Affinage

DDX21

Probable ATP-dependent RNA helicase DDX56 · UniProt Q9NY93

Length
547 aa
Mass
61.6 kDa
Annotated
2026-06-09
78 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DDX21 is a nucleolar DEAD-box RNA helicase that integrates ribosome biogenesis with RNA polymerase activity by directly contacting rRNA, snoRNAs, and 7SK RNA: in the nucleolus it promotes rRNA transcription, processing, and modification, while in the nucleoplasm it binds 7SK snRNP at Pol II promoters and releases P-TEFb in a helicase-dependent manner to drive transcription elongation (PMID:25470060). It enforces the ordered hierarchy of pre-40S maturation by recruiting late-acting snoRNPs to pre-rRNA at sites overlapping its own crosslinking footprint (PMID:25477391), and its activity over Pol I is gated by allosteric inputs—the lncRNA SLERT loosens ring-shaped DDX21 assemblies that otherwise suppress Pol I transcription (PMID:28475895), and U3 snoRNA tunes its mitotic perichromosomal localization and condensate size (PMID:38760378). Crystal structures in apo, pre-hydrolysis, and post-hydrolysis states define an open-to-closed conformational cycle, and DDX21 unwinds dsRNA cooperatively as a dimer whose central dimerization domain is required for both ATP-dependent unwinding and ATP-independent G-quadruplex remodeling, the latter mediated by its Arg/Gly-rich C-terminus (PMID:32714761, PMID:33313488, PMID:28472472). As a genome-stability factor, DDX21 unwinds R-loops to prevent double-strand breaks, and its helicase activity is set by reversible acetylation (CBP/SIRT7 and NAT10) (PMID:28790157, PMID:39394182); at transcription termination regions it recruits METTL3 to deposit m6A on nascent RNA and promote XRN2-mediated RNAPII termination (PMID:38569554). DDX21 localization and abundance are heavily regulated—by c-Jun, WDR46, PARP1-mediated ADP-ribosylation, glucose binding to its ATP pocket, and Ca2+/calmodulin—coupling rRNA biogenesis to cellular state and, upon glucose-driven dimer dissociation and nucleoplasmic relocalization, to mRNA splicing of pro-differentiation genes (PMID:18180292, PMID:23848194, PMID:31351877, PMID:36608661, PMID:39060175). Beyond these nuclear roles, DDX21 acts in cytosolic innate immunity as part of a DDX1-DDX21-DHX36-TRIF dsRNA-sensing complex that activates type I interferon, and it restricts multiple viruses by engaging viral polymerase or IRES components, functions that diverse viral proteins counteract (PMID:21703541, PMID:24721576, PMID:34578346).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 Medium

    Established that DDX21 is a nucleolar protein whose localization is dynamic, revealing that its nucleolar residence reports on transcriptional/metabolic state.

    Evidence Immunofluorescence with cytotoxic drug treatment and washout in MCF-7 cells

    PMID:9299166

    Open questions at the time
    • No molecular function assigned
    • Mechanism of translocation unknown
  2. 1999 Medium

    First demonstrated DDX21 is a bona fide RNA helicase, defining its core enzymatic activity on tailed dsRNA substrates.

    Evidence Recombinant baculovirus-expressed protein in an in vitro helicase assay

    PMID:10600508

    Open questions at the time
    • Single substrate type
    • No cellular substrate identified
    • Adriamycin inhibition acts via RNA, not protein
  3. 2008 Medium

    Identified c-Jun as a regulator of DDX21 nucleolar localization, linking an AP-1 transcription factor to rRNA accumulation.

    Evidence siRNA knockdown, reciprocal Co-IP, RIP, and rescue with immunofluorescence

    PMID:18180292

    Open questions at the time
    • Single lab
    • Mechanism of c-Jun-directed retention unclear
  4. 2011 High

    Placed DDX21 in cytosolic innate immunity as part of a DDX1-DDX21-DHX36-TRIF complex sensing dsRNA, expanding its role beyond the nucleolus.

    Evidence Poly I:C affinity purification, mass spectrometry, domain mapping, shRNA knockdown across virus types in dendritic cells

    PMID:21703541

    Open questions at the time
    • Stoichiometry of the sensing complex not resolved
    • How nucleolar DDX21 partitions to cytosol unclear
  5. 2014 High

    Defined DDX21's dual-compartment role in gene expression—nucleolar rRNA control and nucleoplasmic P-TEFb release from 7SK snRNP—and its ordered control of snoRNP-driven pre-40S maturation, establishing it as a master coordinator of ribosome biogenesis and Pol II elongation.

    Evidence ChIP-seq, CLIP-seq, RIP, helicase-dead mutants, reporters (Nature); CRAC crosslinking and gradient sedimentation (NAR)

    PMID:25470060 PMID:25477391

    Open questions at the time
    • How DDX21 selects late vs early snoRNPs unknown
    • Helicase substrate specificity in vivo not fully mapped
  6. 2014 High

    Showed DDX21 restricts influenza A by binding polymerase subunit PB1, and that viral NS1 displaces PB1, defining a host-virus competition for DDX21.

    Evidence Reciprocal Co-IP, domain mapping, NS1 mutant virus with DDX21 knockdown rescue

    PMID:24721576

    Open questions at the time
    • Whether helicase activity is needed for restriction not resolved
  7. 2017 High

    Identified DDX21 as an R-loop resolvase whose activity is set by acetylation (CBP/SIRT7), tying the helicase to genome stability and transcriptional throughput.

    Evidence In vitro R-loop unwinding, DRIP-seq, SIRT7/DDX21 double knockdown, acetylation assays, γH2AX

    PMID:28790157

    Open questions at the time
    • Genome-wide R-loop targeting determinants incomplete
    • Acetylation site identity not yet mapped here
  8. 2017 High

    Revealed allosteric regulation of DDX21 by the lncRNA SLERT and visualized ring-shaped DDX21 assemblies suppressing Pol I, showing RNA partners gate its enzymatic state.

    Evidence STORM super-resolution imaging, RIP, CRISPR deletion, in vitro binding

    PMID:28475895

    Open questions at the time
    • Molecular basis of ring formation unresolved
    • How SLERT binding propagates to ATPase cycle unclear
  9. 2017 Medium

    Established the Arg/Gly-rich C-terminus as a direct RNA G-quadruplex binder/unwinder, defining a structure-specific RNA recognition activity distinct from canonical duplex unwinding.

    Evidence MS pull-down, fluorescence binding, nuclease sensitivity, domain truncation, mRNA reporter

    PMID:28472472

    Open questions at the time
    • Single lab
    • Cellular scope of rG4 targets limited
  10. 2018 Medium

    Mapped the C-terminal G-quadruplex epitope at residue resolution on TERRA, refining the structural basis of quadruplex specificity.

    Evidence In vitro binding and 2D STD NMR with 2'OH mutagenesis

    PMID:29906500

    Open questions at the time
    • No in-cell functional consequence measured
    • Single lab
  11. 2019 High

    Connected nucleolar PARP1/snoRNA signaling to DDX21 via ADP-ribosylation, providing a post-translational switch for its nucleolar retention and rDNA transcription.

    Evidence Co-IP, PARP inhibitors, ADP-ribosylation site mutagenesis, Pol I assays, xenografts

    PMID:31351877

    Open questions at the time
    • ADP-ribosylation site residues' structural effect unclear
    • Crosstalk with acetylation not addressed
  12. 2020 Medium

    Provided three-state crystal structures and dimerization analysis, defining the conformational cycle and showing dimerization is required for both ATP-dependent and ATP-independent activities.

    Evidence X-ray crystallography (apo/AMPPNP-ssRNA/ADP), ATPase and unwinding assays, mutagenesis (Advanced Science); SAXS with dimerization mutants (iScience)

    PMID:32714761 PMID:33313488

    Open questions at the time
    • Full-length structure including IDR/C-terminus not resolved
    • Dimer architecture from SAXS only
  13. 2023 High

    Showed glucose directly binds the ATP-binding domain to dissociate DDX21 dimers and trigger nucleoplasmic relocalization toward mRNA splicing, linking metabolic state to a function switch during differentiation.

    Evidence Azido-glucose click chemistry, in vitro helicase, SAXS, eCLIP, splicing assays, knockdown/rescue

    PMID:36608661

    Open questions at the time
    • Generality of the SCUGSDGC splicing motif across cell types unknown
    • How monomers recruit splicing factors mechanistically unclear
  14. 2024 High

    Defined a DDX21-METTL3 nexus that couples R-loop recognition and m6A deposition to XRN2-mediated RNAPII termination, integrating DDX21 helicase activity with transcription termination and genome integrity.

    Evidence Co-IP, ChIP-seq, MeRIP, DRIP-seq, helicase-dead mutant, XRN2 cleavage assays, γH2AX

    PMID:38569554

    Open questions at the time
    • Order of R-loop resolution vs m6A deposition not fully resolved
    • Direct DDX21-METTL3 interface unmapped
  15. 2024 High

    Identified NAT10 acetylation of DDX21 at K236/K573 as an activating modification for R-loop resolution, and showed DDX21/NAT10 enhance RNase H1 activity, embedding DDX21 in a modification-controlled R-loop clearance network.

    Evidence MS acetylation mapping, 2KQ/2KR mutants, in vitro helicase, genetic rescue, γH2AX; BioID and in vitro RNase H1 cleavage assays

    PMID:35852833 PMID:39394182

    Open questions at the time
    • Interplay of NAT10 acetylation with SIRT7/CBP acetylation not integrated
    • RNase H1 enhancement mechanism structurally undefined
  16. 2024 Medium

    Showed Ca2+/calmodulin alters DDX21 conformation to liberate sequestered RPA194 and drive rDNA transcription, coupling neuronal activity-induced calcium signaling to nucleolar biogenesis.

    Evidence Co-IP with Ca2+ dependence, conformation assays, small-molecule screen, axon growth assay in hippocampal neurons

    PMID:39060175

    Open questions at the time
    • Single lab
    • Generalizability beyond neurons untested
  17. 2024 Medium

    Demonstrated U3 snoRNA controls mitotic DDX21 perichromosomal localization and condensate behavior, extending DDX21 RNA-dependent regulation into cell division.

    Evidence RIP, immunofluorescence, FRAP, knockdown/depletion, in vitro condensate assay

    PMID:38760378

    Open questions at the time
    • Functional consequence of perichromosomal DDX21 not fully defined
    • Single lab
  18. 2025 Medium

    Identified a selective small-molecule inhibitor (KI-DX-014) that blocks DDX21-RNA binding, ATPase, condensate formation, and 7SK-P-TEFb release, providing a chemical tool validating multiple DDX21 functions.

    Evidence Small-molecule microarray, ATPase and condensate assays, in vitro 7SK P-TEFb release, zebrafish developmental assay

    PMID:40637641

    Open questions at the time
    • Selectivity over other helicases not exhaustively profiled
    • In vivo efficacy limited to zebrafish readout

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many regulatory inputs (ADP-ribosylation, acetylation, glucose, Ca2+/CaM, dimerization, phase separation, and partner RNAs) are integrated to dynamically partition DDX21 among ribosome biogenesis, transcription elongation/termination, splicing, and immune sensing remains unresolved.
  • No unified model of compartment-switching control
  • Crosstalk between PTMs not co-assayed
  • Full-length structure with IDR and bound regulators lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 6 GO:0140098 catalytic activity, acting on RNA 6 GO:0140657 ATP-dependent activity 4 GO:0140299 molecular sensor activity 3
Localization
GO:0005730 nucleolus 7 GO:0005654 nucleoplasm 5 GO:0005829 cytosol 3 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-74160 Gene expression (Transcription) 5 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-168256 Immune System 3 R-HSA-73894 DNA Repair 3 R-HSA-8953854 Metabolism of RNA 3
Partners
DDX1DHX36METTL3NAT10PARP1SIRT7TRIFWDR46
Complex memberships
7SK snRNPDDX1-DDX21-DHX36-TRIF dsRNA-sensing complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 DDX21 widely associates with Pol I- and Pol II-transcribed genes and diverse RNA species including rRNA, snoRNAs, and 7SK RNA. In the nucleolus, DDX21 directly contacts rRNA and snoRNAs to promote rRNA transcription, processing, and modification. In the nucleoplasm, DDX21 binds 7SK RNA as a component of the 7SK snRNP complex and is recruited to Pol II gene promoters where it facilitates P-TEFb release from 7SK snRNP in a helicase-activity-dependent manner, promoting transcription elongation of ribosomal protein and snoRNA genes. ChIP-seq, CLIP-seq, RNA immunoprecipitation, shRNA knockdown, helicase-dead mutant analysis, luciferase reporter assays Nature High 25470060
2017 The lncRNA SLERT interacts with DDX21 via a 143-nt non-snoRNA sequence. DDX21 forms ring-shaped structures (visualized by super-resolution microscopy) surrounding multiple Pol I complexes and suppresses pre-rRNA transcription. SLERT binding allosterically alters individual DDX21 molecules, loosens the DDX21 ring, and relieves DDX21-mediated suppression of Pol I transcription. Super-resolution imaging (STORM), RNA immunoprecipitation, CRISPR deletion, co-immunoprecipitation, in vitro binding assays Cell High 28475895
2019 PARP-1 is activated by snoRNAs in the nucleolus and ADP-ribosylates DDX21. ADP-ribosylated DDX21 localizes to nucleoli and promotes rDNA transcription. Treatment with PARP inhibitors or mutation of the ADP-ribosylation sites on DDX21 reduces its nucleolar localization, rDNA transcription, ribosome biogenesis, protein translation, and cell growth. Co-immunoprecipitation, PARP inhibitor treatment, ADP-ribosylation site mutagenesis, RNA pol I transcription assays, xenograft models, immunofluorescence Molecular cell High 31351877
2017 DDX21 efficiently unwinds R-loops in vitro and in cells; depletion of DDX21 leads to accumulation of cellular R-loops and DNA double-strand breaks. DDX21 helicase activity is regulated by acetylation: CBP acetylates DDX21 to inhibit its activity, while SIRT7 deacetylates DDX21 to augment helicase activity and overcome R-loop-mediated stalling of RNA polymerases. DDX21 also resolves estrogen-induced R-loops on estrogen-responsive genes. In vitro R-loop unwinding assay, DRIP-seq (S9.6 antibody), co-immunoprecipitation, SIRT7/DDX21 knockdown, γH2AX measurement, acetylation/deacetylation assays Genes & development High 28790157
2011 DDX21 forms a complex with DDX1, DHX36, and the adaptor TRIF in the cytosol of myeloid dendritic cells to sense dsRNA. DDX21 binds the TIR domain of TRIF via its PRK domain. Knockdown of DDX21 blocks type I IFN and cytokine responses to poly I:C, influenza A virus, and reovirus, establishing DDX21 as a component of a cytosolic dsRNA sensor that activates the TRIF pathway. Poly I:C affinity purification, mass spectrometry, shRNA knockdown, domain-mapping binding assays, IFN/cytokine reporter assays Immunity High 21703541
2014 DDX21 restricts influenza A virus by binding the viral polymerase subunit PB1 and inhibiting polymerase assembly, reducing viral RNA and protein synthesis. The viral NS1 protein overcomes this restriction by binding DDX21 and displacing PB1. Sequential interaction of PB1 and NS1 with DDX21 temporally regulates viral gene expression. Co-immunoprecipitation, shRNA knockdown, viral replication assays, NS1 mutant viruses with DDX21 knockdown rescue Cell host & microbe High 24721576
2020 Crystal structures of human DDX21 were determined in three states: apo, AMPPNP+ssRNA-bound (pre-hydrolysis), and ADP-bound (post-hydrolysis), revealing an open-to-closed conformational change upon RNA binding. The RNA unwinding machinery includes a wedge helix, sensor motif V, and the DEVD box linking ATP and RNA binding pockets. DDX21 unwinds dsRNA cooperatively (Hill coefficient analysis). The NS1 protein of influenza A inhibits DDX21 ATPase and unwinding activity via small RNAs that cooperatively assemble with DDX21 and NS1. X-ray crystallography, in vitro ATPase assay, RNA unwinding assay, site-directed mutagenesis (D339H/E340G), Hill coefficient analysis Advanced science High 32714761
2023 Glucose binds the ATP-binding domain of DDX21, alters its conformation, inhibits helicase activity, and dissociates DDX21 dimers. During differentiation-associated intracellular glucose elevation, DDX21 re-localizes from the nucleolus to the nucleoplasm, assembles into larger complexes containing RNA splicing factors, and promotes splicing of pro-differentiation genes (GRHL3, KLF4, OVOL1, RBPJ) by binding a specific SCUGSDGC motif in mRNA introns. Azido-glucose click chemistry, in vitro helicase assay, SAXS, immunofluorescence, enhanced CLIP-seq, splicing assays, DDX21 knockdown/rescue Cell High 36608661
2024 DDX21 recruits the m6A methyltransferase METTL3 to chromatin by recognizing co-transcriptionally formed R-loops, and DDX21's helicase activity is required for METTL3-mediated m6A deposition onto nascent RNA. At transcription termination regions, this DDX21-METTL3 nexus promotes XRN2-mediated RNAPII termination. Loss of DDX21 or its enzymatic activity leads to defective termination and DNA damage. Co-immunoprecipitation, ChIP-seq, m6A-seq (MeRIP), DRIP-seq, helicase-dead DDX21 mutant, XRN2 cleavage assays, γH2AX measurement Molecular cell High 38569554
2017 DDX21 binds RNA G-quadruplexes (rG4s) directly and unwinds them. The C-terminus of DDX21 mediates quadruplex RNA binding. DDX21 recognizes the quadruplex topology with specificity involving 2'OH of loop nucleotides. DDX21 binding suppresses expression of a protein with G4s in the 3' UTR of its mRNA. Mass spectrometry pull-down from cell lysate, fluorescence binding assays, nuclease sensitivity assay, domain truncation mapping, mRNA reporter assay Nucleic acids research Medium 28472472
2018 The C-terminus of DDX21 directly binds TERRA (telomeric repeat-containing RNA) G-quadruplex. 2D saturation transfer difference NMR maps the binding site to the phosphoribose backbone of quadruplexes; specificity for TERRA is mediated by 2'OH of loop nucleotides. In vitro binding assays, 2D saturation transfer difference NMR, site-directed mutagenesis of 2'OH Biochimica et biophysica acta. General subjects Medium 29906500
2020 DDX21 is dimeric, with a central dimerization domain identified by SAXS. Intact dimerization is essential for both ATP-dependent dsRNA unwinding and ATP-independent G-quadruplex remodeling activities in vitro. The Arg/Gly-rich C-terminus maintains high RNA affinity independent of dimerization. SAXS, in vitro helicase assays with dimerization-deficient mutants, G-quadruplex remodeling assays iScience Medium 33313488
2014 DDX21 is required for the association of late-acting snoRNPs (SNORD56, SNORD68) with pre-40S ribosomal complexes. DDX21 crosslinking sites on pre-rRNAs overlap with basepairing sites of these late snoRNAs. Earlier snoRNAs are unaffected by DDX21 depletion, establishing DDX21 as a regulator of the ordered hierarchy of snoRNP action in pre-40S maturation. CRAC (crosslinking and analysis of cDNAs), sucrose gradient sedimentation, shRNA knockdown, northern blotting Nucleic acids research High 25477391
2008 c-Jun directly interacts with DDX21 and regulates its nucleolar localization. Depletion of c-Jun causes translocation of DDX21 from nucleolus to nucleoplasm, reduces DDX21 binding to rRNA, and inhibits 28S and 18S rRNA accumulation. Exogenous c-Jun rescues DDX21 nucleolar localization. siRNA knockdown, co-immunoprecipitation, RNA immunoprecipitation, indirect immunofluorescence, northern blotting The Journal of biological chemistry Medium 18180292
1997 DDX21 (RH-II/Gu) is normally a nucleolar protein and undergoes reversible translocation from nucleolus to nucleoplasm upon treatment with cytotoxic drugs (actinomycin D, toyocamycin, mycophenolic acid), with the kinetics of reversibility depending on drug dose and type. Immunofluorescence, drug treatment and washout experiments in MCF-7 cells Experimental cell research Medium 9299166
2014 During dengue virus infection, DDX21 translocates from nucleus to cytoplasm to activate innate immune responses, thereby inhibiting DENV replication in early infection. DENV NS2B-NS3 protease complex subsequently degrades DDX21 to subvert innate immunity and facilitate replication. iTRAQ proteomics, LC-MS/MS, immunofluorescence, viral replication assays, protease inhibitor experiments Biochemical and biophysical research communications Medium 27033607
2021 Caspase-3 and caspase-6 cleave DDX21 at D126 upon virus infection or RNA/DNA ligand treatment. The resulting cytoplasmic cleaved DDX21 fragment negatively regulates IFN-β signaling by suppressing the formation of the DDX1-DDX21-DHX36 dsRNA-sensing complex. Co-immunoprecipitation, site-directed mutagenesis (D126 cleavage site), caspase inhibitor treatment, IFN-β reporter assay, immunofluorescence mBio Medium 34125604
2014 DDX21 promotes rRNA processing in breast cancer cells and is required for phosphorylation of c-Jun on Ser73, thereby promoting AP-1 transcriptional activity. In nuclear (non-nucleolar) localized DDX21, these two functions operate independently. siRNA knockdown, immunofluorescence, rRNA processing assay (northern blot/pulse-chase), luciferase reporter for AP-1 activity, qRT-PCR, xenograft imaging Breast cancer research : BCR Medium 25260534
2017 In HIV-1 context: DDX21 binds the Rev Response Element (RRE) with high affinity, stimulating ATPase activity. DDX21 is both an ATP-dependent and ATP-independent helicase. Rev inhibits DDX21 ATPase and ATP-dependent helicase activities dose-dependently via a conserved DEAD-domain interaction involving Rev's nuclear diffusion inhibitory signal motif. DDX21 enhances Rev binding to the RRE. In vitro RNA binding assays, ATPase assay, helicase assay, pulldown, fluorescence anisotropy Journal of molecular biology Medium 28705764
1999 Recombinant DDX21 (RH-II/Gu) expressed in a baculovirus system has RNA helicase activity on a 5'-tailed dsRNA substrate in vitro. Adriamycin inhibits DDX21 helicase activity (IC50 ~40 µM) by binding to the RNA substrate rather than directly to the protein. Baculovirus expression, in vitro helicase assay, RNA-drug binding assay (gel electrophoresis) Biochemical and biophysical research communications Medium 10600508
2013 WDR46 (nucleolar scaffold protein) is required for proper localization of DDX21 to the granular component of the nucleolus. Upon WDR46 knockdown, DDX21 mislocalizes to the edges of nucleoli, and proper DDX21 recruitment after cell division is impaired. WDR46 physically interacts with DDX21 via its intrinsically disordered N- and C-terminal regions. siRNA knockdown, immunofluorescence, co-immunoprecipitation, cell-cycle analysis Genes to cells Medium 23848194
2012 DDX21 (Gu/Ddx21) is a novel direct interactor of protein phosphatase PP1, identified by mitotic spindle enrichment and mass spectrometry. DDX21 is placed within the toposome (Topoisomerase IIα-containing complex) involved in mitotic chromatin regulation. Mitotic spindle biochemical enrichment, mass spectrometry, co-immunoprecipitation, in vitro binding assay PloS one Medium 22761809
2019 At the ENPP2 locus, JMJD3 interacts with DDX21 (identified by mass spectrometry) and recruits DDX21 to the transcription start site and gene body. DDX21 resolves R-loops formed co-transcriptionally at ENPP2, enabling productive transcription. This JMJD3-DDX21 recruitment is controlled by a distant-acting enhancer. Mass spectrometry, co-immunoprecipitation, ChIP-qPCR, DRIP-qPCR (S9.6 antibody), CRISPR-Cas9 enhancer deletion Nucleic acids research Medium 31251802
2024 NAT10 acetyltransferase acetylates DDX21 at K236 and K573, enhancing DDX21 helicase activity to resolve nucleolar R-loops. Acetylation-mimicking DDX21 (2KQ) has increased helicase activity, and acetylation-deficient DDX21 (2KR) has decreased activity in vitro and in cells. NAT10 loss causes nucleolar R-loop accumulation and DNA damage, rescued by co-expression of acetylation-mimicking DDX21. Co-immunoprecipitation, GST pull-down, mass spectrometry for acetylation sites, in vitro helicase assay, immunofluorescence with RNase H control, CRISPR/shRNA knockdown, γH2AX measurement Cell communication and signaling High 39394182
2022 NAT10 and DDX21 interact with RNase H1 (via BioID proximity labeling confirmed biochemically). Purified NAT10 and DDX21 proteins enhance RNase H1 cleavage rates in vitro. Reduction of either protein decreases PS-ASO activity and increases R-loop levels and impairs pre-rRNA processing. BioID proximity labeling, co-immunoprecipitation, in vitro RNase H1 cleavage assay, DRIP, knockdown, northern blotting Nucleic acid therapeutics Medium 35852833
2021 In zebrafish, Ddx21 cell-autonomously regulates lymphatic vessel development by supporting Vegfc-Flt4-driven endothelial cell proliferation. Loss of Ddx21 reduces ribosome biogenesis, upregulates p53 and p21, and causes cell cycle arrest that blocks lymphangiogenesis. Zebrafish genetic screen, morpholino/mutant analysis, cell-autonomous transplantation experiments, immunofluorescence, ribosome biogenesis assays Nature cell biology Medium 34750583
2020 The phosphatase PRL3 binds DDX21 and restricts productive transcription elongation by RNAPII at MITF-regulated endolysosomal vesicle genes, controlling melanocyte stem cell differentiation. PRL3-DDX21 interaction limits transcriptional elongation as a differentiation checkpoint mechanism. Co-immunoprecipitation, ChIP-seq, RNAPII elongation assays, zebrafish genetic analysis, patient melanoma data Developmental cell Medium 32652076
2020 Nucleotide depletion (via DHODH inhibition with leflunomide) reduces DDX21 chromatin occupancy in melanoma cells. Progesterone receptor (Pgr) binds the RNA helicase Ddx21 (proteomics). DDX21 acts as a sensor and mediator of transcription during nucleotide stress, and ddx21-deficient zebrafish show resistance to leflunomide-induced neural crest defects. In vivo chemical suppressor screen (zebrafish), proteomics (Pgr-DDX21 interaction), ChIP-seq, nucleotide supplementation rescue Nature cell biology Medium 32231306
2018 DDX21 suppresses Snail transcription independently of its helicase activity by recruiting PRC2 subunits SUZ12 and EZH2 to the Snail promoter, establishing a double-negative feedback loop where Snail also represses DDX21 transcription. ChIP assay, co-immunoprecipitation, overexpression/knockdown, luciferase reporter, in vivo metastasis assay Cancer letters Medium 30165191
2019 DDX21 regulates protein expression of MAGED2 through an rG4 structure in the MAGED2 5'-UTR. Cells expressing rG4-binding-deficient DDX21 (M4 mutant) show halved MAGED2 protein (but not mRNA) levels, leading to elevated TRAIL-R2 and TRAIL-mediated apoptosis sensitivity. Label-free proteomics, western blotting, qRT-PCR, rG4-binding-deficient DDX21 mutant expression, TRAIL apoptosis assay RNA Medium 31653714
2022 DDX21 interacts with WDR5 and recruits it to the CDK1 gene promoter, enhancing H3K4me3 trimethylation to activate CDK1 transcription in colorectal cancer cells. DDX21 knockdown reduces CDK1 expression and causes G2/M phase arrest. Co-immunoprecipitation, ChIP assay, gene expression profiling, knockdown experiments, cell cycle analysis Journal of Cancer Medium 35371306
2022 In the context of nuclear RNA activation (RNAa), CDK9 and DDX21 form a complex with nuclear AGO and TNRC6A. DDX21 inhibition suppresses RNAa by miR-34a and other miRNAs without inhibiting post-transcriptional regulation, placing DDX21 as necessary for release of paused RNAPII during RNAa. Co-immunoprecipitation, siRNA knockdown, Pol II ChIP, reporter assay distinguishing transcriptional vs. post-transcriptional regulation Cell reports Medium 35417682
2021 DDX21 interacts with AGO2 in the nucleus in an RNA-dependent indirect manner. DDX21 upregulates AGO2 protein levels and participates in AGO2-dependent alternative splicing of SMN2. Co-immunoprecipitation, GST pulldown, immunofluorescence, splicing assays Bioscience, biotechnology, and biochemistry Low 33604619
2024 DDX21 interacts with TERT to regulate rRNA transcription by affecting the binding of RNA Pol I to rDNA. BRAF mutation upregulates DDX21 expression through the MEK/ERK/GABP transcription factor axis (GABPA binds the DDX21 promoter). DDX21 knockdown suppresses multiple cancer hallmark gene expressions. Co-immunoprecipitation, mass spectrometry, ChIP-seq, Ribo-seq, RNA-seq, luciferase reporter assay, MAPK inhibitor treatment Thyroid Medium 41817108
2024 Calmodulin (CaM) interacts with nucleolar DDX21 in a Ca2+-dependent manner. CaM alters DDX21 conformation to liberate DDX21-sequestered RPA194 (the catalytic subunit of RNA Pol I), facilitating rDNA transcription. This CaM-DDX21 interaction couples activity-induced Ca2+ influx to nucleolar rRNA biogenesis in hippocampal neurons. Co-immunoprecipitation, fluorescence binding assay, Ca2+ chelation, conformation assay, small molecule screening, axon growth assay The Journal of neuroscience Medium 39060175
2024 U3 snoRNA is the predominant DDX21-binding partner during mitosis; DDX21 colocalizes with U3 snoRNA in the perichromosomal region (PR). U3 snoRNA regulates DDX21 PR localization by maintaining its mobility; DDX21 knockdown causes mitotic catastrophe similar to U3 snoRNA depletion. In vitro, Cy5-U3 snoRNA downsizes fibrous DDX21 condensates at proper molecular ratios. RIP, immunofluorescence, FRAP, DDX21 knockdown, U3 snoRNA depletion, in vitro condensate assay Cell death & disease Medium 38760378
2023 DDX21 undergoes phase separation in vitro and in CRC cells via its intrinsically disordered region (IDR). Phase-separated DDX21 binds the MCM5 gene locus; IDR mutations disrupting phase separation reduce MCM5 binding. MCM5 overexpression rescues the impaired metastatic ability of DDX21-depleted cells, placing MCM5 as a downstream target. In vitro phase separation assay, IDR mutagenesis, ChIP, knockdown/rescue experiments, in vivo metastasis model Oncogene Medium 37029300
2023 LINC00240 lncRNA stabilizes DDX21 protein by recruiting the deubiquitinase USP10, which removes ubiquitin from DDX21 and prevents its proteasomal degradation. Co-immunoprecipitation, ubiquitination assay, USP10 overexpression/knockdown, western blotting Journal of experimental & clinical cancer research Medium 37072811
2024 TRIP13 (AAA+ ATPase) directly interacts with DDX21 and stabilizes it by restraining its ubiquitination degradation, promoting gastric cancer progression. Co-immunoprecipitation, ubiquitination assay, knockdown experiments, in vivo tumor model Cell death & disease Low 39187490
2025 DDX21 competitively binds SIRT7, relieving SIRT7-mediated inhibition of NAT10, thereby upregulating NAT10 expression and enhancing NAT10-mediated ac4C modification of ATAD2, SOX4, and SNX5 mRNAs in colorectal cancer. Co-immunoprecipitation, western blotting, MeRIP for ac4C, knockdown/overexpression, in vivo metastasis model Cell death & disease Low 40301349
2025 The small molecule KI-DX-014 (identified by small-molecule microarray against DDX21) inhibits DDX21-RNA interactions, reduces ATPase activity, modulates biomolecular condensate formation, and attenuates DDX21-dependent P-TEFb release from 7SK snRNP in vitro, suppressing RNAPII CTD phosphorylation. Small-molecule microarray, ATPase assay, condensate formation assay, in vitro 7SK snRNP P-TEFb release assay, zebrafish developmental assay ACS chemical biology Medium 40637641
2021 DDX21 inhibits FMDV IRES-dependent translation by binding FMDV IRES domains 2, 3, and 4. FMDV counteracts this by degrading DDX21 via its non-structural proteins 2B and 2C (through the caspase pathway) and 3Cpro (through the lysosomal pathway). Pulldown assay, dual-luciferase assay (IRES activity), knockdown/overexpression, confocal microscopy, pathway inhibitor experiments Viruses Medium 34578346
2025 HTLV-1 Gag interacts with DDX21 through zinc fingers in the NC domain, independently of RNA. DDX21 is packaged into virions. DDX21 alone enhances tRNAPro primer annealing to the HTLV-1 primer binding site, and DDX21 + RPL7 + Gag combination shows synergistic annealing activity. Affinity purification–mass spectrometry, reciprocal co-immunoprecipitation, domain-mapping, in vitro primer-annealing assays bioRxiv (preprint)preprint Medium 40791341
2025 Ddx21 interacts with the histone demethylase Kdm5a and co-occupies H3K4me3-marked active promoters. Loss of Ddx21 reduces H3K4me3 at rDNA and hematopoietic genes (cKit, Gata1). Kdm5a inhibition restores rRNA expression and translation in Ddx21-deficient fetal hematopoietic cells, demonstrating that Ddx21 sequesters Kdm5a to maintain active chromatin for ribosomal transcription. Conditional knockout, multi-omics (ChIP-seq, RNA-seq, ribosome profiling), co-immunoprecipitation, Kdm5a inhibitor rescue bioRxiv (preprint)preprint Medium bio_10.1101_2025.09.04.674186

Source papers

Stage 0 corpus · 78 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 306 21703541
2014 RNA helicase DDX21 coordinates transcription and ribosomal RNA processing. Nature 266 25470060
2017 SLERT Regulates DDX21 Rings Associated with Pol I Transcription. Cell 238 28475895
2019 Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21. Molecular cell 215 31351877
2017 SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability. Genes & development 198 28790157
2014 DAMP molecule S100A9 acts as a molecular pattern to enhance inflammation during influenza A virus infection: role of DDX21-TRIF-TLR4-MyD88 pathway. PLoS pathogens 155 24391503
2014 Cellular DDX21 RNA helicase inhibits influenza A virus replication but is counteracted by the viral NS1 protein. Cell host & microbe 99 24721576
2017 Human DDX21 binds and unwinds RNA guanine quadruplexes. Nucleic acids research 87 28472472
2014 Elevated DDX21 regulates c-Jun activity and rRNA processing in human breast cancers. Breast cancer research : BCR 70 25260534
2014 The association of late-acting snoRNPs with human pre-ribosomal complexes requires the RNA helicase DDX21. Nucleic acids research 68 25477391
2023 Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation. Cell 60 36608661
2023 Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway. Oncogene 60 37029300
2024 DDX21 mediates co-transcriptional RNA m6A modification to promote transcription termination and genome stability. Molecular cell 58 38569554
2008 c-Jun supports ribosomal RNA processing and nucleolar localization of RNA helicase DDX21. The Journal of biological chemistry 56 18180292
2016 DDX21 translocates from nucleus to cytoplasm and stimulates the innate immune response due to dengue virus infection. Biochemical and biophysical research communications 48 27033607
2018 A double-negative feedback loop between DEAD-box protein DDX21 and Snail regulates epithelial-mesenchymal transition and metastasis in breast cancer. Cancer letters 45 30165191
2020 RNA helicase DDX21 mediates nucleotide stress responses in neural crest and melanoma cells. Nature cell biology 42 32231306
2021 The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function. Nature cell biology 40 34750583
2020 Structural Basis of Human Helicase DDX21 in RNA Binding, Unwinding, and Antiviral Signal Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 40 32714761
2018 DDX21 promotes gastric cancer proliferation by regulating cell cycle. Biochemical and biophysical research communications 40 30322617
2020 PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation. Developmental cell 35 32652076
2023 LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization. Journal of experimental & clinical cancer research : CR 32 37072811
2020 The Human RNA Helicase DDX21 Presents a Dimerization Interface Necessary for Helicase Activity. iScience 31 33313488
2019 Enhancer-mediated enrichment of interacting JMJD3-DDX21 to ENPP2 locus prevents R-loop formation and promotes transcription. Nucleic acids research 29 31251802
2024 Lnc-PLCB1 is stabilized by METTL14 induced m6A modification and inhibits Helicobacter pylori mediated gastric cancer by destabilizing DDX21. Cancer letters 27 38387756
2020 Long non-coding RNA ZFAS1 promotes colorectal cancer tumorigenesis and development through DDX21-POLR1B regulatory axis. Aging 27 33202381
2021 Caspase-Dependent Cleavage of DDX21 Suppresses Host Innate Immunity. mBio 26 34125604
2021 DDX21, a Host Restriction Factor of FMDV IRES-Dependent Translation and Replication. Viruses 24 34578346
2017 A Survey of DDX21 Activity During Rev/RRE Complex Formation. Journal of molecular biology 24 28705764
1997 Effects of cytotoxic drugs on translocation of nucleolar RNA helicase RH-II/Gu. Experimental cell research 24 9299166
2019 Dissecting the Role of DDX21 in Regulating Human Cytomegalovirus Replication. Journal of virology 23 31554690
2021 The RNA-helicase DDX21 upregulates CEP55 expression and promotes neuroblastoma. Molecular oncology 22 33497018
2024 m6A-dependent upregulation of DDX21 by super-enhancer-driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia. Clinical and translational medicine 20 38572589
2019 An RNA guanine quadruplex regulated pathway to TRAIL-sensitization by DDX21. RNA (New York, N.Y.) 19 31653714
2013 Nucleolar scaffold protein, WDR46, determines the granular compartmental localization of nucleolin and DDX21. Genes to cells : devoted to molecular & cellular mechanisms 18 23848194
1999 Adriamycin inhibits human RH II/Gu RNA helicase activity by binding to its substrate. Biochemical and biophysical research communications 18 10600508
2022 2B and 3C Proteins of Senecavirus A Antagonize the Antiviral Activity of DDX21 via the Caspase-Dependent Degradation of DDX21. Frontiers in immunology 17 35911774
2022 DEAD-Box RNA Helicase 21 (DDX21) Positively Regulates the Replication of Porcine Reproductive and Respiratory Syndrome Virus via Multiple Mechanisms. Viruses 16 35336874
2022 DDX21 Interacts with WDR5 to Promote Colorectal Cancer Cell Proliferation by Activating CDK1 Expression. Journal of Cancer 16 35371306
2022 Nuclear microRNAs release paused Pol II via the DDX21-CDK9 complex. Cell reports 16 35417682
2021 Downregulation of DEAD-box helicase 21 (DDX21) inhibits proliferation, cell cycle, and tumor growth in colorectal cancer via targeting cell division cycle 5-like (CDC5L). Bioengineered 16 34903139
2018 Insights into the RNA quadruplex binding specificity of DDX21. Biochimica et biophysica acta. General subjects 16 29906500
2021 DDX21 interacts with nuclear AGO2 and regulates the alternative splicing of SMN2. Bioscience, biotechnology, and biochemistry 11 33604619
2021 DDX21 is a p38-MAPK-sensitive nucleolar protein necessary for mouse preimplantation embryo development and cell-fate specification. Open biology 10 34255976
2012 Isolation of human mitotic protein phosphatase complexes: identification of a complex between protein phosphatase 1 and the RNA helicase Ddx21. PloS one 10 22761809
1998 Green fluorescent protein tag for studies of drug-induced translocation of nucleolar protein RH-II/Gu. BioTechniques 10 9631199
2021 Downregulation of lncRNA HCP5 has inhibitory effects on gastric cancer cells by regulating DDX21 expression. Cytotechnology 9 33505109
2021 Identification of MDM2, YTHDF2 and DDX21 as potential biomarkers and targets for treatment of type 2 diabetes. Biochemical and biophysical research communications 9 34688145
2024 NAT10 resolves harmful nucleolar R-loops depending on its helicase domain and acetylation of DDX21. Cell communication and signaling : CCS 8 39394182
2022 NAT10 and DDX21 Proteins Interact with RNase H1 and Affect the Performance of Phosphorothioate Oligonucleotides. Nucleic acid therapeutics 8 35852833
2024 TRIP13 regulates progression of gastric cancer through stabilising the expression of DDX21. Cell death & disease 7 39187490
2001 Immunocytochemical localization of nucleophosmin and RH-II/Gu protein in nucleoli of HeLa cells after treatment with actinomycin D. Acta histochemica 7 11482378
2024 DDX21 functions as a potential novel oncopromoter in pancreatic ductal adenocarcinoma: a comprehensive analysis of the DExD box family. Discover oncology 6 39095628
2024 The RNA helicase DDX21 activates YAP to promote tumorigenesis and is transcriptionally upregulated by β-catenin in colorectal cancer. Oncogene 5 39285230
2025 Competitive binding between DDX21 and SIRT7 enhances NAT10-mediated ac4C modification to promote colorectal cancer metastasis and angiogenesis- DDX21 promotes colorectal cancer metastasis. Cell death & disease 4 40301349
2024 U3 snoRNA inter-regulates with DDX21 in the perichromosomal region to control mitosis. Cell death & disease 4 38760378
2024 Calmodulin Triggers Activity-Dependent rRNA Biogenesis via Interaction with DDX21. The Journal of neuroscience : the official journal of the Society for Neuroscience 4 39060175
2024 DDX21 at the Nexus of RNA Metabolism, Cancer Oncogenesis, and Host-Virus Crosstalk: Decoding Its Biomarker Potential and Therapeutic Implications. International journal of molecular sciences 4 39769343
2023 RRP9 and DDX21 as new biomarkers of colorectal cancer. Medicine 4 37904456
2024 DDX21: The link between m6A and R-loops. Molecular cell 3 38701738
2023 Joint effect of RRP9 and DDX21 on development of colorectal cancer and keloid. Aging 3 37988222
2022 Protein purification, crystallization, and structure determination of human DEAD-box RNA helicase DDX21 in different unwinding states. STAR protocols 3 36042885
2025 TAMs-derived IL-1β inducing DDX21 enhances CRC proliferation and metastasis via JAK2/STAT3 pathway. Cancer treatment and research communications 2 41160952
2025 Ddx21 mutant peptide is an effective neoantigen in prophylactic lung cancer vaccines and activates long-term anti-tumor immunity. Frontiers in immunology 1 39981234
2025 DDX21 Controls Cell Cycle Progression and Autophagy in Pancreatic Cancer Cells. Cancers 1 40002164
2025 DDX21 Promotes PCV3 Replication by Binding to Cap Protein and Inhibiting Interferon Responses. Viruses 1 40006921
2025 Epigenetic Silencing of miR-218-5p Modulates BIRC5 and DDX21 Expression to Promote Colorectal Cancer Progression. International journal of molecular sciences 1 40362385
2025 [Effect and mechanism of DDX21 on improving myocardial ischemia-reperfusion injury by regulating ATP5J alternative splicing]. Zhonghua xin xue guan bing za zhi 1 40528601
2025 Chemical Probe Discovery for DEAD-Box RNA-Binding Protein DDX21 Using Small-Molecule Microarrays. ACS chemical biology 1 40637641
2025 The tegument protein VP22 of pseudorabies virus inhibits cGAS condensation by inducing nuclear-to-cytoplasmic translocation of DDX21. PLoS pathogens 1 41021645
2026 Chicken DDX21 inhibits H9N2 avian influenza virus replication by modulating type I interferon signaling pathway. Developmental and comparative immunology 0 41763505
2026 DDX21 Links BRAF and TERT to Promote Thyroid Cancer Progression. Thyroid : official journal of the American Thyroid Association 0 41817108
2026 Ubiquitination of DDX21 by HERC2 induces a dormancy-like phenotype via the NUCKS1-p21/p27 axis to promote radio-resistance in colorectal cancer cells. Cell death & disease 0 42071007
2026 The RPS15-DDX21 complex drives prostate malignancy through transcriptional activation of SCD1. Oncogene 0 42098442
2026 RNA Helicase DDX21 Controls CD4+ T Cell Proliferation and Promotes Inflammatory Bowel Disease via Translational Control. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 42210780
2025 Human RPL7 and DDX21 interact with HTLV-1 Gag and enhance tRNAPro primer annealing to genomic RNA. bioRxiv : the preprint server for biology 0 40791341
2025 DDX21 nuclear-cytoplasmic shuttling recruits RPS18 to viral dsRNA to promote CSFV replication. Veterinary microbiology 0 41337972
2024 Nucleolar Localization of the RNA Helicase DDX21 Predicts Survival Outcomes in Gynecologic Cancers. Cancer research communications 0 38767454

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