https://www.omim.org/entry/180630"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DDX17"},"hgnc":{"alias_symbol":["P72"],"prev_symbol":[]},"alphafold":{"accession":"Q92841","domains":[{"cath_id":"3.40.50.300","chopping":"140-380","consensus_level":"high","plddt":91.9827,"start":140,"end":380},{"cath_id":"3.40.50.300","chopping":"391-552","consensus_level":"high","plddt":91.3336,"start":391,"end":552}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92841","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92841-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92841-F1-predicted_aligned_error_v6.png","plddt_mean":71.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDX17","jax_strain_url":"https://www.jax.org/strain/search?query=DDX17"},"sequence":{"accession":"Q92841","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92841.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92841/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92841"}},"corpus_meta":[{"pmid":"12664294","id":"PMC_12664294","title":"Genotyping 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p72 in colon cancer.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17699760","citation_count":161,"is_preprint":false},{"pmid":"17485482","id":"PMC_17485482","title":"Redundant role of DEAD box proteins p68 (Ddx5) and p72/p82 (Ddx17) in ribosome biogenesis and cell proliferation.","date":"2007","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/17485482","citation_count":131,"is_preprint":false},{"pmid":"23523990","id":"PMC_23523990","title":"The DEAD box proteins DDX5 (p68) and DDX17 (p72): multi-tasking transcriptional regulators.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23523990","citation_count":127,"is_preprint":false},{"pmid":"15298701","id":"PMC_15298701","title":"The p68 and p72 DEAD box RNA helicases interact with HDAC1 and repress transcription in a promoter-specific manner.","date":"2004","source":"BMC molecular 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  {\n      \"year\": 1996,\n      \"finding\": \"DDX17 (p72) is a nuclear DEAD-box protein that exhibits ATPase activity in the presence of RNA; immunocytochemistry showed it co-localizes with p68 in the nucleus of HeLa cells, consistent with a nuclear function.\",\n      \"method\": \"Recombinant protein purification, ATPase assay, immunocytochemistry\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — in vitro ATPase assay and direct localization, single study, no functional mutagenesis\",\n      \"pmids\": [\"8871553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"DDX17 (p72) possesses both RNA helicase (unwinding) and RNA annealing activities, and can catalyze ATP-dependent rearrangement of stable RNA secondary structures via branch migration intermediates, analogous to certain DNA helicases.\",\n      \"method\": \"In vitro biochemical assays with recombinant p72 protein; RNA unwinding and annealing assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro helicase and annealing assays, two activities characterized, single lab but rigorous biochemical demonstration\",\n      \"pmids\": [\"11353078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The p72 mRNA contains a 5'-UTR with an upstream non-AUG codon that drives alternative translation to produce an 82 kDa isoform (p82) with RNA helicase activity nearly identical to p72; p82 is a naturally expressed protein in HeLa cells.\",\n      \"method\": \"5' UTR mapping, in vitro translation, immunological characterization, purification and helicase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — alternative translation mechanism established by molecular mapping and biochemical validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11675387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DDX17 (p72) specifically promotes inclusion of CD44 alternative exons containing AC-rich exon enhancer elements; this requires both the helicase ATP-binding activity and the C-terminal region of p72. The related protein p68 does not share this splicing activity. p72 associates with pre-mRNA complexes in vitro.\",\n      \"method\": \"Transient transfection of minigenes, ATPase-site mutants, deletion mutants, in vitro splicing extracts, co-immunoprecipitation with pre-mRNA\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — functional mutagenesis (ATP-binding and C-terminal deletion) plus in vitro extract assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"12138182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DDX17 (p72) and p68 interact with each other and self-associate; they preferentially exist as heterodimers in cells. p68 also interacts with NFAR-2. Gel filtration indicates p68/p72 exist in complexes of ~150–400 kDa, with a subset of p68 in very large complexes (>2 MDa).\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, gel filtration chromatography\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal co-IP and yeast two-hybrid, single lab, two orthogonal methods\",\n      \"pmids\": [\"12595555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DDX17 (p72) and p68 associate with histone deacetylase 1 (HDAC1) and repress transcription in a promoter-specific manner when targeted to constitutive promoters.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene transcription repression assays\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct Co-IP interaction and functional reporter assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"15298701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DDX17 (p72) and p68 are MyoD-associated proteins that co-activate MyoD-dependent muscle gene expression; knockdown of p68/p72 impairs recruitment of TBP, RNA polymerase II, and Brg-1 (SWI/SNF ATPase subunit) to muscle gene promoters, and blocks chromatin remodeling and skeletal muscle differentiation. The noncoding RNA SRA also co-immunoprecipitates with MyoD.\",\n      \"method\": \"Co-immunoprecipitation, RNA interference, chromatin immunoprecipitation, differentiation assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, RNAi loss-of-function with defined transcriptional phenotype, ChIP, replicated with multiple methods\",\n      \"pmids\": [\"17011493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DDX17 (p72) and p68 form complexes with beta-catenin and promote beta-catenin-dependent transcription of target genes (c-Myc, cyclin D1, c-jun, fra-1); simultaneous knockdown reduces beta-catenin target gene expression, enhances p21 expression, inhibits proliferation, and reduces tumor formation in vivo.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, reporter gene assays, xenograft tumor assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional knockdown with defined transcriptional readout, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"17699760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DDX17 (p72) RNA helicase forms complexes with the coactivators p300/CBP via its N-terminal 63 amino acids, and also binds P/CAF; these three proteins synergize to activate the Mdm2 promoter. Knockdown of p72 reduces Mdm2 transcription in a p53-dependent and -independent manner.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, reporter gene assays, siRNA knockdown\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP (in vitro and in vivo), N-terminal domain mapping, functional reporter assay, single lab\",\n      \"pmids\": [\"17226766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"p68 negatively controls p72/p82 gene expression (but not vice versa). Co-silencing of both p68 and p72/p82 causes perturbation of nucleolar structure and cell death; the nucleolytic cleavage of 32S pre-rRNA is reduced, consistent with a role in structural rearrangement of the pre-60S ribosomal subunit. The redundant function maps to RNA rearrangement (not unwinding) activity.\",\n      \"method\": \"siRNA knockdown, mutant studies distinguishing rearrangement vs. unwinding activity, nucleolar morphology, pre-rRNA processing assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutant analysis distinguishing biochemical activities, knockdown with specific rRNA processing readout, single lab\",\n      \"pmids\": [\"17485482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DDX17 (p72), but not the highly similar p68, is identified as a ZAP (zinc-finger antiviral protein)-interacting protein. ZAP binds via its N-terminal domain; both N- and C-terminal domains of p72 bind ZAP. p72 RNA helicase activity is required for promoting ZAP-mediated viral RNA degradation. Overexpression of the p72 C-terminal domain reduces ZAP activity; full-length p72 enhances it. Knockdown of p72 reduces ZAP activity but does not affect tristetraprolin-mediated RNA degradation.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, RNAi knockdown, viral RNA degradation assays, helicase-dead mutant\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain mapping, helicase-activity mutant, gain/loss-of-function, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"18334637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"siRNA-mediated knockdown of DDX17 (p72), but not p68, significantly inhibits oestrogen-dependent transcription of endogenous ERα-responsive genes and oestrogen-dependent proliferation of MCF-7 and ZR75-1 breast cancer cells, demonstrating a non-redundant role for p72 in ERα co-activation.\",\n      \"method\": \"siRNA knockdown, RT-PCR of endogenous ERα target genes, cell proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined transcriptional and cellular phenotype, isoform-specific comparison, single lab\",\n      \"pmids\": [\"19718048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DDX17 (p72) and p68 are sumoylated at a single, homologous consensus SUMO site; sumoylation significantly increases protein stability of both proteins. Preventing sumoylation of p72 increases its ability to transactivate estrogen receptor and p53, while sumoylation promotes interaction of p68/p72 with HDAC1 (but not HDAC2/3, p300, or estrogen receptor). p68 but not p72 is polyubiquitylated, and mutation of the sumoylation site increases p68 polyubiquitylation, suggesting SUMO competes with ubiquitin-mediated proteasomal degradation for p68.\",\n      \"method\": \"Sumoylation site mutagenesis, protein stability assays, co-immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-directed mutagenesis of PTM site, multiple functional readouts, protein stability and interaction studies, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19995069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DDX17 (p72) and p68 are substrates for acetylation by the acetyltransferase p300 in vitro and in vivo. Mutation of acetylation sites affects binding to HDACs (but not to p300 or estrogen receptor). Acetylation increases protein stability and coactivation of estrogen receptor. Acetylation of p72 (but not p68) also enhances p53-dependent MDM2 promoter activation. Blocking p72 acetylation causes cell cycle arrest and apoptosis.\",\n      \"method\": \"In vitro acetylation assay, acetylation-site mutagenesis, co-immunoprecipitation, reporter gene assays, cell cycle/apoptosis analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro and in vivo acetylation validated, mutagenesis, multiple functional readouts, single lab\",\n      \"pmids\": [\"20663877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DDX5 and DDX17 act as transcriptional coactivators of NFAT5 and are required for activating NFAT5 target genes involved in tumor cell migration. In parallel, DDX5/DDX17 promote inclusion of NFAT5 exon 5 (which contains a premature stop codon), coupling transcriptional activation to NMD-mediated reduction of NFAT5 protein levels — a dual regulatory role.\",\n      \"method\": \"Co-immunoprecipitation, reporter gene assays, siRNA knockdown, alternative splicing assays, migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — RNAi loss-of-function with defined transcriptional and splicing phenotype, functional migration assay, single lab\",\n      \"pmids\": [\"22266867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"p68 (Ddx5) binds Upf3 protein of the NMD machinery; this interaction interferes with EJC binding. Ddx5 activates NMD of Ddx17/p72 mRNA (and Smg5 mRNA) in an ATP-binding-dependent manner requiring the 3'-UTR of target mRNAs, thereby establishing a regulatory loop controlling p72 expression levels.\",\n      \"method\": \"Co-immunoprecipitation, NMD reporter assays, ATPase mutant studies, 3'-UTR deletion analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ATPase mutant, 3'-UTR requirement defined, single lab\",\n      \"pmids\": [\"23788676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DDX17 promotes production of infectious HIV-1 particles; its helicase activity is required. A DQAD helicase-dead mutant reduces packaging of viral genomic RNA and diminishes HIV-1 Gag-Pol frameshift, demonstrating that DDX17 modulates HIV-1 RNA metabolism to support infectious particle production.\",\n      \"method\": \"Overexpression of helicase-dead mutant (DQAD), viral RNA packaging assay, frameshifting assay\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant defines helicase activity requirement, multiple RNA-level readouts, single lab\",\n      \"pmids\": [\"23769241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DDX17 cooperates with hnRNP H/F splicing factors to define epithelial- and myoblast-specific splicing subprograms. Downregulation of DDX5/DDX17 protein during myogenesis and EMT is mediated by differentiation-induced miRNAs whose biogenesis itself depends on DDX5/DDX17. DDX5/DDX17 also function as coregulators of master transcriptional regulators of differentiation.\",\n      \"method\": \"siRNA knockdown, RNA-seq, CLIP-seq, miRNA profiling, alternative splicing assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi, transcriptome-wide splicing analysis, miRNA profiling, CLIP-seq, multiple biological contexts tested, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"24910439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DDX17 binds the stem loops of host pri-miRNA to facilitate their processing by Drosha (nuclear function), and also directly binds a specific stem loop in bunyaviral (RVFV) RNA to restrict infection (cytoplasmic function). Loss of DDX17 (but not the related DDX5) specifically increases RVFV replication. This dual stem-loop recognition underlies both roles.\",\n      \"method\": \"RNAi screening, CLIP-seq, genetic depletion in Drosophila and human cells, viral replication assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CLIP-seq for direct RNA binding, depletion in two organisms, DDX5 specificity control, multiple orthogonal methods\",\n      \"pmids\": [\"25126784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DDX17 (p72) physically interacts with Sox2 via co-immunoprecipitation, and this interaction is preferentially restricted to Sox2-reporter-responsive (stem-like) breast cancer cells where DDX17 is nuclear. DDX17 knockdown reduces Sox2-SRR2 promoter binding and Sox2-dependent target gene expression (MUC15, CCND1, CD133), as well as colony and mammosphere formation in stem-like cells.\",\n      \"method\": \"LC-MS (initial identification), co-immunoprecipitation, siRNA knockdown, ChIP-PCR, reporter assays, colony/mammosphere assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP confirmed, ChIP, functional knockdown, but single lab\",\n      \"pmids\": [\"26569340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"DDX17 promotes gefitinib resistance in NSCLC cells by dissociating the E-cadherin/β-catenin complex, causing β-catenin nuclear translocation and transcription of β-catenin target genes. DDX17 undergoes nucleocytoplasmic shuttling via nuclear localization signals (NLS) and nuclear export signals (NES) through an exportin/importin-dependent pathway; disrupting this shuttling impairs β-catenin activation and acquired resistance.\",\n      \"method\": \"Co-immunoprecipitation, NLS/NES sequence identification, nuclear/cytoplasmic fractionation, β-catenin reporter assays, drug resistance assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP, subcellular fractionation, functional resistance assay, NLS/NES defined, single lab\",\n      \"pmids\": [\"28259822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX17 controls REST-dependent transcriptional repression of neuronal genes by associating with REST and promoting its binding to a subset of REST-target gene promoters. During neuronal differentiation, DDX17 downregulation contributes to REST complex release and neuronal gene activation. DDX17 and DDX5 also regulate processing of proneural miRNAs (including miR-26a/b) that target the REST complex; an intronic regulatory region negatively impacts miR-26a2 processing and splicing in a DDX17-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, siRNA knockdown, miRNA processing assays, luciferase reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, miRNA processing functional assays, single lab with multiple methods\",\n      \"pmids\": [\"29931089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX17 controls HIV-1 splicing specifically at the A4/A5 splice acceptor cluster (but not A1), independently of DDX5. In the absence of DDX17, viral envelope protein production and other accessory proteins are severely reduced. DDX17 interacts with splicing factors SRSF1/SF2 and U2AF65/35. Specific RNA-binding motifs (not the Walker A, Walker B/DEAD, Q motif, or glycine doublet) are essential for this splicing function.\",\n      \"method\": \"siRNA knockdown, splicing assays, motif-deletion mutagenesis, co-immunoprecipitation with splicing factors\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — domain mutagenesis, Co-IP with splicing factors, specific isoform comparison (DDX5 vs DDX17), multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"30131116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Under hypoxia, the E3 ubiquitin ligase HectH9 mediates K63-linked polyubiquitination of DDX17. Polyubiquitinated DDX17 dissociates from the Drosha-DGCR8 complex (reducing biogenesis of anti-stemness miRNAs) and associates with p300-YAP, leading to H3K56 acetylation at stemness-related gene promoters and their transcriptional activation, promoting cancer stem-like properties.\",\n      \"method\": \"Ubiquitination assays (K63-linkage specific), Co-IP, Drosha complex pulldown, ChIP (H3K56ac), miRNA profiling, tumor-initiating capacity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — specific K63-ubiquitination mapped, complex dissociation demonstrated, ChIP for histone modification, multiple functional readouts, single lab\",\n      \"pmids\": [\"30877109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Crystal structures of the DDX17 core catalytic domain revealed sequence-specific RNA recognition; the catalytic core binds and remodels a specific region of primary miRNA 3' to the mature sequence, enhancing Drosha processing. An intramolecular interaction between the DDX17 N-terminal tail and the DEAD domain acts as an autoregulatory mechanism controlling ATPase activity.\",\n      \"method\": \"X-ray crystallography, biochemical RNA-binding and ATPase assays, pri-miRNA processing assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional biochemical validation, intramolecular regulatory mechanism defined, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31851931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DDX17 physically interacts with Klf4 (demonstrated by co-IP and GST pull-down); DDX17 inhibits Klf4 transcriptional activity at target gene promoters (E-cadherin, MMP2) and prevents Klf4 from binding the MMP2 promoter. The interaction requires the zinc-finger domain of Klf4.\",\n      \"method\": \"Co-immunoprecipitation, GST pull-down, luciferase reporter assay, ChIP (Klf4 promoter binding), Klf4 domain deletion\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal Co-IP and pull-down, functional reporter and ChIP, domain requirement defined, single lab\",\n      \"pmids\": [\"31653828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX17 directly binds RVFV non-coding RNAs (intergenic region, IGR, and 5' NCR) with Kd values of 5.77 µM and 9.85 µM respectively (measured by microscale thermophoresis), and the helicase domain (DDX17135-555) can unwind both RNAs in vitro.\",\n      \"method\": \"Microscale thermophoresis, SAXS, analytical ultracentrifugation, helicase unwinding assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding quantification, SAXS structural analysis, in vitro helicase activity measured, multiple biophysical methods, single lab\",\n      \"pmids\": [\"33374561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX17 is identified as the sensor of endogenous SINE RNAs (retrotransposon RNAs) that activates the NLRC4 inflammasome independently of NAIPs. DDX17 licenses assembly of an inflammasome comprising NLRC4, NLRP3, and ASC, driving caspase-1 activation and cytokine (IL-18) release. Inhibiting DDX17-mediated NLRC4 activation reduced IL-18 in SLE patient PBMCs and prevented retinal degeneration in an AMD animal model.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, caspase-1 activation assay, cytokine release assay, in vivo retinal degeneration model\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct SINE RNA sensing mechanism, inflammasome assembly by Co-IP, loss-of-function in patient cells and animal model, multiple orthogonal methods\",\n      \"pmids\": [\"34860583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX17 inhibits HBV replication primarily by blocking cytoplasmic encapsidation of pregenomic RNA (pgRNA). DDX17 competes with HBV polymerase to bind the 5' epsilon stem-loop of pgRNA. Immunofluorescence showed DDX17 translocates from nucleus to cytoplasm in the presence of HBV RNA. This antiviral function is helicase-activity dependent.\",\n      \"method\": \"RNA immunoprecipitation, EMSA (electrophoretic mobility shift assay), immunofluorescence, encapsidation assay, helicase-dead mutant\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct RNA binding by RIP and EMSA, competition assay with viral polymerase, helicase mutant requirement, subcellular localization linked to function\",\n      \"pmids\": [\"34287051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mutant FUS recruits nuclear DDX17 into cytoplasmic stress granules and physically interacts with DDX17 through the RGG1 domain of FUS. Ectopic expression of DDX17 reduces cytoplasmic mislocalization of mutant FUS and suppresses FUS-mediated neurodegeneration in vivo. DDX17 functions as a regulator of the DNA damage response and its upregulation repairs defective DDR caused by mutant FUS.\",\n      \"method\": \"Co-immunoprecipitation (RGG1 domain), immunofluorescence (stress granule localization), overexpression rescue in vivo (Drosophila), DNA damage assays\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, functional rescue in vivo, localization studies, single lab\",\n      \"pmids\": [\"34061233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX17 regulates alternative splicing of PXN-AS1 by inducing intron 3 retention, producing transcript PXN-AS1-IR3 that recruits TEX10 and p300 to the MYC enhancer to activate MYC transcription and downstream metastasis-associated genes. DDX17 knockout in a mouse model inhibits HCC metastasis.\",\n      \"method\": \"RNA-seq, splicing assays, Co-IP (TEX10/p300 complex), ChIP (MYC enhancer), DDX17 knockout mouse model\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanism involves splicing event producing specific isoform, complex demonstrated by Co-IP, ChIP for MYC enhancer binding, in vivo model, single lab\",\n      \"pmids\": [\"34626132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DDX17 helicase unwinds R-loops in vitro and promotes MUS81-dependent restart of R-loop-stalled replication forks in human cells. Loss of DDX17 causes R-loop accumulation, anaphase bridges, and micronuclei. DDX17 associates with R-loops and facilitates their formation (specifically at loci with low pre-existing hybrid levels) to allow propagation of DSB ubiquitin cascade responses.\",\n      \"method\": \"In vitro R-loop unwinding assay, S9.6 immunofluorescence (R-loop detection), genome-wide R-loop mapping (DRIP-seq), DNA fiber assay (fork restart), helicase mutant\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro helicase activity on R-loops, genome-wide R-loop mapping, fork restart assay, helicase mutant, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36453994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DDX17 is required for efficient DSB repair; it is recruited early in the DSB ubiquitin cascade and promotes formation of DNA:RNA hybrids (R-loops) at DSB sites specifically at loci with low pre-existing hybrids. Loss of DDX17 impairs cell survival and DNA repair in response to DSB-inducing agents.\",\n      \"method\": \"Proteomic meta-analysis, siRNA knockdown, γH2AX foci assay, R-loop mapping (DRIP), DSB repair factor recruitment assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with DSB repair phenotype, DRIP mapping, recruitment assay, single lab\",\n      \"pmids\": [\"36200807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DDX17 acts as a transcriptional regulator that interacts with Y-box binding protein 1 (YB1) in the nucleus, driving YB1 binding to the EGFR promoter to activate EGFR transcription and downstream MEK/pERK signaling. MTDH stabilizes DDX17 by inhibiting its ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, ChIP-seq, promoter reporter assay, ubiquitination assay, in vitro and in vivo functional studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, promoter assay, ubiquitination mechanism defined, single lab\",\n      \"pmids\": [\"36385375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"THOC5 interacts with DDX17 (and DDX5) specifically in slow RNA polymerase II cells; this chromatin-associated complex also includes CDK12 and THOC6, and is involved in regulating R-loop structures and transcription elongation rate.\",\n      \"method\": \"Co-immunoprecipitation, THOC5 depletion, transcription elongation measurement, R-loop analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP in specific cellular context, depletion phenotype, single lab\",\n      \"pmids\": [\"36590164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JICD1 (JAG1 intracellular domain) forms a transcriptional complex with DDX17, SMAD3, and TGIF2 to drive SOX2 expression and cancer stem-like transformation of astrocytes. ChIP-seq confirmed complex binding at the SOX2 locus.\",\n      \"method\": \"Proteomics, co-immunoprecipitation, ChIP-seq, reporter assays, functional transformation assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP-seq, functional assays in same study, single lab\",\n      \"pmids\": [\"36417870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX17 binds the transcriptional repressor BCL6 and inhibits expression of DRP1 (a mitochondrial fission protein). When DDX17 is reduced (as in heart failure), BCL6 repression is attenuated, DRP1 expression increases, mitochondrial fission is enhanced, and autophagy flux is blocked, leading to cardiomyocyte apoptosis and progressive cardiac dysfunction. Cardiomyocyte-specific Ddx17 knockout mice develop heart failure, while DDX17 restoration protects cardiac function.\",\n      \"method\": \"Co-immunoprecipitation (DDX17-BCL6), cardiomyocyte-specific KO and transgenic mice, mitochondrial morphology assays, autophagic flux assays, DRP1 expression analysis\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, KO and transgenic mouse models, multiple mechanistic readouts (BCL6, DRP1, mitochondrial fission, autophagy), single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"38782919\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DDX17 (p72) is a nuclear DEAD-box RNA helicase with ATPase-driven RNA unwinding, annealing, and rearrangement activities that underlie its roles in alternative splicing (via cooperation with hnRNP H/F and U2AF/SRSF1), pri-miRNA processing (through sequence-specific stem-loop recognition and enhancement of Drosha cleavage, regulated by an intramolecular N-tail/DEAD-domain autoregulatory interaction), ribosome biogenesis (32S pre-rRNA processing), and R-loop resolution at stalled replication forks; it also functions as a transcriptional co-regulator—forming complexes with ERα, MyoD, p53/MDM2, β-catenin, NFAT5, REST, SOX2, Klf4, YB1, BCL6, and coactivators p300/CBP/P/CAF/HDAC1—with its activity tuned by SUMO-ylation, K63-linked polyubiquitination (by HectH9 under hypoxia), and acetylation by p300; in antiviral defense it directly senses structured viral and retrotransposon RNAs (RVFV stem loops, HBV pgRNA epsilon, SINE RNAs) and can activate the non-canonical NLRC4 inflammasome, while its nucleocytoplasmic shuttling (via defined NLS/NES sequences) links nuclear transcription/splicing functions to cytoplasmic roles in viral RNA metabolism and β-catenin signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDX17 (p72) is a nuclear DEAD-box RNA helicase whose ATP-dependent RNA unwinding, annealing, and structural rearrangement activities underpin a broad range of RNA-processing and gene-regulatory functions [#1]. As an enzyme it binds RNA in an ATP-dependent manner, possesses both unwinding and annealing activities, and can catalyze branch-migration-type rearrangement of stable RNA secondary structures; an alternative non-AUG translation start produces a larger p82 isoform with comparable helicase activity [#1, #2]. In RNA metabolism it promotes alternative exon inclusion (e.g., AC-rich CD44 exons) in a manner requiring both ATP-binding and its C-terminal region, cooperates with hnRNP H/F and the splicing factors SRSF1 and U2AF to define cell-type-specific splicing programs, and contributes to ribosome biogenesis through structural rearrangement during 32S pre-rRNA processing [#3, #17, #22, #9]. DDX17 also acts in microRNA biogenesis by sequence-specifically recognizing and remodeling pri-miRNA stem-loops to enhance Drosha cleavage, an activity tuned by an autoregulatory intramolecular interaction between its N-terminal tail and the DEAD domain [#24, #18]. Beyond RNA processing, DDX17 functions as a transcriptional co-regulator, partnering with diverse factors including MyoD, \\u03b2-catenin, ER\\u03b1, p53/MDM2, REST, SOX2, Klf4, YB1, BCL6, NFAT5, and the coactivators p300/CBP/P/CAF and HDAC1 to activate or repress target genes and to drive differentiation, proliferation, and stem-like programs [#6, #7, #11, #8, #21]. Its activity and stability are controlled by SUMOylation, p300-mediated acetylation, and HectH9-mediated K63-linked polyubiquitination under hypoxia, the latter switching DDX17 from a Drosha-associated miRNA-processing role to a p300-YAP-associated chromatin-activating role [#12, #13, #23]. In the nucleus DDX17 resolves R-loops to promote MUS81-dependent restart of stalled replication forks and participates in the DNA double-strand-break response [#31, #32]. Through helicase-dependent recognition of structured viral and retrotransposon RNAs it acts in antiviral defense\\u2014restricting bunyaviral (RVFV) and hepatitis B virus replication and sensing endogenous SINE RNAs to license a non-canonical NLRC4 inflammasome\\u2014while its NLS/NES-dependent nucleocytoplasmic shuttling couples these cytoplasmic roles to nuclear transcription and splicing [#18, #28, #27, #20]. Cardiomyocyte-specific Ddx17 loss in mice causes heart failure via derepression of the mitochondrial fission gene DRP1 [#36].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing DDX17 as a bona fide nuclear DEAD-box protein with RNA-stimulated ATPase activity placed it among catalytically active RNA helicases and predicted a nuclear RNA-processing function.\",\n      \"evidence\": \"Recombinant ATPase assay and immunocytochemistry co-localizing with p68 in HeLa nuclei\",\n      \"pmids\": [\"8871553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No RNA substrate or unwinding activity demonstrated\", \"No functional mutagenesis linking ATPase activity to a cellular role\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reconstituted biochemistry showed DDX17 is not merely an ATPase but a true helicase with both unwinding and annealing activities capable of RNA structural rearrangement, defining its core enzymatic repertoire; alternative non-AUG translation additionally produces an active p82 isoform.\",\n      \"evidence\": \"In vitro RNA unwinding/annealing/branch-migration assays with recombinant protein, plus 5'-UTR mapping and in vitro translation\",\n      \"pmids\": [\"11353078\", \"11675387\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular substrates of unwinding vs. annealing not identified\", \"Distinct functions of p72 vs p82 isoforms unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linking DDX17's ATPase/helicase activity to CD44 alternative exon inclusion provided the first specific RNA-processing function and distinguished it from the paralog p68, showing isoform-specific roles.\",\n      \"evidence\": \"Minigene transfection, ATP-binding and C-terminal deletion mutants, in vitro splicing extracts, pre-mRNA Co-IP\",\n      \"pmids\": [\"12138182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding to AC-rich enhancer not structurally defined\", \"Generality across other exons untested at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrating that DDX17 and p68 heterodimerize and assemble into larger complexes established the physical basis for their frequently shared, sometimes redundant functions.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP, gel filtration sizing of complexes\",\n      \"pmids\": [\"12595555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and other subunits of the large complexes unknown\", \"Functional consequence of heterodimerization not directly tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying HDAC1 association and promoter-targeted repression revealed that DDX17 functions in transcriptional regulation, not only RNA processing.\",\n      \"evidence\": \"Co-IP and reporter repression assays at constitutive promoters\",\n      \"pmids\": [\"15298701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous target genes not defined\", \"Mechanism coupling helicase activity to repression unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defining DDX17/p68 as MyoD coactivators required for recruiting the basal machinery and the Brg-1 chromatin remodeler tied DDX17 to chromatin remodeling and developmental differentiation programs.\",\n      \"evidence\": \"Reciprocal Co-IP, RNAi loss-of-function, ChIP, myogenic differentiation assays; SRA ncRNA co-IP with MyoD\",\n      \"pmids\": [\"17011493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of SRA RNA in DDX17 function not mechanistically resolved\", \"Whether helicase activity is needed for coactivation untested here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery of DDX17 in \\u03b2-catenin and p53/MDM2-p300/CBP/P/CAF transcriptional complexes broadened its co-regulator role into oncogenic and tumor-suppressor pathways, with N-terminal mapping to coactivator binding.\",\n      \"evidence\": \"Co-IP, in vitro binding, N-terminal domain mapping, siRNA knockdown, reporter and xenograft assays\",\n      \"pmids\": [\"17699760\", \"17226766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect contacts within multiprotein complexes unresolved\", \"Contribution of helicase catalysis to transcriptional output unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Co-silencing experiments revealed a non-redundant requirement for DDX17/p68 RNA-rearrangement activity in 32S pre-rRNA processing, assigning a role in ribosome biogenesis.\",\n      \"evidence\": \"siRNA knockdown, rearrangement vs unwinding mutant analysis, nucleolar morphology and pre-rRNA processing assays\",\n      \"pmids\": [\"17485482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct pre-rRNA substrate engagement not shown\", \"Position within pre-60S assembly pathway not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Isoform-specific knockdown established that DDX17, but not p68, is uniquely required for ER\\u03b1-dependent transcription and estrogen-driven breast cancer cell proliferation.\",\n      \"evidence\": \"siRNA knockdown, endogenous ER\\u03b1 target gene RT-PCR, proliferation assays in MCF-7/ZR75-1\",\n      \"pmids\": [\"19718048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of isoform specificity unexplained\", \"Direct DDX17-ER\\u03b1 contact not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defining SUMOylation and p300 acetylation as stability- and activity-controlling modifications established a PTM layer governing DDX17's transcriptional coactivation and its HDAC interactions, with SUMO competing against ubiquitin-mediated degradation.\",\n      \"evidence\": \"Site-directed PTM mutagenesis, protein stability assays, Co-IP, transcriptional reporters, cell-cycle/apoptosis analysis\",\n      \"pmids\": [\"19995069\", \"20663877\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes catalyzing DDX17 SUMOylation not identified\", \"Crosstalk between SUMO, acetylation, and ubiquitin not integrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing DDX5/DDX17 both transcriptionally activate NFAT5 and promote an NMD-coupled splicing event revealed a dual transcription-plus-splicing regulatory logic controlling target protein levels.\",\n      \"evidence\": \"Co-IP, reporter assays, siRNA knockdown, alternative splicing and migration assays\",\n      \"pmids\": [\"22266867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct splicing substrate recognition not defined\", \"Balance between activation and NMD-mediated reduction in vivo unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying that p68/Ddx5 drives NMD of DDX17 mRNA via Upf3, and that DDX17 supports HIV-1 particle production, defined an autoregulatory expression loop and an early viral RNA-metabolism role.\",\n      \"evidence\": \"Co-IP, NMD reporter and 3'-UTR analysis, ATPase mutants; HIV-1 DQAD helicase-dead packaging and frameshift assays\",\n      \"pmids\": [\"23788676\", \"23769241\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological setting of the Ddx5-Ddx17 NMD loop untested\", \"Direct viral RNA target of DDX17 in HIV-1 not mapped here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Transcriptome-wide analyses showed DDX17 cooperates with hnRNP H/F to define epithelial/myoblast splicing subprograms and that its own downregulation during differentiation is driven by miRNAs whose biogenesis it controls\\u2014revealing a feedback circuit linking splicing, miRNA processing, and differentiation; the same dual stem-loop recognition supports both pri-miRNA processing and direct antiviral RNA binding.\",\n      \"evidence\": \"siRNA, RNA-seq, CLIP-seq, miRNA profiling, splicing assays; CLIP-seq and viral replication assays in fly and human cells\",\n      \"pmids\": [\"24910439\", \"25126784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sequence determinants of stem-loop selectivity not yet structurally defined\", \"Coordination between nuclear and cytoplasmic RNA-binding pools unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying a SOX2-DDX17 interaction restricted to stem-like breast cancer cells extended DDX17's co-regulator role to cancer stemness programs.\",\n      \"evidence\": \"LC-MS, Co-IP, siRNA, ChIP-PCR, reporter and mammosphere assays\",\n      \"pmids\": [\"26569340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why the interaction is context-restricted not explained\", \"Direct vs bridged DDX17-SOX2 contact unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping functional NLS/NES sequences and an exportin/importin-dependent shuttling pathway explained how DDX17 couples nuclear functions to cytoplasmic \\u03b2-catenin activation and drug resistance.\",\n      \"evidence\": \"Co-IP, NLS/NES identification, nuclear/cytoplasmic fractionation, \\u03b2-catenin reporter and gefitinib-resistance assays\",\n      \"pmids\": [\"28259822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signals triggering shuttling not defined\", \"Direct cytoplasmic action on E-cadherin/\\u03b2-catenin complex not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining DDX17-specific control of HIV-1 A4/A5 splice-acceptor usage via SRSF1 and U2AF, and dissecting REST-dependent neuronal gene repression coupled to proneural miRNA processing, demonstrated context-specific splicing/transcription mechanisms relying on specific RNA-binding motifs rather than canonical helicase motifs.\",\n      \"evidence\": \"siRNA, splicing assays, motif-deletion mutagenesis, Co-IP with splicing factors; ChIP and miRNA processing assays for REST\",\n      \"pmids\": [\"30131116\", \"29931089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of motif-dependent splicing recognition undefined\", \"Generality of REST-DDX17 control across neuronal genes incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Crystal structures plus hypoxia-driven K63-ubiquitination by HectH9 explained, at atomic and signaling levels, how DDX17 sequence-specifically remodels pri-miRNA 3' regions and how a PTM switch toggles it between Drosha-associated miRNA processing and p300-YAP-associated chromatin activation of stemness genes.\",\n      \"evidence\": \"X-ray crystallography with RNA-binding/ATPase/processing assays; K63-linkage ubiquitination, complex pulldowns, H3K56ac ChIP, tumor-initiation assays; plus Klf4 interaction studies\",\n      \"pmids\": [\"31851931\", \"30877109\", \"31653828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length DDX17 structure with bound pri-miRNA not resolved\", \"Deubiquitinase reversing the HectH9 switch unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Biophysical and functional studies established DDX17 as a direct sensor of structured RNAs in innate immunity and viral restriction\\u2014quantifying RVFV RNA binding, blocking HBV pgRNA encapsidation by competing with viral polymerase, and licensing a non-canonical NLRC4 inflammasome in response to SINE RNAs\\u2014while also showing it rescues mutant-FUS neurodegeneration via stress-granule recruitment and DDR support.\",\n      \"evidence\": \"MST/SAXS and in vitro unwinding (RVFV); RIP/EMSA, encapsidation and helicase-mutant assays (HBV); Co-IP, caspase-1/IL-18 assays and disease models (NLRC4); Co-IP and in vivo rescue (FUS)\",\n      \"pmids\": [\"33374561\", \"34287051\", \"34860583\", \"34061233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DDX17 discriminates self from non-self structured RNAs is unresolved\", \"Mechanism of NLRC4 licensing downstream of RNA sensing not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that DDX17 unwinds R-loops to enable MUS81-dependent fork restart and is recruited in the DSB ubiquitin cascade, while also engaging YB1/EGFR transcription, PXN-AS1 splicing-driven MYC activation, and THOC5/CDK12 elongation complexes, established central roles in genome stability and oncogenic gene expression.\",\n      \"evidence\": \"In vitro R-loop unwinding, DRIP-seq, DNA fiber and \\u03b3H2AX assays, helicase mutants; Co-IP, ChIP-seq, splicing assays, and KO/transgenic mouse models\",\n      \"pmids\": [\"36453994\", \"36200807\", \"36385375\", \"36590164\", \"36417870\", \"34626132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DDX17 both promotes and resolves R-loops at different loci is mechanistically unreconciled\", \"Direct DNA/RNA substrate selection at DSB sites not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cardiomyocyte-specific genetics linked DDX17 to organ physiology, showing that DDX17-BCL6 repression of DRP1 restrains mitochondrial fission and that DDX17 loss causes heart failure.\",\n      \"evidence\": \"Co-IP, cardiomyocyte-specific KO/transgenic mice, mitochondrial morphology and autophagic flux assays\",\n      \"pmids\": [\"38782919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether helicase activity is required for BCL6-mediated DRP1 repression untested\", \"Upstream signals reducing DDX17 in heart failure unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how DDX17's single enzymatic core is partitioned among its many functions\\u2014how RNA-binding specificity, PTMs, and shuttling jointly determine whether it acts as a splicing factor, miRNA-processing enzyme, R-loop helicase, RNA sensor, or transcriptional co-regulator at a given locus and time.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model linking PTM state to functional output\", \"Substrate-selection rules distinguishing antiviral, processing, and genome-stability roles undefined\", \"Structural basis for partner discrimination among transcription factors unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 9, 26, 31]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [18, 24, 26, 28]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 7, 21, 33]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [27, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 20]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [20, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3, 9, 18, 24]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7, 33]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [31, 32]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [27, 18, 28]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [23, 30, 36]}\n    ],\n    \"complexes\": [\n      \"Drosha-DGCR8 microprocessor\",\n      \"NLRC4-NLRP3-ASC inflammasome\",\n      \"THOC5-DDX5-DDX17-CDK12-THOC6 complex\"\n    ],\n    \"partners\": [\n      \"DDX5\",\n      \"HDAC1\",\n      \"p300\",\n      \"SRSF1\",\n      \"U2AF2\",\n      \"CTNNB1\",\n      \"ESR1\",\n      \"BCL6\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}