Affinage

DDX18

ATP-dependent RNA helicase DDX18 · UniProt Q9NVP1

Length
670 aa
Mass
75.4 kDa
Annotated
2026-06-09
20 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DDX18 is a nucleolus-resident DEAD-box RNA helicase that maintains genome stability and nuclear architecture while serving as a transcriptional regulator of cell-cycle and immune-evasion programs (PMID:35858569, PMID:39738032, PMID:38732173). Within the nucleolus, DDX18 organizes the granular component through an RNA-driven interaction with NPM1, sustaining nucleolar phase separation, perinucleolar heterochromatin formation, and centromere clustering; its loss disrupts these substructures and abolishes pluripotency in human embryonic stem cells (PMID:39738032). DDX18 also governs R-loop homeostasis: PARP-1 recruits DDX18 to R-loops, and its depletion drives aberrant R-loop accumulation, replication defects, impaired RPA32/RAD51 focus formation, and genome instability that is reversed by RNase H1 overexpression, establishing R-loops as the causal intermediate (PMID:35858569). Beyond RNA metabolism, DDX18 acts on chromatin as a transcriptional activator, directly occupying the CDK4 promoter to promote G1 progression (PMID:38732173) and binding the STAT1 promoter to counteract PRC2-mediated H3K27me3 deposition, thereby elevating STAT1 and downstream PD-L1 to drive immune evasion (PMID:37620449). DDX18 additionally promotes microRNA-21 maturation through interaction with Drosha, lowering PTEN and activating AKT signaling (PMID:33489896). Genetic studies place DDX18 upstream of p53-dependent G1 arrest, with a leukemia-associated E76del allele acting as a dominant negative (PMID:21653321). Its own expression is controlled by YY1 transcriptional activation (PMID:40394670) and by ALKBH1-mediated erasure of promoter DNA N6-methyladenine (PMID:36976498).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 Medium

    Established DDX18 as a nucleolar protein whose activity supports tumor cell proliferation, distinguishing a growth-promoting role from cell-cycle or apoptotic checkpoints.

    Evidence subcellular fractionation/immunofluorescence and dominant-negative/shRNA inhibition with proliferation, cell-cycle, and apoptosis readouts in tumor cells

    PMID:18351129

    Open questions at the time
    • No molecular substrate or helicase target identified
    • Mechanism linking nucleolar residence to proliferation not resolved
  2. 2011 High

    Placed DDX18 genetically upstream of p53-dependent G1 arrest and showed an AML-associated allele behaves as a dominant negative, linking DDX18 dysfunction to hematopoietic disease.

    Evidence zebrafish insertional mutagenesis with p53 and Bcl-xl epistasis and wild-type/mutant mRNA rescue

    PMID:21653321

    Open questions at the time
    • Molecular trigger of p53 activation upon Ddx18 loss not defined
    • Biochemical defect of E76del allele not characterized
  3. 2021 Medium

    Connected DDX18 to microRNA processing, showing it promotes miR-21 maturation via Drosha to suppress PTEN and activate AKT.

    Evidence Co-IP (DDX18-Drosha), small RNA-seq, western blot, xenograft/PDX in gastric cancer

    PMID:33489896

    Open questions at the time
    • Whether DDX18 helicase activity is required for miR-21 processing untested
    • Generality beyond miR-21 unknown
  4. 2022 High

    Defined a direct role for DDX18 in R-loop homeostasis and DNA repair, with PARP-1 mediating its recruitment and RNase H1 rescue proving R-loops as the causal intermediate.

    Evidence shRNA depletion, RNase H1 overexpression rescue, gammaH2AX/RPA32/RAD51 foci assays, PARP-1/DDX18/R-loop Co-IP

    PMID:35858569

    Open questions at the time
    • Direct R-loop unwinding activity not biochemically reconstituted
    • How PARP-1 selects DDX18 to specific R-loops unknown
  5. 2023 Medium

    Revealed DDX18 as a chromatin-acting transcriptional regulator that counteracts PRC2/H3K27me3 at the STAT1 promoter to drive PD-L1-mediated immune evasion.

    Evidence DDX18 and H3K27me3 ChIP, PRC2 Co-IP, knockdown with STAT1/PD-L1 readouts, anti-PD-L1 combination in vivo (pancreatic cancer)

    PMID:37620449

    Open questions at the time
    • Mechanism by which DDX18 inhibits PRC2 assembly unresolved
    • Whether RNA binding is required for promoter occupancy unknown
  6. 2023 Medium

    Identified epigenetic control of DDX18 itself through ALKBH1-mediated DNA 6mA demethylation at its promoter.

    Evidence MeDIP-seq, dual-luciferase reporter, dot blot, siRNA knockdown and DDX18 overexpression rescue, patient-derived organoids

    PMID:36976498

    Open questions at the time
    • Direct demethylation of DDX18 promoter by ALKBH1 not shown biochemically
    • Other regulators of the promoter not excluded
  7. 2024 Medium

    Established CDK4 as a direct transcriptional target of DDX18 driving G1 progression, while ruling out c-Myc as a DDX18 transcriptional regulator.

    Evidence RNA-seq, ChIP (DDX18 on CDK4 promoter; c-Myc on DDX18 promoter), siRNA, cell-cycle analysis, xenograft

    PMID:38732173

    Open questions at the time
    • How a helicase achieves sequence-specific promoter activation unresolved
    • Cofactors at the CDK4 promoter not defined
  8. 2024 High

    Demonstrated DDX18 organizes nucleolar phase separation and nuclear architecture via NPM1, linking nucleolar integrity to stem-cell pluripotency.

    Evidence Hi-C, DNA/RNA-FISH, condensate analysis, DDX18-NPM1 Co-IP, NoCasDrop targeting, knockdown in hESCs

    PMID:39738032

    Open questions at the time
    • Which nucleolar RNAs drive the interaction not fully defined
    • Role of helicase catalysis in condensate formation untested
  9. 2025 Medium

    Placed DDX18 in a YY1-driven transcriptional axis promoting EMT and AKT/mTOR signaling.

    Evidence ChIP, dual-luciferase reporter, knockdown/overexpression, AKT inhibitor rescue, xenograft in esophageal cancer

    PMID:40394670

    Open questions at the time
    • Direct DDX18 effectors in AKT/mTOR activation not identified
    • Relationship to its nucleolar function unclear
  10. 2025 Low

    Implicated DDX18 in nucleolar pH stress responses by enabling SRSF1 nucleolar localization.

    Evidence immunofluorescence of SRSF1 shuttling, interaction assay, SRSF1 knockdown with pH/phase readouts (preprint)

    PMID:bio_10.1101_2025.04.12.648491

    Open questions at the time
    • Preprint; biochemical validation of DDX18-SRSF1 binding not fully detailed
    • Direction of regulation unconfirmed
  11. 2025 Low

    Reported DDX18 interaction with REXO4 promoting HCC growth and metastasis through EMT and MAPK signaling.

    Evidence Co-IP, immunofluorescence colocalization, knockdown/overexpression with REXO4 rescue, xenograft, MAPK/EMT western blots

    PMID:40950356

    Open questions at the time
    • Single Co-IP without reciprocal mechanistic dissection
    • How the interaction engages MAPK/EMT not biochemically resolved
  12. 2026 Low

    Positioned DDX18 downstream of NOP58 in DNA-damage repair underlying radioresistance.

    Evidence pull-down, siRNA, DDX18 overexpression rescue, gammaH2AX, comet and clonogenic assays

    PMID:41834519

    Open questions at the time
    • Pull-down without reciprocal validation
    • Mechanism of NOP58-DDX18 cooperation in repair unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether DDX18's enzymatic helicase activity is the unifying biochemical basis for its roles in R-loop resolution, nucleolar condensation, miRNA processing, and promoter regulation remains unresolved.
  • No in vitro reconstitution of DDX18 RNA/R-loop unwinding reported in the corpus
  • How a single helicase achieves sequence-specific transcriptional and structural functions is undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0140110 transcription regulator activity 2 GO:0140098 catalytic activity, acting on RNA 1
Localization
GO:0005730 nucleolus 2 GO:0005634 nucleus 1
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-73894 DNA Repair 1 R-HSA-8953854 Metabolism of RNA 1
Partners
DROSHANOP58NPM1PARP1REXO4SRSF1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2022 PARP-1 mediates the association of DDX18 with R-loops, and DDX18 depletion causes aberrant endogenous R-loop accumulation, DNA-replication defects, reduced RPA32 and RAD51 foci formation after irradiation, γH2AX accumulation, and genome instability; RNase H1 overexpression rescues all DNA-repair defects caused by DDX18 depletion, confirming R-loop as the causal intermediate. shRNA depletion, RNase H1 overexpression rescue, γH2AX immunofluorescence, RPA32/RAD51 foci assay, Co-IP (PARP-1/DDX18/R-loop association) Cell reports High 35858569
2024 DDX18 is a nucleolus-resident protein that regulates nucleolus phase separation and nuclear organization by interacting with NPM1 in the granular nucleolar component, driven by specific nucleolar RNAs; loss of DDX18 disrupts nucleolar substructures, impairs centromere clustering, and disrupts perinucleolar heterochromatin (PNH) formation, leading to loss of pluripotency in human embryonic stem cells. Hi-C, DNA/RNA-FISH, biomolecular condensate analysis, Co-IP (DDX18–NPM1), NoCasDrop nucleolar targeting tool, DDX18 knockdown in hESCs Nature communications High 39738032
2011 In zebrafish, loss of Ddx18 causes p53-dependent G1 cell-cycle arrest and hematopoietic defects; loss of p53, but not Bcl-xl overexpression, rescues myeloid cells, placing Ddx18 upstream of p53-dependent G1 arrest; a human AML mutation DDX18-E76del acts as a dominant-negative allele, failing to rescue hematopoiesis in ddx18 mutant embryos. Zebrafish insertional mutagenesis, p53 loss-of-function epistasis, Bcl-xl overexpression epistasis, mRNA rescue experiments with wild-type and mutant DDX18 Blood High 21653321
2007 DDX18 (MrDb) is a nucleolar protein ubiquitously expressed in tumor cells; inhibition by dominant-negative mutant or shRNA reduces tumor cell proliferation without inducing cell-cycle arrest or apoptosis. Subcellular fractionation/immunofluorescence (nucleolar localization), dominant-negative mutant expression, shRNA knockdown, cell proliferation assay, cell-cycle analysis, apoptosis assay Oncology research Medium 18351129
2017 DDX18 interacts with PRRSV nsp2 (via nsp2 N-terminus) and nsp10 (via both N- and C-termini); expression of nsp2 or nsp10 redistributes DDX18 from the nucleus to the cytoplasm; DDX18 silencing down-regulates PRRSV replication. Co-immunoprecipitation, deletion-mapping of binding regions, immunofluorescence (subcellular redistribution), siRNA knockdown, viral replication assay Virus research Medium 28648849
2021 DDX18 promotes maturation of microRNA-21 through direct interaction with Drosha; this reduces PTEN levels and upregulates AKT signaling in gastric cancer cells. Co-immunoprecipitation (DDX18–Drosha), small RNA sequencing, western blotting, xenograft and PDX models Frontiers in oncology Medium 33489896
2023 DDX18 deposits on the STAT1 promoter region and counteracts H3K27me3 deposition by modulating formation of the PRC2 complex, thereby transcriptionally upregulating STAT1, which in turn elevates PD-L1 expression and promotes immune evasion in pancreatic cancer. ChIP (DDX18 binding to STAT1 promoter), H3K27me3 ChIP, PRC2 complex co-IP, DDX18 knockdown with STAT1/PD-L1 expression readouts, anti-PD-L1 combination treatment in vivo Oncogene Medium 37620449
2023 ALKBH1 (DNA 6mA demethylase) regulates DDX18 expression by erasing DNA N6-methyladenine at the DDX18 promoter, thereby increasing DDX18 transcription; dual-luciferase reporter assay confirmed that 6mA levels modulate DDX18 promoter activity; exogenous DDX18 overexpression rescues proliferation arrested by ALKBH1 knockdown. MeDIP-seq, RNA sequencing, dual-luciferase reporter assay, Dot blotting, qRT-PCR, siRNA knockdown, overexpression rescue, patient-derived organoid assay Cellular oncology Medium 36976498
2024 DDX18 directly transcriptionally activates CDK4 expression (identified by RNA-seq and ChIP); DDX18 depletion induces G1 cell-cycle arrest; c-Myc binds the DDX18 promoter but does not influence DDX18 expression (negative result for c-Myc as DDX18 transcriptional regulator). RNA sequencing, chromatin immunoprecipitation (DDX18 on CDK4 promoter; c-Myc on DDX18 promoter), siRNA knockdown, cell-cycle analysis, in vivo xenograft International journal of molecular sciences Medium 38732173
2025 YY1 binds to and stimulates DDX18 transcription (confirmed by dual-luciferase reporter and ChIP assays); DDX18 promotes EMT and activates the AKT/mTOR signaling pathway in esophageal cancer; AKT inhibitors abrogate the oncogenic effects of DDX18. ChIP assay, dual-luciferase reporter assay, DDX18 knockdown/overexpression, AKT inhibitor treatment, rescue experiments, xenograft model Journal of translational medicine Medium 40394670
2024 DDX18 expression positively correlates with R-loop accumulation in colorectal cancer; elevated DDX18 delays completion of DNA damage repair and increases double-strand DNA breaks, promoting genomic instability and enhancing sensitivity to DNA-damaging agents. Colon cancer tissue/cell lines/patient-derived organoids, R-loop detection, DSB assays (γH2AX), DDX18 knockdown, chemosensitivity assays Experimental cell research Low 39577603
2025 DDX18 interacts with REXO4 (confirmed by Co-IP and immunofluorescence colocalization); DDX18/REXO4 axis promotes HCC tumor growth and metastasis by regulating EMT and MAPK signaling; overexpression of REXO4 reverses the inhibitory effects of DDX18 knockdown. Co-immunoprecipitation, immunofluorescence colocalization, DDX18 knockdown/overexpression, REXO4 overexpression rescue, xenograft model, western blot for MAPK/EMT markers Journal of gastrointestinal oncology Low 40950356
2026 NOP58 directly interacts with DDX18 (confirmed by pull-down assay) and regulates DDX18 expression; DDX18 overexpression reverses the radiosensitizing effects of NOP58 knockdown, indicating that NOP58 promotes radioresistance through DDX18-mediated DNA damage repair. Pull-down assay, siRNA knockdown, DDX18 overexpression rescue, γH2AX immunofluorescence, comet assay, clonogenic survival assay Journal of radiation research Low 41834519
2025 DDX18 (as a nucleolar-resident protein) interacts with SRSF1, which is recruited to the nucleolus under pH stress; this interaction is required for SRSF1 nucleolar localization and the restoration of nucleolar pH homeostasis and multiphase organization. Immunofluorescence (SRSF1 nuclear speckle-to-nucleolus shuttling), protein interaction assay (molecular interaction with DDX18 described), SRSF1 knockdown with nucleolar pH and phase readouts bioRxivpreprint Low bio_10.1101_2025.04.12.648491

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1980 Cluster of mrdA and mrdB genes responsible for the rod shape and mecillinam sensitivity of Escherichia coli. Journal of bacteriology 103 6243629
2013 Mutations in cell elongation genes mreB, mrdA and mrdB suppress the shape defect of RodZ-deficient cells. Molecular microbiology 57 23301723
2022 DDX18 prevents R-loop-induced DNA damage and genome instability via PARP-1. Cell reports 49 35858569
2011 Ddx18 is essential for cell-cycle progression in zebrafish hematopoietic cells and is mutated in human AML. Blood 45 21653321
2017 Cellular DEAD-box RNA helicase 18 (DDX18) Promotes the PRRSV Replication via Interaction with Virus nsp2 and nsp10. Virus research 37 28648849
2014 Genomic interaction between ER and HMGB2 identifies DDX18 as a novel driver of endocrine resistance in breast cancer cells. Oncogene 35 25284587
2023 DDX18 drives tumor immune escape through transcription-activated STAT1 expression in pancreatic cancer. Oncogene 15 37620449
2021 The RNA-Binding Protein DDX18 Promotes Gastric Cancer by Affecting the Maturation of MicroRNA-21. Frontiers in oncology 15 33489896
2024 DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells. Nature communications 12 39738032
2023 DNA 6mA demethylase ALKBH1 regulates DDX18 expression to promote proliferation of human head and neck squamous cell carcinoma. Cellular oncology (Dordrecht, Netherlands) 12 36976498
2024 DDX18 Facilitates the Tumorigenesis of Lung Adenocarcinoma by Promoting Cell Cycle Progression through the Upregulation of CDK4. International journal of molecular sciences 6 38732173
2007 Cellular studies of MrDb (DDX18). Oncology research 6 18351129
2025 Sub-inhibitory gentamicin promotes extracellular vesicles biogenesis and blaNDM dissemination in carbapenem-resistant Escherichia coli via mrdA/mrdB pathway. Veterinary microbiology 3 40907215
2025 YY1-induced DDX18 modulates EMT via the AKT/mTOR pathway in esophageal cancer: a novel therapeutic target. Journal of translational medicine 2 40394670
2024 DDX18 influences chemotherapy sensitivity in colorectal cancer by regulating genomic stability. Experimental cell research 2 39577603
2024 In Vivo-Matured Oocyte Resists Post-Ovulatory Aging through the Hub Genes DDX18 and DNAJC7 in Pigs. Antioxidants (Basel, Switzerland) 1 39061935
2024 Liriodendrin stimulates proliferation and milk protein synthesis of mammary epithelial cells via the PI3K-DDX18 signaling. In vitro cellular & developmental biology. Animal 1 39134870
2026 NOP58 modulates radiosensitivity in non-small cell lung cancer via DDX18-mediated DNA damage repair. Journal of radiation research 0 41834519
2025 DDX18 promotes growth and metastasis of hepatocellular carcinoma via activating EMT and MAPK signaling. Journal of gastrointestinal oncology 0 40950356
2025 MRdb: a comprehensive database of univariate and multivariate Mendelian randomization with large-scale GWAS summary data. Database : the journal of biological databases and curation 0 40996707

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