{"gene":"DDX11","run_date":"2026-06-09T23:54:41","timeline":{"discoveries":[{"year":2006,"finding":"Human ChlR1 (DDX11) is required for sister chromatid cohesion in mammalian cells. ChlR1 diffusely coats mitotic chromatin in prophase then translocates to spindle poles at metaphase. RNAi depletion causes mitotic failure, pro-metaphase arrest, and increased centromeric chromatid separation. ChlR1 co-immunoprecipitates with cohesin subunits Scc1, Smc1, and Smc3.","method":"RNAi knockdown, immunofluorescence localization, Co-IP with cohesin subunits, chromosome spread analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with multiple cohesin subunits, RNAi with defined cellular phenotype, localization studies; replicated across multiple subsequent studies","pmids":["17105772"],"is_preprint":false},{"year":2008,"finding":"Purified human ChlR1 possesses DNA-dependent ATPase and 5'-to-3' helicase activities, requires a 5' single-stranded region for loading, and can unwind duplexes up to 100 bp (extended to 500 bp by RPA or Ctf18-RFC). ChlR1 physically interacts with the Ctf18-RFC complex, PCNA, and Fen1; the ChlR1-Fen1 interaction stimulates Fen1 flap endonuclease activity. Depletion of either ChlR1 or Fen1 by siRNA causes precocious sister chromatid separation.","method":"Purification from 293 cells, in vitro ATPase and helicase assays, Co-IP/pulldown with Ctf18-RFC/PCNA/Fen1, siRNA knockdown with chromatid cohesion readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution of helicase activity, multiple binding partners confirmed by pulldown/Co-IP, functional validation by siRNA; multiple orthogonal methods in single rigorous study","pmids":["18499658"],"is_preprint":false},{"year":2006,"finding":"Papillomavirus E2 protein binds ChlR1 (DDX11), and this interaction is required for loading E2 onto mitotic chromosomes. An E2 W130R mutation abolishes ChlR1 binding and correspondingly prevents E2 association with mitotic chromosomes; viral genomes encoding W130R are not episomally maintained. RNAi depletion of ChlR1 significantly reduces E2 localization to mitotic chromosomes.","method":"Co-IP, site-directed mutagenesis of E2 (W130R), RNAi knockdown, immunofluorescence localization, episome maintenance assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — binding confirmed by Co-IP, mutagenesis establishes required residue, RNAi phenocopies mutation, functional consequence (episome loss) measured; multiple orthogonal methods","pmids":["17189189"],"is_preprint":false},{"year":2007,"finding":"Loss of mouse Ddx11 causes embryonic lethality at E10.5 with placental malformation, G2/M cell cycle delay, increased chromosome missegregation, decreased sister chromatid cohesion at centromeres and arms, and increased aneuploidy. ChlR1 is required for proper cohesin complex binding to both centromere and chromosome arms; cohesin binds more loosely to chromatin in ChlR1-depleted cells.","method":"Ddx11 knockout mouse, siRNA depletion in HeLa cells, chromosome spreads, FACS cell cycle analysis, immunofluorescence, cohesin chromatin binding assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout phenotype in mouse confirmed by siRNA in cell lines, multiple cellular readouts (cohesion, segregation, aneuploidy, cohesin loading); replicated by other labs","pmids":["17611414"],"is_preprint":false},{"year":2010,"finding":"Biallelic loss-of-function mutations in DDX11 cause Warsaw breakage syndrome, a cohesinopathy with features of both Fanconi anemia (drug-induced chromosomal breakage) and Roberts syndrome (sister chromatid cohesion defects), establishing DDX11 functions at the interface of DNA repair and sister chromatid cohesion.","method":"Patient genetic analysis, cytogenetic analysis (MMC-induced breakage, sister chromatid cohesion assay)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics with cellular phenotypic validation; single patient but cellular phenotype is diagnostic and consistent with molecular function established by other studies","pmids":["20137776"],"is_preprint":false},{"year":2012,"finding":"A homozygous p.R263Q mutation in DDX11 impairs helicase activity by perturbing DNA binding and DNA-dependent ATP hydrolysis, while leaving overall protein structure intact, confirming the functional importance of the Fe-S domain region for DDX11 enzymatic activity.","method":"Purification of recombinant wild-type and p.R263Q DDX11, in vitro helicase assay, ATPase assay, DNA binding assay","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with disease-relevant mutant, multiple enzymatic readouts (helicase, ATPase, DNA binding); single lab but orthogonal methods","pmids":["23033317"],"is_preprint":false},{"year":2015,"finding":"Tim (Timeless) physically interacts with DDX11 (confirmed by surface plasmon resonance), stimulates DDX11 unwinding activity up to 10-fold on forked DNA and 4-5-fold on G-quadruplex and D-loop substrates by enhancing DDX11 DNA binding. Tim and DDX11 are epistatic for replication fork progression and fork restart after hydroxyurea treatment; their chromatin association increases after hydroxyurea exposure.","method":"Surface plasmon resonance, in vitro helicase stimulation assay, EMSA, DNA fiber assay, siRNA co-depletion epistasis, chromatin fractionation Co-IP","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding confirmed by SPR, in vitro stimulation assay, genetic epistasis by fiber assay; multiple orthogonal methods in single study","pmids":["26503245"],"is_preprint":false},{"year":2015,"finding":"DDX11/ChlR1 efficiently unwinds both intermolecular and intramolecular DNA triplex substrates in an ATP-dependent manner; triplex DNA is a preferred substrate compared to replication fork and G-quadruplex DNA. The WABS patient mutant (R263Q) fails to unwind triplexes. ChlR1-depleted cells show increased triplex DNA content and double-strand breaks upon treatment with a triplex-stabilizing compound, while FANCJ-deficient cells do not.","method":"In vitro helicase assay with triplex substrates, recombinant protein purification, siRNA depletion, immunofluorescence for triplex content and DSBs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with disease mutant and WT, cellular validation by siRNA; multiple orthogonal methods","pmids":["25561740"],"is_preprint":false},{"year":2015,"finding":"The Q motif glutamine (Q23) of ChlR1 is required for DNA binding and helicase activity but not ATP binding; Q23A mutant shows impaired ATPase activity and reduced DNA binding while retaining normal ATP binding and similar overall structure. ChlR1 functions as a monomer in solution.","method":"Site-directed mutagenesis, purification of recombinant ChlR1 from HEK293T, in vitro helicase assay, ATPase assay, ATP binding assay, thermal shift assay, partial proteolysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, multiple orthogonal biochemical assays; single lab","pmids":["26474416"],"is_preprint":false},{"year":2015,"finding":"DDX11 is a nucleolar protein that binds hypomethylated active rDNA gene loci, where it interacts with upstream binding factor (UBF) and RNA polymerase I. DDX11 knockdown increases heterochromatin at rDNA loci, reduces UBF activity and recruitment of UBF and RPA194 to rDNA promoters, suppresses rRNA transcription, and inhibits cell growth. WABS-derived mutants (R263Q, K897del) and Fe-S deletion show reduced rDNA promoter binding and ATPase activity.","method":"Immunofluorescence, ChIP, Co-IP with UBF and Pol I, siRNA knockdown, rRNA transcription assay, recombinant mutant protein analysis, zebrafish morpholino knockdown","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, functional knockdown in cells and zebrafish, mutant analysis; single lab but multiple orthogonal methods","pmids":["26089203"],"is_preprint":false},{"year":2011,"finding":"ChlR1 (DDX11) is required for proper heterochromatin organization; ChlR1-depleted cells show dispersed localization of constitutive heterochromatin, disrupted centromere clustering, decreased HP1α at pericentric regions (by IF and ChIP), modest reduction of H3K9-me3, decreased DNA methylation at major satellite repeats, and decreased chromatin density at telomeres (by MNase assay).","method":"siRNA knockdown in HeLa cells, Ddx11-/- mouse embryo cells, immunofluorescence, ChIP for HP1α and H3K9-me3, bisulfite DNA methylation analysis, MNase assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (IF, ChIP, bisulfite, MNase), confirmed in two model systems (siRNA and KO cells); single lab","pmids":["21854770"],"is_preprint":false},{"year":2018,"finding":"DDX11 interacts with Timeless through a conserved peptide motif; this interaction is critical for sister chromatid cohesion in interphase and mitosis. DDX11 localizes at nascent DNA (SIRF analysis). DDX11 promotes cohesin binding to DNA replication forks in concert with Timeless. Purified recombinant cohesin directly interacts with DDX11 in vitro. Loss of DDX11-Timeless interaction impairs cohesin association with chromatin.","method":"Co-IP, peptide motif mutagenesis, immunofluorescence, SIRF assay (nascent DNA localization), iPOND, in vitro binding of recombinant cohesin with DDX11","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of DDX11-cohesin interaction, SIRF for nascent DNA localization, Co-IP, mutagenesis of interaction motif with functional cohesion readout; multiple orthogonal methods","pmids":["30303954"],"is_preprint":false},{"year":2018,"finding":"In avian DT40 cells, DDX11 functions as a backup for the FA pathway in interstrand crosslink repair. DDX11 acts jointly with the 9-1-1 checkpoint clamp and its loader RAD17 in a postreplicative fashion to promote homologous recombination repair of bulky lesions. DDX11 also facilitates diversification of the chicken Ig-variable gene (hypermutation and gene conversion), processes triggered by programmed abasic sites. DDX11 is not required for intra-S checkpoint activation or efficient fork progression.","method":"DT40 genetic knockout, epistasis analysis with 9-1-1/RAD17 mutants, ICL sensitivity assays, DNA fiber assay, Ig gene diversification assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in DT40 system with multiple mutant combinations, multiple functional readouts; rigorous genetic approach","pmids":["30061412"],"is_preprint":false},{"year":2020,"finding":"The iron-sulfur (FeS) cluster in DDX11 is required for DNA binding, ATP hydrolysis, and DNA helicase activity; arginine-263 in the FeS cluster-binding motif affects FeS cluster binding via its positive charge. DDX11 interacts with DNA polymerase delta and WDHD1. In vitro, DDX11 removes DNA obstacles ahead of Pol δ in an ATPase- and FeS-domain-dependent manner, generating single-stranded DNA. DDX11 depletion reduces ssDNA levels, chromatin-bound RPA, and impairs CHK1 phosphorylation at serine-345.","method":"In vitro helicase assay with Pol δ, mutagenesis of FeS domain, Co-IP with Pol δ and WDHD1, siRNA depletion, RPA chromatin fractionation, CHK1 phosphorylation assay","journal":"Life science alliance","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with Pol δ obstacle removal, FeS domain mutagenesis, multiple cellular readouts; orthogonal methods linking biochemistry to cell biology","pmids":["32071282"],"is_preprint":false},{"year":2020,"finding":"Timeless harbors a C-terminal G-quadruplex (G4) DNA-binding domain. This domain contributes to processive replication through G4-forming sequences and shows partial redundancy with an adjacent PARP-binding domain. Timeless G4 function requires interaction with and activity of DDX11 helicase. Loss of both Timeless and DDX11 causes epigenetic instability at G4-forming sequences and DNA damage.","method":"G4 DNA binding assay, DNA replication assay through G4 sequences, genetic interaction (co-depletion), epigenetic stability assay, DNA damage assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical G4 binding domain characterization, functional replication assays, genetic interaction between Timeless and DDX11; multiple orthogonal methods, independent corroboration of Tim-DDX11 axis","pmids":["32705708"],"is_preprint":false},{"year":2020,"finding":"The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4-stabilizing compounds. G4-stabilizing compounds induce chromosome breaks and cohesion defects that are strongly aggravated by DDX11 inactivation but not FANCJ inactivation. DDX11 deletion in RPE1-TERT cells inhibits proliferation in a TP53-dependent manner and causes chromosome breaks and cohesion defects independent of DDX12p.","method":"CRISPR knockout in RPE1-TERT cells, helicase domain mutant complementation, G4 stabilizer treatment, chromosome break assay, cohesion assay, FANCJ comparison","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with domain-specific rescue, multiple patient cell lines, comparison with FANCJ; replicated in multiple cell lines and patient-derived cells","pmids":["32855419"],"is_preprint":false},{"year":2020,"finding":"DDX11 loss causes replication stress and sensitizes cancer cells to PARP inhibitors and platinum drugs. DDX11 acts downstream of 53BP1 to mediate homology-directed repair and RAD51 focus formation in a manner nonredundant with BRCA1 and BRCA2. DDX11 facilitates recombination repair by assisting double-strand break resection and loading of RPA and RAD51 onto ssDNA. DDX11 down-regulation aggravates chemotherapeutic sensitivity of BRCA1/2-mutated cancers and resensitizes drug-resistant BRCA1/2-mutated cells.","method":"siRNA/shRNA knockdown, RAD51 and RPA focus formation assay, epistasis with 53BP1 and BRCA1/2, DNA resection assay, PARP inhibitor and cisplatin sensitivity assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with 53BP1/BRCA1/BRCA2, RAD51/RPA loading assays, resection assay, multiple cell lines; orthogonal methods supporting mechanistic placement","pmids":["33879618"],"is_preprint":false},{"year":2021,"finding":"CTF18 and DDX11 act complementarily in sister chromatid cohesion (SCC) and proliferation in DT40 cells. Lethality and cohesion defects of ctf18 ddx11 double mutants are associated with reduced chromatin-bound cohesin and rescued by WAPL depletion (cohesin-removal factor), but not by overexpression of ESCO1/2 acetyltransferases. CTF18 and DDX11 collaborate to maintain sufficient chromatin-loaded cohesin against WAPL-mediated unloading.","method":"DT40 double KO genetic epistasis, cohesin chromatin loading assay, WAPL depletion rescue, ESCO1/2 overexpression rescue, chromosome bridge assay","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple combinations, rescue experiments with WAPL depletion, biochemical cohesin loading assay; mechanistically precise placement of DDX11 in cohesin regulation","pmids":["34503989"],"is_preprint":false},{"year":2020,"finding":"WABS-derived cells with DDX11 mutations show non-redundant roles for ESCO2 (not ESCO1) in residual SCC; reciprocally, Roberts syndrome (ESCO2-mutant) cells depend on DDX11 for residual cohesion. Synthetic lethality of DDX11 and ESCO2 is rescued by WAPL knockdown. A DNA-binding DDX11 mutant fails to correct SCC in WABS cells, and DDX11 deficiency reduces replication fork speed.","method":"Patient-derived cell lines, siRNA combinatorial knockdown, WAPL rescue, DDX11 DNA-binding mutant complementation, DNA fiber assay for fork speed","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient cells with orthogonal siRNA epistasis and mutant complementation; single lab but multiple cell line types","pmids":["31935221"],"is_preprint":false},{"year":2021,"finding":"DDX11 interacts with EZH2 in HCC cells and protects EZH2 from ubiquitination-mediated protein degradation, resulting in downregulation of p21. DDX11 knockdown arrests cells at G1 phase and induces p21 without altering p53. E2F1 is identified as an upstream transcriptional regulator of DDX11, forming a positive feedback loop with EZH2.","method":"Co-IP (DDX11-EZH2), ubiquitination assay, siRNA knockdown, p21/p53 western blot, E2F1 ChIP and luciferase reporter assay, rescue with p21 siRNA","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for DDX11-EZH2 interaction, ubiquitination assay, multiple functional readouts; single lab","pmids":["33614480"],"is_preprint":false},{"year":2011,"finding":"BPV-1 E2 and ChlR1 interact during specific phases of the cell cycle, confirmed by FRET in live synchronized cells. The E2-ChlR1 association occurs during DNA replication rather than during mitotic tethering.","method":"FRET in live synchronized cells, cell cycle synchronization","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET in live cells with cell cycle synchronization establishes timing of interaction; single lab, single method","pmids":["21489590"],"is_preprint":false},{"year":2016,"finding":"ChlR1 regulates the chromatin and nuclear matrix association of HPV16 E2 during S phase. An HPV16 E2 Y131A mutation reduces ChlR1 binding, decreases the chromatin-bound pool of E2, increases nuclear matrix association in mid-S phase, reduces HPV16 episome copy number at establishment, and prevents episome maintenance upon cell passage. ChlR1 silencing phenocopies the E2 Y131A mutation.","method":"Co-IP/binding assay, site-directed mutagenesis (E2 Y131A), subcellular fractionation, cell cycle synchronization, HPV16 life cycle model in primary keratinocytes, siRNA knockdown","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis, fractionation, siRNA knockdown phenocopy, episome maintenance assay in primary keratinocytes; multiple orthogonal methods","pmids":["27795438"],"is_preprint":false},{"year":2013,"finding":"ChlR1 depletion renders human cells sensitive to cisplatin (interstrand crosslink agent causing stalled replication forks), leads to accumulation of DNA damage and delayed resolution, impairs repair of double-strand breaks induced by I-PpoI endonuclease and bleomycin, and causes significant delays in DNA replication recovery after cisplatin treatment.","method":"siRNA depletion, cisplatin/bleomycin sensitivity assay, I-PpoI DSB assay, DNA damage marker (γH2AX) kinetics, DNA replication recovery assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with multiple DNA damage readouts; single lab, no in vitro reconstitution","pmids":["23797032"],"is_preprint":false},{"year":2014,"finding":"DDX11 (FANCM) was identified as a determinant of PARP inhibitor sensitivity; DDX11-deficient lymphoblastoid cell lines derived from Warsaw breakage syndrome patients show strong sensitivity to PARP inhibitors.","method":"PARP inhibitor sensitivity assay in patient-derived DDX11-deficient lymphoblastoid cell lines","journal":"DNA repair","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — patient-derived cell lines with defined phenotypic readout; single assay type, single lab","pmids":["25583207"],"is_preprint":false},{"year":2023,"finding":"DDX11 promotes homologous recombination in hepatocellular carcinoma by facilitating RAD51 recruitment to damaged DNA through the BRCA2-RAD51 interaction. A natural DDX11 Q238H mutation impedes ATM-mediated phosphorylation of DDX11 at serine-237, preventing recruitment of RAD51 to damage sites by disrupting BRCA2-RAD51 interaction. CRISPR knock-in reverting Q238H to wild-type restores HR competence.","method":"Co-IP (DDX11-BRCA2-RAD51), CRISPR/Cas9 knock-in, ATM phosphorylation assay, RAD51 focus formation, PARP inhibitor sensitivity assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, CRISPR knock-in for causal validation, phosphorylation assay, RAD51 focus formation; single lab, multiple methods","pmids":["38007537"],"is_preprint":false},{"year":2024,"finding":"DDX11 acts as a novel co-sensor for cytosolic nucleic acids in innate immunity. DDX11 knockdown/knockout attenuates IFN-β production in response to Sendai virus and poly(I:C). DDX11 operates dependent on RIG-I and MAVS (not STING). DDX11 binds nucleic acids and directly interacts with RIG-I and MAVS, enhancing RIG-I dsRNA binding affinity and RIG-I-MAVS binding affinity. DDX11 promotes TANK-binding kinase 1 and IRF3 activation.","method":"siRNA/CRISPR KO, IFN-β reporter assay, Co-IP (DDX11-RIG-I, DDX11-MAVS), nucleic acid binding assay, STING/RIG-I/MAVS epistasis knockdown","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct interactions, epistasis knockdown, functional IFN-β assay; single lab, novel function with limited replication","pmids":["39470258"],"is_preprint":false},{"year":2025,"finding":"DDX11 has a novel cytoplasmic role in regulating macroautophagy. DDX11 knockout in RPE-1 cells impairs autophagosome biogenesis, reduces LC3 lipidation/conversion, impairs ATG16L1-precursor trafficking and maturation, and reduces clearance of mutant HTT aggregates. DDX11 functionally interacts with SQSTM1 (p62) cargo receptor in supporting LC3 modification during autophagosome biogenesis.","method":"CRISPR KO in RPE-1 cells, mRFP-GFP-LC3 tandem reporter imaging, LC3 western blot, ATG16L1 trafficking assay, HTTQ74-GFP aggregate clearance assay, proximity ligation assay (DDX11-SQSTM1)","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple orthogonal autophagy readouts, PLA for interaction; single lab, novel function","pmids":["40413757"],"is_preprint":false},{"year":2025,"finding":"DDX11 interacts with PARP1 (confirmed by Co-IP from proteomic analysis), and this interaction promotes increased poly(ADP-ribosyl)ation (PARylation), facilitating DNA repair and gemcitabine resistance in gallbladder cancer. DDX11 knockdown inhibits cell proliferation and restores gemcitabine sensitivity.","method":"Proteomic analysis, Co-IP (DDX11-PARP1), PARylation assay, siRNA knockdown, gemcitabine sensitivity assay","journal":"Acta biochimica et biophysica Sinica","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP confirmed interaction, PARylation assay, but limited mechanistic depth; single lab, single study","pmids":["40859772"],"is_preprint":false},{"year":2024,"finding":"CRISPR genome-wide screen in DDX11-deficient cells identified a strong enrichment of sister chromatid cohesion genes as genetic dependencies; synthetic lethal relationships confirmed between DDX11 and cohesin subunit STAG2 and kinase HASPIN.","method":"Genome-wide CRISPR dropout screen in DDX11-WT vs DDX11-deficient cells, confirmation of STAG2 and HASPIN synthetic lethality","journal":"G3 (Bethesda, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide genetic interaction screen with confirmation of specific hits; single lab but genome-scale approach with orthogonal validation","pmids":["38478595"],"is_preprint":false},{"year":2020,"finding":"E2F1 transcriptionally activates DDX11 in hepatocellular carcinoma, as demonstrated by ChIP and luciferase reporter assays. DDX11 overexpression promotes HCC cell proliferation, migration, and invasion through activation of the PI3K/AKT/mTOR signaling pathway.","method":"ChIP for E2F1 at DDX11 promoter, luciferase reporter assay, DDX11 gain/loss-of-function, PI3K/AKT/mTOR pathway analysis","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP and reporter for E2F1-DDX11 transcriptional regulation confirmed, but PI3K/AKT/mTOR pathway activation is indirect downstream inference; single lab","pmids":["32332880"],"is_preprint":false},{"year":2025,"finding":"DDX11 interacts with ATAD5 (confirmed by co-immunoprecipitation and immunofluorescence co-localization in gallbladder cancer cells). ATAD5 silencing attenuates DDX11-mediated oncogenic effects. The DDX11-ATAD5 complex promotes epithelial-mesenchymal transition (EMT) to facilitate GBC invasion and metastasis.","method":"Co-IP, immunofluorescence co-localization, siRNA knockdown of ATAD5, EMT marker analysis, xenograft model","journal":"CytoJournal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — Co-IP confirmed interaction, but mechanistic detail of DDX11-ATAD5 action is limited; single lab, single study","pmids":["41664698"],"is_preprint":false}],"current_model":"DDX11 (ChlR1) is an iron-sulfur cluster-containing 5'-to-3' DNA helicase that unwinds duplex DNA, G-quadruplex structures, DNA triplexes, and D-loops in an ATP-dependent manner; it physically associates with the cohesin complex (Smc1, Smc3, Scc1), the replication fork protection factor Timeless, Ctf18-RFC, PCNA, Fen1, DNA polymerase delta, and WDHD1 to couple DNA replication with sister chromatid cohesion establishment by promoting cohesin loading onto chromatin against WAPL-mediated unloading, while also acting downstream of 53BP1 to facilitate homologous recombination repair via RAD51/RPA loading, and additionally regulates rRNA transcription at rDNA loci, heterochromatin organization, autophagosome biogenesis, and innate immune signaling through RIG-I-MAVS; biallelic loss-of-function mutations cause Warsaw breakage syndrome, characterized by cohesion defects, chromosomal breakage, and developmental anomalies."},"narrative":{"mechanistic_narrative":"DDX11 (ChlR1) is an iron-sulfur cluster-containing, ATP-dependent 5'-to-3' DNA helicase that couples DNA replication to the establishment of sister chromatid cohesion and to the repair of replication-blocking lesions [PMID:18499658, PMID:17105772]. The enzyme requires a 5' single-stranded loading region and unwinds duplex DNA as well as the secondary structures that obstruct forks—G-quadruplexes, D-loops, and DNA triplexes—the latter being a preferred substrate [PMID:18499658, PMID:25561740]. Catalysis depends on an intact Fe-S cluster and on the Q-motif and Fe-S-region residues (Q23, R263), which are needed for DNA binding and DNA-stimulated ATP hydrolysis [PMID:32071282, PMID:26474416, PMID:23033317]. At the replication fork, DDX11 localizes to nascent DNA and acts with Timeless—which binds it directly and stimulates its unwinding up to 10-fold—and with the Ctf18-RFC clamp loader, PCNA, Fen1, and DNA polymerase delta to clear obstacles ahead of the polymerase and generate ssDNA [PMID:30303954, PMID:26503245, PMID:18499658, PMID:32071282]. Through these contacts DDX11 physically engages cohesin (Smc1, Smc3, Scc1) and promotes its loading onto replicating chromatin, collaborating with CTF18 to maintain chromatin-bound cohesin against WAPL-mediated unloading [PMID:17105772, PMID:30303954, PMID:34503989]. In genome maintenance, DDX11 functions downstream of 53BP1 in homologous recombination, assisting end resection and RPA/RAD51 loading nonredundantly with BRCA1/2, such that its loss sensitizes cells to PARP inhibitors and crosslinking agents [PMID:33879618, PMID:30061412, PMID:23797032]. Biallelic loss-of-function mutations in DDX11 cause Warsaw breakage syndrome, a cohesinopathy combining drug-induced chromosomal breakage with sister chromatid cohesion defects [PMID:20137776]. Beyond replication and repair, DDX11 binds active rDNA and supports RNA polymerase I transcription [PMID:26089203], organizes constitutive heterochromatin [PMID:21854770], and has reported roles in autophagosome biogenesis and RIG-I/MAVS innate immune signaling [PMID:40413757, PMID:39470258].","teleology":[{"year":2006,"claim":"Established that human DDX11/ChlR1 is a cohesion factor in mammalian cells, linking it physically to the cohesin complex and answering whether it has a mitotic chromosome-segregation role.","evidence":"RNAi depletion with mitotic phenotyping, immunofluorescence, and Co-IP with cohesin subunits in human cells","pmids":["17105772"],"confidence":"High","gaps":["Did not define the enzymatic activity underlying cohesion","Mechanism of cohesin loading not addressed"]},{"year":2006,"claim":"Identified a host-pathogen use of DDX11, showing papillomavirus E2 hijacks it to tether viral genomes to mitotic chromosomes.","evidence":"Co-IP, E2 W130R mutagenesis, RNAi, and episome maintenance assays","pmids":["17189189"],"confidence":"High","gaps":["Whether E2 tethering reflects a normal DDX11 chromatin function was unclear","Cell-cycle timing of the interaction not defined"]},{"year":2007,"claim":"Demonstrated organismal requirement and the cohesin-loading defect underlying DDX11 loss, showing cohesin binds chromatin more loosely without it.","evidence":"Ddx11 knockout mouse plus siRNA in HeLa with chromosome spreads, FACS, and cohesin chromatin-binding assays","pmids":["17611414"],"confidence":"High","gaps":["Did not establish how DDX11 helicase activity promotes cohesin loading","Coupling to replication not yet shown"]},{"year":2008,"claim":"Reconstituted DDX11 as a 5'-to-3' ATP-dependent helicase and placed it among replication-fork factors, answering its biochemical identity.","evidence":"In vitro ATPase/helicase assays of purified protein with pulldowns against Ctf18-RFC, PCNA, and Fen1","pmids":["18499658"],"confidence":"High","gaps":["Physiological substrates at forks not yet defined","Direct link from helicase activity to cohesion remained inferential"]},{"year":2010,"claim":"Connected DDX11 to human disease, defining Warsaw breakage syndrome at the interface of cohesion and DNA repair.","evidence":"Patient genetics with cytogenetic breakage and cohesion assays","pmids":["20137776"],"confidence":"Medium","gaps":["Single patient","Did not resolve which DDX11 catalytic step is disease-critical"]},{"year":2012,"claim":"Showed a disease mutation (R263Q) acts by impairing DNA binding and DNA-stimulated ATP hydrolysis, pinpointing the Fe-S region as functionally essential.","evidence":"In vitro helicase, ATPase, and DNA-binding assays of recombinant WT vs R263Q","pmids":["23033317"],"confidence":"High","gaps":["Direct role of the Fe-S cluster itself not yet dissected","Structural basis not resolved"]},{"year":2015,"claim":"Defined the Timeless-DDX11 axis and the substrate repertoire (forks, G4, D-loops, triplexes), establishing how DDX11 unwinding is stimulated and which structures it resolves at forks.","evidence":"SPR, in vitro stimulation/EMSA, DNA fiber epistasis, and triplex/G4 helicase assays with the R263Q mutant","pmids":["26503245","25561740"],"confidence":"High","gaps":["In vivo contribution of each substrate class not separately quantified","How Timeless enhances DNA binding mechanistically unresolved"]},{"year":2015,"claim":"Mapped catalytic determinants, showing the Q-motif Q23 governs DNA binding/helicase activity independent of ATP binding and that DDX11 acts as a monomer.","evidence":"Mutagenesis with helicase, ATPase, ATP-binding, thermal shift, and proteolysis assays","pmids":["26474416"],"confidence":"High","gaps":["Full structural model absent","Coupling of ATP binding to unwinding not detailed"]},{"year":2015,"claim":"Extended DDX11 function to rDNA, identifying a nucleolar role supporting Pol I transcription and heterochromatin restriction at rDNA.","evidence":"Immunofluorescence, ChIP, Co-IP with UBF/Pol I, knockdown, and zebrafish morpholino with WABS-mutant analysis","pmids":["26089203"],"confidence":"Medium","gaps":["Whether the helicase acts directly on rDNA structures unresolved","Relationship to its cohesion role unclear"]},{"year":2011,"claim":"Linked DDX11 to chromatin architecture, showing it is required for heterochromatin organization and centromere clustering.","evidence":"siRNA and KO-cell IF, ChIP for HP1α/H3K9me3, bisulfite methylation, and MNase assays","pmids":["21854770"],"confidence":"Medium","gaps":["Mechanistic basis of heterochromatin defects not defined","Single lab"]},{"year":2018,"claim":"Resolved how DDX11 loads cohesin, showing a Timeless-binding motif targets it to nascent DNA where it directly contacts cohesin to promote cohesin association during replication.","evidence":"Co-IP, motif mutagenesis, SIRF/iPOND nascent-DNA localization, and in vitro binding of recombinant cohesin with DDX11","pmids":["30303954"],"confidence":"High","gaps":["Whether cohesin loading requires unwinding catalysis not fully separated","Stoichiometry of the DDX11-cohesin contact unknown"]},{"year":2018,"claim":"Placed DDX11 in postreplicative HR/ICL repair as an FA-pathway backup acting with the 9-1-1 clamp and RAD17.","evidence":"DT40 genetic epistasis, ICL sensitivity, DNA fiber, and Ig diversification assays","pmids":["30061412"],"confidence":"High","gaps":["Direct enzymatic step in HR not defined here","Human relevance shown only indirectly"]},{"year":2020,"claim":"Demonstrated the Fe-S cluster is required for activity and that DDX11 clears obstacles ahead of Pol delta to generate ssDNA needed for checkpoint signaling.","evidence":"In vitro Pol delta obstacle-removal assay, Fe-S mutagenesis, Co-IP with Pol delta/WDHD1, RPA fractionation, and CHK1 phosphorylation","pmids":["32071282"],"confidence":"High","gaps":["Nature of in vivo obstacles not specified","WDHD1 role mechanistically undefined"]},{"year":2020,"claim":"Tied G-quadruplex traversal to the Timeless-DDX11 axis and confirmed the helicase domain is essential for cohesion and G4-stabilizer resistance, distinguishing DDX11 from FANCJ.","evidence":"G4 binding/replication assays, co-depletion genetic interactions, and CRISPR KO with helicase-domain rescue in RPE1-TERT cells","pmids":["32705708","32855419"],"confidence":"High","gaps":["Relative in vivo G4 vs triplex contributions unresolved","TP53-dependence of proliferation defect mechanistically unexplained"]},{"year":2020,"claim":"Positioned DDX11 in homology-directed repair downstream of 53BP1, mediating RPA/RAD51 loading nonredundantly with BRCA1/2 and defining a chemosensitization vulnerability.","evidence":"Knockdown with RAD51/RPA focus and resection assays, epistasis with 53BP1/BRCA1/2, and PARPi/cisplatin sensitivity","pmids":["33879618"],"confidence":"High","gaps":["Direct enzymatic substrate during resection not defined","How DDX11 acts relative to BRCA pathway molecularly unresolved"]},{"year":2020,"claim":"Defined non-redundant ESCO2-DDX11 and WAPL-dependent relationships in residual cohesion in patient cells.","evidence":"Patient-derived cells, combinatorial siRNA with WAPL rescue, DNA-binding mutant complementation, and fiber assays","pmids":["31935221"],"confidence":"Medium","gaps":["Single lab","Mechanistic basis of ESCO2 specificity not resolved"]},{"year":2021,"claim":"Precisely placed DDX11 in cohesin homeostasis, showing it and CTF18 maintain chromatin-bound cohesin against WAPL unloading rather than via ESCO acetyltransferases.","evidence":"DT40 double-KO epistasis with WAPL-depletion and ESCO1/2-overexpression rescue and cohesin loading assays","pmids":["34503989"],"confidence":"High","gaps":["How DDX11 counteracts WAPL biochemically unknown","Direct DDX11 action on cohesin ring not shown"]},{"year":2024,"claim":"Confirmed cohesion machinery as the dominant genetic dependency of DDX11-deficient cells, identifying STAG2 and HASPIN synthetic lethality.","evidence":"Genome-wide CRISPR dropout screen with validation of specific hits","pmids":["38478595"],"confidence":"Medium","gaps":["Mechanism of HASPIN dependency not explained","Therapeutic translation untested"]},{"year":2024,"claim":"Refined the HR role mechanistically, showing ATM phosphorylation of DDX11 at S237 enables RAD51 recruitment via the BRCA2-RAD51 interaction in hepatocellular carcinoma.","evidence":"Co-IP, CRISPR knock-in reversion of Q238H, ATM phosphorylation assay, and RAD51 focus formation","pmids":["38007537"],"confidence":"Medium","gaps":["Single tumor context","How phosphorylation alters DDX11 activity unclear"]},{"year":2024,"claim":"Proposed a cytosolic immune role, identifying DDX11 as a co-sensor enhancing RIG-I dsRNA binding and RIG-I-MAVS signaling.","evidence":"siRNA/CRISPR KO, IFN-β reporter, Co-IP with RIG-I/MAVS, and STING/RIG-I/MAVS epistasis","pmids":["39470258"],"confidence":"Medium","gaps":["Novel function with limited replication","Relationship to nuclear helicase activity unknown"]},{"year":2025,"claim":"Identified a cytoplasmic role in macroautophagy, with DDX11 supporting LC3 lipidation and ATG16L1 trafficking via interaction with SQSTM1.","evidence":"CRISPR KO in RPE-1, tandem LC3 reporter imaging, ATG16L1 trafficking, HTT aggregate clearance, and PLA with SQSTM1","pmids":["40413757"],"confidence":"Medium","gaps":["Whether helicase activity is required for autophagy unknown","Single lab, novel function"]},{"year":null,"claim":"It remains unresolved how a single Fe-S helicase mechanistically partitions among its replication/cohesion, DNA-repair, nucleolar, heterochromatin, autophagy, and innate-immune roles, and whether the non-genomic functions depend on its catalytic activity.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of DDX11 reported in the corpus","Catalytic requirement for autophagy and immune signaling untested","Regulation directing DDX11 between nuclear and cytoplasmic roles unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[1,7,13]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,8,13]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,8,13]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,13]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[25]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,11]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[25,26]}],"pathway":[{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[1,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3,17]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[25]}],"complexes":["cohesin"],"partners":["TIMELESS","FEN1","PCNA","WDHD1","RIG-I","MAVS","EZH2","PARP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96FC9","full_name":"ATP-dependent DNA helicase DDX11","aliases":["CHL1-related protein 1","hCHLR1","DEAD/H-box protein 11","DNA 5'-3' helicase DDX11","Keratinocyte growth factor-regulated gene 2 protein","KRG-2"],"length_aa":970,"mass_kda":108.3,"function":"DNA-dependent ATPase and ATP-dependent DNA helicase that participates in various functions in genomic stability, including DNA replication, DNA repair and heterochromatin organization as well as in ribosomal RNA synthesis (PubMed:10648783, PubMed:21854770, PubMed:23797032, PubMed:26089203, PubMed:26503245). Its double-stranded DNA helicase activity requires either a minimal 5'-single-stranded tail length of approximately 15 nt (flap substrates) or 10 nt length single-stranded gapped DNA substrates of a partial duplex DNA structure for helicase loading and translocation along DNA in a 5' to 3' direction (PubMed:10648783, PubMed:18499658, PubMed:22102414). The helicase activity is capable of displacing duplex regions up to 100 bp, which can be extended up to 500 bp by the replication protein A (RPA) or the cohesion CTF18-replication factor C (Ctf18-RFC) complex activities (PubMed:18499658). Also shows ATPase- and helicase activities on substrates that mimic key DNA intermediates of replication, repair and homologous recombination reactions, including forked duplex, anti-parallel G-quadruplex and three-stranded D-loop DNA molecules (PubMed:22102414, PubMed:26503245). Plays a role in DNA double-strand break (DSB) repair at the DNA replication fork during DNA replication recovery from DNA damage (PubMed:23797032). Recruited with TIMELESS factor upon DNA-replication stress response at DNA replication fork to preserve replication fork progression, and hence ensure DNA replication fidelity (PubMed:26503245). Also cooperates with TIMELESS factor during DNA replication to regulate proper sister chromatid cohesion and mitotic chromosome segregation (PubMed:17105772, PubMed:18499658, PubMed:20124417, PubMed:23116066, PubMed:23797032). Stimulates 5'-single-stranded DNA flap endonuclease activity of FEN1 in an ATP- and helicase-independent manner; and hence it may contribute in Okazaki fragment processing at DNA replication fork during lagging strand DNA synthesis (PubMed:18499658). Its ability to function at DNA replication fork is modulated by its binding to long non-coding RNA (lncRNA) cohesion regulator non-coding RNA DDX11-AS1/CONCR, which is able to increase both DDX11 ATPase activity and binding to DNA replicating regions (PubMed:27477908). Also plays a role in heterochromatin organization (PubMed:21854770). Involved in rRNA transcription activation through binding to active hypomethylated rDNA gene loci by recruiting UBTF and the RNA polymerase Pol I transcriptional machinery (PubMed:26089203). Plays a role in embryonic development and prevention of aneuploidy (By similarity). Involved in melanoma cell proliferation and survival (PubMed:23116066). Associates with chromatin at DNA replication fork regions (PubMed:27477908). Binds to single- and double-stranded DNAs (PubMed:18499658, PubMed:22102414, PubMed:9013641) (Microbial infection) Required for bovine papillomavirus type 1 regulatory protein E2 loading onto mitotic chromosomes during DNA replication for the viral genome to be maintained and segregated","subcellular_location":"Chromosome","url":"https://www.uniprot.org/uniprotkb/Q96FC9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/DDX11","classification":"Common Essential","n_dependent_lines":1081,"n_total_lines":1208,"dependency_fraction":0.8948675496688742},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DDX11","total_profiled":1310},"omim":[{"mim_id":"613398","title":"WARSAW BREAKAGE SYNDROME; WABS","url":"https://www.omim.org/entry/613398"},{"mim_id":"609113","title":"TELOMERE LENGTH, MEAN LEUKOCYTE; LTL","url":"https://www.omim.org/entry/609113"},{"mim_id":"601150","title":"DEAD/H-BOX HELICASE 11; DDX11","url":"https://www.omim.org/entry/601150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/DDX11"},"hgnc":{"alias_symbol":["ChlR1","KRG-2","CHL1","WABS"],"prev_symbol":[]},"alphafold":{"accession":"Q96FC9","domains":[{"cath_id":"1.10.275.40","chopping":"410-519_560-603","consensus_level":"high","plddt":87.1852,"start":410,"end":603},{"cath_id":"3.40.50,3.40.50","chopping":"656-797","consensus_level":"high","plddt":87.7789,"start":656,"end":797}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FC9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FC9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96FC9-F1-predicted_aligned_error_v6.png","plddt_mean":71.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DDX11","jax_strain_url":"https://www.jax.org/strain/search?query=DDX11"},"sequence":{"accession":"Q96FC9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96FC9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96FC9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96FC9"}},"corpus_meta":[{"pmid":"20137776","id":"PMC_20137776","title":"Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20137776","citation_count":166,"is_preprint":false},{"pmid":"17105772","id":"PMC_17105772","title":"The DNA helicase ChlR1 is required for sister chromatid cohesion in mammalian cells.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17105772","citation_count":93,"is_preprint":false},{"pmid":"18499658","id":"PMC_18499658","title":"Studies with the human cohesin establishment factor, ChlR1. 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ChlR1 diffusely coats mitotic chromatin in prophase then translocates to spindle poles at metaphase. RNAi depletion causes mitotic failure, pro-metaphase arrest, and increased centromeric chromatid separation. ChlR1 co-immunoprecipitates with cohesin subunits Scc1, Smc1, and Smc3.\",\n      \"method\": \"RNAi knockdown, immunofluorescence localization, Co-IP with cohesin subunits, chromosome spread analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with multiple cohesin subunits, RNAi with defined cellular phenotype, localization studies; replicated across multiple subsequent studies\",\n      \"pmids\": [\"17105772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Purified human ChlR1 possesses DNA-dependent ATPase and 5'-to-3' helicase activities, requires a 5' single-stranded region for loading, and can unwind duplexes up to 100 bp (extended to 500 bp by RPA or Ctf18-RFC). ChlR1 physically interacts with the Ctf18-RFC complex, PCNA, and Fen1; the ChlR1-Fen1 interaction stimulates Fen1 flap endonuclease activity. Depletion of either ChlR1 or Fen1 by siRNA causes precocious sister chromatid separation.\",\n      \"method\": \"Purification from 293 cells, in vitro ATPase and helicase assays, Co-IP/pulldown with Ctf18-RFC/PCNA/Fen1, siRNA knockdown with chromatid cohesion readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution of helicase activity, multiple binding partners confirmed by pulldown/Co-IP, functional validation by siRNA; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"18499658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Papillomavirus E2 protein binds ChlR1 (DDX11), and this interaction is required for loading E2 onto mitotic chromosomes. An E2 W130R mutation abolishes ChlR1 binding and correspondingly prevents E2 association with mitotic chromosomes; viral genomes encoding W130R are not episomally maintained. RNAi depletion of ChlR1 significantly reduces E2 localization to mitotic chromosomes.\",\n      \"method\": \"Co-IP, site-directed mutagenesis of E2 (W130R), RNAi knockdown, immunofluorescence localization, episome maintenance assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — binding confirmed by Co-IP, mutagenesis establishes required residue, RNAi phenocopies mutation, functional consequence (episome loss) measured; multiple orthogonal methods\",\n      \"pmids\": [\"17189189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of mouse Ddx11 causes embryonic lethality at E10.5 with placental malformation, G2/M cell cycle delay, increased chromosome missegregation, decreased sister chromatid cohesion at centromeres and arms, and increased aneuploidy. ChlR1 is required for proper cohesin complex binding to both centromere and chromosome arms; cohesin binds more loosely to chromatin in ChlR1-depleted cells.\",\n      \"method\": \"Ddx11 knockout mouse, siRNA depletion in HeLa cells, chromosome spreads, FACS cell cycle analysis, immunofluorescence, cohesin chromatin binding assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout phenotype in mouse confirmed by siRNA in cell lines, multiple cellular readouts (cohesion, segregation, aneuploidy, cohesin loading); replicated by other labs\",\n      \"pmids\": [\"17611414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Biallelic loss-of-function mutations in DDX11 cause Warsaw breakage syndrome, a cohesinopathy with features of both Fanconi anemia (drug-induced chromosomal breakage) and Roberts syndrome (sister chromatid cohesion defects), establishing DDX11 functions at the interface of DNA repair and sister chromatid cohesion.\",\n      \"method\": \"Patient genetic analysis, cytogenetic analysis (MMC-induced breakage, sister chromatid cohesion assay)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics with cellular phenotypic validation; single patient but cellular phenotype is diagnostic and consistent with molecular function established by other studies\",\n      \"pmids\": [\"20137776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A homozygous p.R263Q mutation in DDX11 impairs helicase activity by perturbing DNA binding and DNA-dependent ATP hydrolysis, while leaving overall protein structure intact, confirming the functional importance of the Fe-S domain region for DDX11 enzymatic activity.\",\n      \"method\": \"Purification of recombinant wild-type and p.R263Q DDX11, in vitro helicase assay, ATPase assay, DNA binding assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with disease-relevant mutant, multiple enzymatic readouts (helicase, ATPase, DNA binding); single lab but orthogonal methods\",\n      \"pmids\": [\"23033317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tim (Timeless) physically interacts with DDX11 (confirmed by surface plasmon resonance), stimulates DDX11 unwinding activity up to 10-fold on forked DNA and 4-5-fold on G-quadruplex and D-loop substrates by enhancing DDX11 DNA binding. Tim and DDX11 are epistatic for replication fork progression and fork restart after hydroxyurea treatment; their chromatin association increases after hydroxyurea exposure.\",\n      \"method\": \"Surface plasmon resonance, in vitro helicase stimulation assay, EMSA, DNA fiber assay, siRNA co-depletion epistasis, chromatin fractionation Co-IP\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding confirmed by SPR, in vitro stimulation assay, genetic epistasis by fiber assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"26503245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DDX11/ChlR1 efficiently unwinds both intermolecular and intramolecular DNA triplex substrates in an ATP-dependent manner; triplex DNA is a preferred substrate compared to replication fork and G-quadruplex DNA. The WABS patient mutant (R263Q) fails to unwind triplexes. ChlR1-depleted cells show increased triplex DNA content and double-strand breaks upon treatment with a triplex-stabilizing compound, while FANCJ-deficient cells do not.\",\n      \"method\": \"In vitro helicase assay with triplex substrates, recombinant protein purification, siRNA depletion, immunofluorescence for triplex content and DSBs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with disease mutant and WT, cellular validation by siRNA; multiple orthogonal methods\",\n      \"pmids\": [\"25561740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The Q motif glutamine (Q23) of ChlR1 is required for DNA binding and helicase activity but not ATP binding; Q23A mutant shows impaired ATPase activity and reduced DNA binding while retaining normal ATP binding and similar overall structure. ChlR1 functions as a monomer in solution.\",\n      \"method\": \"Site-directed mutagenesis, purification of recombinant ChlR1 from HEK293T, in vitro helicase assay, ATPase assay, ATP binding assay, thermal shift assay, partial proteolysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis, multiple orthogonal biochemical assays; single lab\",\n      \"pmids\": [\"26474416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DDX11 is a nucleolar protein that binds hypomethylated active rDNA gene loci, where it interacts with upstream binding factor (UBF) and RNA polymerase I. DDX11 knockdown increases heterochromatin at rDNA loci, reduces UBF activity and recruitment of UBF and RPA194 to rDNA promoters, suppresses rRNA transcription, and inhibits cell growth. WABS-derived mutants (R263Q, K897del) and Fe-S deletion show reduced rDNA promoter binding and ATPase activity.\",\n      \"method\": \"Immunofluorescence, ChIP, Co-IP with UBF and Pol I, siRNA knockdown, rRNA transcription assay, recombinant mutant protein analysis, zebrafish morpholino knockdown\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, functional knockdown in cells and zebrafish, mutant analysis; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26089203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ChlR1 (DDX11) is required for proper heterochromatin organization; ChlR1-depleted cells show dispersed localization of constitutive heterochromatin, disrupted centromere clustering, decreased HP1α at pericentric regions (by IF and ChIP), modest reduction of H3K9-me3, decreased DNA methylation at major satellite repeats, and decreased chromatin density at telomeres (by MNase assay).\",\n      \"method\": \"siRNA knockdown in HeLa cells, Ddx11-/- mouse embryo cells, immunofluorescence, ChIP for HP1α and H3K9-me3, bisulfite DNA methylation analysis, MNase assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (IF, ChIP, bisulfite, MNase), confirmed in two model systems (siRNA and KO cells); single lab\",\n      \"pmids\": [\"21854770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DDX11 interacts with Timeless through a conserved peptide motif; this interaction is critical for sister chromatid cohesion in interphase and mitosis. DDX11 localizes at nascent DNA (SIRF analysis). DDX11 promotes cohesin binding to DNA replication forks in concert with Timeless. Purified recombinant cohesin directly interacts with DDX11 in vitro. Loss of DDX11-Timeless interaction impairs cohesin association with chromatin.\",\n      \"method\": \"Co-IP, peptide motif mutagenesis, immunofluorescence, SIRF assay (nascent DNA localization), iPOND, in vitro binding of recombinant cohesin with DDX11\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of DDX11-cohesin interaction, SIRF for nascent DNA localization, Co-IP, mutagenesis of interaction motif with functional cohesion readout; multiple orthogonal methods\",\n      \"pmids\": [\"30303954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In avian DT40 cells, DDX11 functions as a backup for the FA pathway in interstrand crosslink repair. DDX11 acts jointly with the 9-1-1 checkpoint clamp and its loader RAD17 in a postreplicative fashion to promote homologous recombination repair of bulky lesions. DDX11 also facilitates diversification of the chicken Ig-variable gene (hypermutation and gene conversion), processes triggered by programmed abasic sites. DDX11 is not required for intra-S checkpoint activation or efficient fork progression.\",\n      \"method\": \"DT40 genetic knockout, epistasis analysis with 9-1-1/RAD17 mutants, ICL sensitivity assays, DNA fiber assay, Ig gene diversification assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in DT40 system with multiple mutant combinations, multiple functional readouts; rigorous genetic approach\",\n      \"pmids\": [\"30061412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The iron-sulfur (FeS) cluster in DDX11 is required for DNA binding, ATP hydrolysis, and DNA helicase activity; arginine-263 in the FeS cluster-binding motif affects FeS cluster binding via its positive charge. DDX11 interacts with DNA polymerase delta and WDHD1. In vitro, DDX11 removes DNA obstacles ahead of Pol δ in an ATPase- and FeS-domain-dependent manner, generating single-stranded DNA. DDX11 depletion reduces ssDNA levels, chromatin-bound RPA, and impairs CHK1 phosphorylation at serine-345.\",\n      \"method\": \"In vitro helicase assay with Pol δ, mutagenesis of FeS domain, Co-IP with Pol δ and WDHD1, siRNA depletion, RPA chromatin fractionation, CHK1 phosphorylation assay\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with Pol δ obstacle removal, FeS domain mutagenesis, multiple cellular readouts; orthogonal methods linking biochemistry to cell biology\",\n      \"pmids\": [\"32071282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Timeless harbors a C-terminal G-quadruplex (G4) DNA-binding domain. This domain contributes to processive replication through G4-forming sequences and shows partial redundancy with an adjacent PARP-binding domain. Timeless G4 function requires interaction with and activity of DDX11 helicase. Loss of both Timeless and DDX11 causes epigenetic instability at G4-forming sequences and DNA damage.\",\n      \"method\": \"G4 DNA binding assay, DNA replication assay through G4 sequences, genetic interaction (co-depletion), epigenetic stability assay, DNA damage assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical G4 binding domain characterization, functional replication assays, genetic interaction between Timeless and DDX11; multiple orthogonal methods, independent corroboration of Tim-DDX11 axis\",\n      \"pmids\": [\"32705708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4-stabilizing compounds. G4-stabilizing compounds induce chromosome breaks and cohesion defects that are strongly aggravated by DDX11 inactivation but not FANCJ inactivation. DDX11 deletion in RPE1-TERT cells inhibits proliferation in a TP53-dependent manner and causes chromosome breaks and cohesion defects independent of DDX12p.\",\n      \"method\": \"CRISPR knockout in RPE1-TERT cells, helicase domain mutant complementation, G4 stabilizer treatment, chromosome break assay, cohesion assay, FANCJ comparison\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with domain-specific rescue, multiple patient cell lines, comparison with FANCJ; replicated in multiple cell lines and patient-derived cells\",\n      \"pmids\": [\"32855419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DDX11 loss causes replication stress and sensitizes cancer cells to PARP inhibitors and platinum drugs. DDX11 acts downstream of 53BP1 to mediate homology-directed repair and RAD51 focus formation in a manner nonredundant with BRCA1 and BRCA2. DDX11 facilitates recombination repair by assisting double-strand break resection and loading of RPA and RAD51 onto ssDNA. DDX11 down-regulation aggravates chemotherapeutic sensitivity of BRCA1/2-mutated cancers and resensitizes drug-resistant BRCA1/2-mutated cells.\",\n      \"method\": \"siRNA/shRNA knockdown, RAD51 and RPA focus formation assay, epistasis with 53BP1 and BRCA1/2, DNA resection assay, PARP inhibitor and cisplatin sensitivity assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with 53BP1/BRCA1/BRCA2, RAD51/RPA loading assays, resection assay, multiple cell lines; orthogonal methods supporting mechanistic placement\",\n      \"pmids\": [\"33879618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTF18 and DDX11 act complementarily in sister chromatid cohesion (SCC) and proliferation in DT40 cells. Lethality and cohesion defects of ctf18 ddx11 double mutants are associated with reduced chromatin-bound cohesin and rescued by WAPL depletion (cohesin-removal factor), but not by overexpression of ESCO1/2 acetyltransferases. CTF18 and DDX11 collaborate to maintain sufficient chromatin-loaded cohesin against WAPL-mediated unloading.\",\n      \"method\": \"DT40 double KO genetic epistasis, cohesin chromatin loading assay, WAPL depletion rescue, ESCO1/2 overexpression rescue, chromosome bridge assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple combinations, rescue experiments with WAPL depletion, biochemical cohesin loading assay; mechanistically precise placement of DDX11 in cohesin regulation\",\n      \"pmids\": [\"34503989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WABS-derived cells with DDX11 mutations show non-redundant roles for ESCO2 (not ESCO1) in residual SCC; reciprocally, Roberts syndrome (ESCO2-mutant) cells depend on DDX11 for residual cohesion. Synthetic lethality of DDX11 and ESCO2 is rescued by WAPL knockdown. A DNA-binding DDX11 mutant fails to correct SCC in WABS cells, and DDX11 deficiency reduces replication fork speed.\",\n      \"method\": \"Patient-derived cell lines, siRNA combinatorial knockdown, WAPL rescue, DDX11 DNA-binding mutant complementation, DNA fiber assay for fork speed\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient cells with orthogonal siRNA epistasis and mutant complementation; single lab but multiple cell line types\",\n      \"pmids\": [\"31935221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DDX11 interacts with EZH2 in HCC cells and protects EZH2 from ubiquitination-mediated protein degradation, resulting in downregulation of p21. DDX11 knockdown arrests cells at G1 phase and induces p21 without altering p53. E2F1 is identified as an upstream transcriptional regulator of DDX11, forming a positive feedback loop with EZH2.\",\n      \"method\": \"Co-IP (DDX11-EZH2), ubiquitination assay, siRNA knockdown, p21/p53 western blot, E2F1 ChIP and luciferase reporter assay, rescue with p21 siRNA\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for DDX11-EZH2 interaction, ubiquitination assay, multiple functional readouts; single lab\",\n      \"pmids\": [\"33614480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"BPV-1 E2 and ChlR1 interact during specific phases of the cell cycle, confirmed by FRET in live synchronized cells. The E2-ChlR1 association occurs during DNA replication rather than during mitotic tethering.\",\n      \"method\": \"FRET in live synchronized cells, cell cycle synchronization\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET in live cells with cell cycle synchronization establishes timing of interaction; single lab, single method\",\n      \"pmids\": [\"21489590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ChlR1 regulates the chromatin and nuclear matrix association of HPV16 E2 during S phase. An HPV16 E2 Y131A mutation reduces ChlR1 binding, decreases the chromatin-bound pool of E2, increases nuclear matrix association in mid-S phase, reduces HPV16 episome copy number at establishment, and prevents episome maintenance upon cell passage. ChlR1 silencing phenocopies the E2 Y131A mutation.\",\n      \"method\": \"Co-IP/binding assay, site-directed mutagenesis (E2 Y131A), subcellular fractionation, cell cycle synchronization, HPV16 life cycle model in primary keratinocytes, siRNA knockdown\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis, fractionation, siRNA knockdown phenocopy, episome maintenance assay in primary keratinocytes; multiple orthogonal methods\",\n      \"pmids\": [\"27795438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ChlR1 depletion renders human cells sensitive to cisplatin (interstrand crosslink agent causing stalled replication forks), leads to accumulation of DNA damage and delayed resolution, impairs repair of double-strand breaks induced by I-PpoI endonuclease and bleomycin, and causes significant delays in DNA replication recovery after cisplatin treatment.\",\n      \"method\": \"siRNA depletion, cisplatin/bleomycin sensitivity assay, I-PpoI DSB assay, DNA damage marker (γH2AX) kinetics, DNA replication recovery assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with multiple DNA damage readouts; single lab, no in vitro reconstitution\",\n      \"pmids\": [\"23797032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DDX11 (FANCM) was identified as a determinant of PARP inhibitor sensitivity; DDX11-deficient lymphoblastoid cell lines derived from Warsaw breakage syndrome patients show strong sensitivity to PARP inhibitors.\",\n      \"method\": \"PARP inhibitor sensitivity assay in patient-derived DDX11-deficient lymphoblastoid cell lines\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — patient-derived cell lines with defined phenotypic readout; single assay type, single lab\",\n      \"pmids\": [\"25583207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DDX11 promotes homologous recombination in hepatocellular carcinoma by facilitating RAD51 recruitment to damaged DNA through the BRCA2-RAD51 interaction. A natural DDX11 Q238H mutation impedes ATM-mediated phosphorylation of DDX11 at serine-237, preventing recruitment of RAD51 to damage sites by disrupting BRCA2-RAD51 interaction. CRISPR knock-in reverting Q238H to wild-type restores HR competence.\",\n      \"method\": \"Co-IP (DDX11-BRCA2-RAD51), CRISPR/Cas9 knock-in, ATM phosphorylation assay, RAD51 focus formation, PARP inhibitor sensitivity assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, CRISPR knock-in for causal validation, phosphorylation assay, RAD51 focus formation; single lab, multiple methods\",\n      \"pmids\": [\"38007537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DDX11 acts as a novel co-sensor for cytosolic nucleic acids in innate immunity. DDX11 knockdown/knockout attenuates IFN-β production in response to Sendai virus and poly(I:C). DDX11 operates dependent on RIG-I and MAVS (not STING). DDX11 binds nucleic acids and directly interacts with RIG-I and MAVS, enhancing RIG-I dsRNA binding affinity and RIG-I-MAVS binding affinity. DDX11 promotes TANK-binding kinase 1 and IRF3 activation.\",\n      \"method\": \"siRNA/CRISPR KO, IFN-β reporter assay, Co-IP (DDX11-RIG-I, DDX11-MAVS), nucleic acid binding assay, STING/RIG-I/MAVS epistasis knockdown\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct interactions, epistasis knockdown, functional IFN-β assay; single lab, novel function with limited replication\",\n      \"pmids\": [\"39470258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX11 has a novel cytoplasmic role in regulating macroautophagy. DDX11 knockout in RPE-1 cells impairs autophagosome biogenesis, reduces LC3 lipidation/conversion, impairs ATG16L1-precursor trafficking and maturation, and reduces clearance of mutant HTT aggregates. DDX11 functionally interacts with SQSTM1 (p62) cargo receptor in supporting LC3 modification during autophagosome biogenesis.\",\n      \"method\": \"CRISPR KO in RPE-1 cells, mRFP-GFP-LC3 tandem reporter imaging, LC3 western blot, ATG16L1 trafficking assay, HTTQ74-GFP aggregate clearance assay, proximity ligation assay (DDX11-SQSTM1)\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple orthogonal autophagy readouts, PLA for interaction; single lab, novel function\",\n      \"pmids\": [\"40413757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX11 interacts with PARP1 (confirmed by Co-IP from proteomic analysis), and this interaction promotes increased poly(ADP-ribosyl)ation (PARylation), facilitating DNA repair and gemcitabine resistance in gallbladder cancer. DDX11 knockdown inhibits cell proliferation and restores gemcitabine sensitivity.\",\n      \"method\": \"Proteomic analysis, Co-IP (DDX11-PARP1), PARylation assay, siRNA knockdown, gemcitabine sensitivity assay\",\n      \"journal\": \"Acta biochimica et biophysica Sinica\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP confirmed interaction, PARylation assay, but limited mechanistic depth; single lab, single study\",\n      \"pmids\": [\"40859772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRISPR genome-wide screen in DDX11-deficient cells identified a strong enrichment of sister chromatid cohesion genes as genetic dependencies; synthetic lethal relationships confirmed between DDX11 and cohesin subunit STAG2 and kinase HASPIN.\",\n      \"method\": \"Genome-wide CRISPR dropout screen in DDX11-WT vs DDX11-deficient cells, confirmation of STAG2 and HASPIN synthetic lethality\",\n      \"journal\": \"G3 (Bethesda, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide genetic interaction screen with confirmation of specific hits; single lab but genome-scale approach with orthogonal validation\",\n      \"pmids\": [\"38478595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"E2F1 transcriptionally activates DDX11 in hepatocellular carcinoma, as demonstrated by ChIP and luciferase reporter assays. DDX11 overexpression promotes HCC cell proliferation, migration, and invasion through activation of the PI3K/AKT/mTOR signaling pathway.\",\n      \"method\": \"ChIP for E2F1 at DDX11 promoter, luciferase reporter assay, DDX11 gain/loss-of-function, PI3K/AKT/mTOR pathway analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP and reporter for E2F1-DDX11 transcriptional regulation confirmed, but PI3K/AKT/mTOR pathway activation is indirect downstream inference; single lab\",\n      \"pmids\": [\"32332880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DDX11 interacts with ATAD5 (confirmed by co-immunoprecipitation and immunofluorescence co-localization in gallbladder cancer cells). ATAD5 silencing attenuates DDX11-mediated oncogenic effects. The DDX11-ATAD5 complex promotes epithelial-mesenchymal transition (EMT) to facilitate GBC invasion and metastasis.\",\n      \"method\": \"Co-IP, immunofluorescence co-localization, siRNA knockdown of ATAD5, EMT marker analysis, xenograft model\",\n      \"journal\": \"CytoJournal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — Co-IP confirmed interaction, but mechanistic detail of DDX11-ATAD5 action is limited; single lab, single study\",\n      \"pmids\": [\"41664698\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DDX11 (ChlR1) is an iron-sulfur cluster-containing 5'-to-3' DNA helicase that unwinds duplex DNA, G-quadruplex structures, DNA triplexes, and D-loops in an ATP-dependent manner; it physically associates with the cohesin complex (Smc1, Smc3, Scc1), the replication fork protection factor Timeless, Ctf18-RFC, PCNA, Fen1, DNA polymerase delta, and WDHD1 to couple DNA replication with sister chromatid cohesion establishment by promoting cohesin loading onto chromatin against WAPL-mediated unloading, while also acting downstream of 53BP1 to facilitate homologous recombination repair via RAD51/RPA loading, and additionally regulates rRNA transcription at rDNA loci, heterochromatin organization, autophagosome biogenesis, and innate immune signaling through RIG-I-MAVS; biallelic loss-of-function mutations cause Warsaw breakage syndrome, characterized by cohesion defects, chromosomal breakage, and developmental anomalies.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DDX11 (ChlR1) is an iron-sulfur cluster-containing, ATP-dependent 5'-to-3' DNA helicase that couples DNA replication to the establishment of sister chromatid cohesion and to the repair of replication-blocking lesions [#1, #0]. The enzyme requires a 5' single-stranded loading region and unwinds duplex DNA as well as the secondary structures that obstruct forks—G-quadruplexes, D-loops, and DNA triplexes—the latter being a preferred substrate [#1, #7]. Catalysis depends on an intact Fe-S cluster and on the Q-motif and Fe-S-region residues (Q23, R263), which are needed for DNA binding and DNA-stimulated ATP hydrolysis [#13, #8, #5]. At the replication fork, DDX11 localizes to nascent DNA and acts with Timeless—which binds it directly and stimulates its unwinding up to 10-fold—and with the Ctf18-RFC clamp loader, PCNA, Fen1, and DNA polymerase delta to clear obstacles ahead of the polymerase and generate ssDNA [#11, #6, #1, #13]. Through these contacts DDX11 physically engages cohesin (Smc1, Smc3, Scc1) and promotes its loading onto replicating chromatin, collaborating with CTF18 to maintain chromatin-bound cohesin against WAPL-mediated unloading [#0, #11, #17]. In genome maintenance, DDX11 functions downstream of 53BP1 in homologous recombination, assisting end resection and RPA/RAD51 loading nonredundantly with BRCA1/2, such that its loss sensitizes cells to PARP inhibitors and crosslinking agents [#16, #12, #22]. Biallelic loss-of-function mutations in DDX11 cause Warsaw breakage syndrome, a cohesinopathy combining drug-induced chromosomal breakage with sister chromatid cohesion defects [#4]. Beyond replication and repair, DDX11 binds active rDNA and supports RNA polymerase I transcription [#9], organizes constitutive heterochromatin [#10], and has reported roles in autophagosome biogenesis and RIG-I/MAVS innate immune signaling [#26, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that human DDX11/ChlR1 is a cohesion factor in mammalian cells, linking it physically to the cohesin complex and answering whether it has a mitotic chromosome-segregation role.\",\n      \"evidence\": \"RNAi depletion with mitotic phenotyping, immunofluorescence, and Co-IP with cohesin subunits in human cells\",\n      \"pmids\": [\"17105772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the enzymatic activity underlying cohesion\", \"Mechanism of cohesin loading not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified a host-pathogen use of DDX11, showing papillomavirus E2 hijacks it to tether viral genomes to mitotic chromosomes.\",\n      \"evidence\": \"Co-IP, E2 W130R mutagenesis, RNAi, and episome maintenance assays\",\n      \"pmids\": [\"17189189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether E2 tethering reflects a normal DDX11 chromatin function was unclear\", \"Cell-cycle timing of the interaction not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated organismal requirement and the cohesin-loading defect underlying DDX11 loss, showing cohesin binds chromatin more loosely without it.\",\n      \"evidence\": \"Ddx11 knockout mouse plus siRNA in HeLa with chromosome spreads, FACS, and cohesin chromatin-binding assays\",\n      \"pmids\": [\"17611414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how DDX11 helicase activity promotes cohesin loading\", \"Coupling to replication not yet shown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Reconstituted DDX11 as a 5'-to-3' ATP-dependent helicase and placed it among replication-fork factors, answering its biochemical identity.\",\n      \"evidence\": \"In vitro ATPase/helicase assays of purified protein with pulldowns against Ctf18-RFC, PCNA, and Fen1\",\n      \"pmids\": [\"18499658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates at forks not yet defined\", \"Direct link from helicase activity to cohesion remained inferential\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected DDX11 to human disease, defining Warsaw breakage syndrome at the interface of cohesion and DNA repair.\",\n      \"evidence\": \"Patient genetics with cytogenetic breakage and cohesion assays\",\n      \"pmids\": [\"20137776\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient\", \"Did not resolve which DDX11 catalytic step is disease-critical\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed a disease mutation (R263Q) acts by impairing DNA binding and DNA-stimulated ATP hydrolysis, pinpointing the Fe-S region as functionally essential.\",\n      \"evidence\": \"In vitro helicase, ATPase, and DNA-binding assays of recombinant WT vs R263Q\",\n      \"pmids\": [\"23033317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct role of the Fe-S cluster itself not yet dissected\", \"Structural basis not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the Timeless-DDX11 axis and the substrate repertoire (forks, G4, D-loops, triplexes), establishing how DDX11 unwinding is stimulated and which structures it resolves at forks.\",\n      \"evidence\": \"SPR, in vitro stimulation/EMSA, DNA fiber epistasis, and triplex/G4 helicase assays with the R263Q mutant\",\n      \"pmids\": [\"26503245\", \"25561740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of each substrate class not separately quantified\", \"How Timeless enhances DNA binding mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped catalytic determinants, showing the Q-motif Q23 governs DNA binding/helicase activity independent of ATP binding and that DDX11 acts as a monomer.\",\n      \"evidence\": \"Mutagenesis with helicase, ATPase, ATP-binding, thermal shift, and proteolysis assays\",\n      \"pmids\": [\"26474416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full structural model absent\", \"Coupling of ATP binding to unwinding not detailed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended DDX11 function to rDNA, identifying a nucleolar role supporting Pol I transcription and heterochromatin restriction at rDNA.\",\n      \"evidence\": \"Immunofluorescence, ChIP, Co-IP with UBF/Pol I, knockdown, and zebrafish morpholino with WABS-mutant analysis\",\n      \"pmids\": [\"26089203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the helicase acts directly on rDNA structures unresolved\", \"Relationship to its cohesion role unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked DDX11 to chromatin architecture, showing it is required for heterochromatin organization and centromere clustering.\",\n      \"evidence\": \"siRNA and KO-cell IF, ChIP for HP1\\u03b1/H3K9me3, bisulfite methylation, and MNase assays\",\n      \"pmids\": [\"21854770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of heterochromatin defects not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved how DDX11 loads cohesin, showing a Timeless-binding motif targets it to nascent DNA where it directly contacts cohesin to promote cohesin association during replication.\",\n      \"evidence\": \"Co-IP, motif mutagenesis, SIRF/iPOND nascent-DNA localization, and in vitro binding of recombinant cohesin with DDX11\",\n      \"pmids\": [\"30303954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cohesin loading requires unwinding catalysis not fully separated\", \"Stoichiometry of the DDX11-cohesin contact unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed DDX11 in postreplicative HR/ICL repair as an FA-pathway backup acting with the 9-1-1 clamp and RAD17.\",\n      \"evidence\": \"DT40 genetic epistasis, ICL sensitivity, DNA fiber, and Ig diversification assays\",\n      \"pmids\": [\"30061412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic step in HR not defined here\", \"Human relevance shown only indirectly\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated the Fe-S cluster is required for activity and that DDX11 clears obstacles ahead of Pol delta to generate ssDNA needed for checkpoint signaling.\",\n      \"evidence\": \"In vitro Pol delta obstacle-removal assay, Fe-S mutagenesis, Co-IP with Pol delta/WDHD1, RPA fractionation, and CHK1 phosphorylation\",\n      \"pmids\": [\"32071282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nature of in vivo obstacles not specified\", \"WDHD1 role mechanistically undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Tied G-quadruplex traversal to the Timeless-DDX11 axis and confirmed the helicase domain is essential for cohesion and G4-stabilizer resistance, distinguishing DDX11 from FANCJ.\",\n      \"evidence\": \"G4 binding/replication assays, co-depletion genetic interactions, and CRISPR KO with helicase-domain rescue in RPE1-TERT cells\",\n      \"pmids\": [\"32705708\", \"32855419\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo G4 vs triplex contributions unresolved\", \"TP53-dependence of proliferation defect mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned DDX11 in homology-directed repair downstream of 53BP1, mediating RPA/RAD51 loading nonredundantly with BRCA1/2 and defining a chemosensitization vulnerability.\",\n      \"evidence\": \"Knockdown with RAD51/RPA focus and resection assays, epistasis with 53BP1/BRCA1/2, and PARPi/cisplatin sensitivity\",\n      \"pmids\": [\"33879618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic substrate during resection not defined\", \"How DDX11 acts relative to BRCA pathway molecularly unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined non-redundant ESCO2-DDX11 and WAPL-dependent relationships in residual cohesion in patient cells.\",\n      \"evidence\": \"Patient-derived cells, combinatorial siRNA with WAPL rescue, DNA-binding mutant complementation, and fiber assays\",\n      \"pmids\": [\"31935221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanistic basis of ESCO2 specificity not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Precisely placed DDX11 in cohesin homeostasis, showing it and CTF18 maintain chromatin-bound cohesin against WAPL unloading rather than via ESCO acetyltransferases.\",\n      \"evidence\": \"DT40 double-KO epistasis with WAPL-depletion and ESCO1/2-overexpression rescue and cohesin loading assays\",\n      \"pmids\": [\"34503989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DDX11 counteracts WAPL biochemically unknown\", \"Direct DDX11 action on cohesin ring not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed cohesion machinery as the dominant genetic dependency of DDX11-deficient cells, identifying STAG2 and HASPIN synthetic lethality.\",\n      \"evidence\": \"Genome-wide CRISPR dropout screen with validation of specific hits\",\n      \"pmids\": [\"38478595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of HASPIN dependency not explained\", \"Therapeutic translation untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the HR role mechanistically, showing ATM phosphorylation of DDX11 at S237 enables RAD51 recruitment via the BRCA2-RAD51 interaction in hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP, CRISPR knock-in reversion of Q238H, ATM phosphorylation assay, and RAD51 focus formation\",\n      \"pmids\": [\"38007537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tumor context\", \"How phosphorylation alters DDX11 activity unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Proposed a cytosolic immune role, identifying DDX11 as a co-sensor enhancing RIG-I dsRNA binding and RIG-I-MAVS signaling.\",\n      \"evidence\": \"siRNA/CRISPR KO, IFN-\\u03b2 reporter, Co-IP with RIG-I/MAVS, and STING/RIG-I/MAVS epistasis\",\n      \"pmids\": [\"39470258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Novel function with limited replication\", \"Relationship to nuclear helicase activity unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a cytoplasmic role in macroautophagy, with DDX11 supporting LC3 lipidation and ATG16L1 trafficking via interaction with SQSTM1.\",\n      \"evidence\": \"CRISPR KO in RPE-1, tandem LC3 reporter imaging, ATG16L1 trafficking, HTT aggregate clearance, and PLA with SQSTM1\",\n      \"pmids\": [\"40413757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether helicase activity is required for autophagy unknown\", \"Single lab, novel function\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single Fe-S helicase mechanistically partitions among its replication/cohesion, DNA-repair, nucleolar, heterochromatin, autophagy, and innate-immune roles, and whether the non-genomic functions depend on its catalytic activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of DDX11 reported in the corpus\", \"Catalytic requirement for autophagy and immune signaling untested\", \"Regulation directing DDX11 between nuclear and cytoplasmic roles unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [1, 7, 13]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 8, 13]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 8, 13]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [25, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3, 17]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"complexes\": [\"cohesin\"],\n    \"partners\": [\"TIMELESS\", \"FEN1\", \"PCNA\", \"WDHD1\", \"RIG-I\", \"MAVS\", \"EZH2\", \"PARP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}