Affinage

DDX21

Nucleolar RNA helicase 2 · UniProt Q9NR30

Length
783 aa
Mass
87.3 kDa
Annotated
2026-04-28
75 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DDX21 is a nucleolar DEAD-box RNA helicase that integrates ribosome biogenesis, transcription regulation, R-loop resolution, and innate immune sensing. In the nucleolus, DDX21 promotes rRNA transcription, processing, and modification by facilitating ordered snoRNP assembly on pre-rRNA, forming ring-shaped structures that modulate Pol I activity — relieved by the lncRNA SLERT — and its nucleolar retention requires ADP-ribosylation by PARP-1 and interactions with c-Jun and WDR46 (PMID:25470060, PMID:25477391, PMID:28475895, PMID:31351877, PMID:18180292). In the nucleoplasm, DDX21 promotes Pol II elongation by releasing P-TEFb from the 7SK snRNP complex, resolves co-transcriptional R-loops in a manner regulated by opposing acetylation (NAT10/CBP) and deacetylation (SIRT7), recruits METTL3 to deposit m6A on nascent RNA for transcription termination, and — upon glucose-induced dimer dissociation during differentiation — switches to promoting mRNA splicing of pro-differentiation genes (PMID:25470060, PMID:28790157, PMID:39394182, PMID:38569554, PMID:36608661). Structurally, DDX21 functions as a dimer whose C-terminal Arg/Gly-rich domain mediates RNA G-quadruplex unwinding, and crystal structures reveal open-to-closed conformational transitions during the ATPase cycle (PMID:32714761, PMID:33313488, PMID:28472472). In the cytoplasm, DDX21 forms a complex with DDX1, DHX36, and TRIF to sense dsRNA and activate type I interferon responses, a pathway negatively regulated by caspase-3/6 cleavage of DDX21 at D126 following viral infection (PMID:21703541, PMID:34125604).

Mechanistic history

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

    Establishing DDX21 as a dynamic nucleolar helicase: the initial question of whether DDX21 was a fixed nucleolar component was resolved by showing reversible nucleolus-to-nucleoplasm translocation upon transcriptional stress, indicating its localization is actively regulated.

    Evidence Immunofluorescence of drug-treated and drug-washout MCF-7 cells

    PMID:9299166

    Open questions at the time
    • Drug mechanism of translocation not defined
    • No identification of translocation signals or post-translational modifications involved
  2. 1999 High

    Confirming DDX21 possesses bona fide RNA helicase activity resolved whether the predicted DEAD-box motif was catalytically functional.

    Evidence In vitro helicase assay with baculovirus-expressed recombinant DDX21 on 5'-tailed dsRNA

    PMID:10600508

    Open questions at the time
    • Substrate specificity in vivo unknown
    • No structural information on the catalytic mechanism
  3. 2008 High

    Identification of c-Jun as a direct DDX21 interactor that controls nucleolar localization and rRNA binding established that DDX21 function depends on signal-regulated protein partners, not just intrinsic RNA-binding properties.

    Evidence Co-IP, siRNA knockdown with rescue, RNA binding and rRNA accumulation assays

    PMID:18180292

    Open questions at the time
    • How c-Jun reaches the nucleolus to interact with DDX21 is unclear
    • Signaling pathways controlling c-Jun–DDX21 interaction unresolved
  4. 2011 High

    Discovery of an unexpected cytoplasmic innate immune role answered whether DDX21 functions outside ribosome biogenesis: DDX21 forms a DDX1–DDX21–DHX36–TRIF complex that senses dsRNA and activates type I IFN in myeloid dendritic cells.

    Evidence Poly I:C pulldown/MS, domain mapping, shRNA knockdown with cytokine readouts across multiple viral stimuli

    PMID:21703541

    Open questions at the time
    • How DDX21 is partitioned between nucleolar and cytoplasmic pools is unresolved
    • Structural basis of DDX21–TRIF interaction unknown
  5. 2014 High

    Genome-wide profiling revealed DDX21 occupies both Pol I and Pol II genes and couples ribosome biogenesis to Pol II transcription elongation by releasing P-TEFb from 7SK snRNP, answering how a single helicase coordinates two transcription machineries.

    Evidence ChIP-seq, CLIP-seq, RIP, helicase-dead mutant analysis in human cells

    PMID:25470060

    Open questions at the time
    • How DDX21 chromatin occupancy is targeted to specific Pol II genes is unclear
    • Whether P-TEFb release requires additional cofactors is unresolved
  6. 2014 High

    Mapping DDX21 crosslinking sites on pre-rRNA revealed it is required specifically for late-acting snoRNP (SNORD56, SNORD68) association with pre-40S particles, establishing a hierarchical role in ribosome maturation rather than a generic chaperone function.

    Evidence UV crosslinking/CRAC, snoRNA co-IP, DDX21 depletion with snoRNP association readout

    PMID:25477391

    Open questions at the time
    • Mechanism by which DDX21 remodels pre-rRNA structure to permit snoRNP access is unknown
    • Whether DDX21 similarly controls snoRNP association on pre-60S particles is untested
  7. 2014 High

    Demonstrating that DDX21 restricts influenza A virus by binding PB1 and that NS1 counteracts this restriction established DDX21 as a direct antiviral effector beyond innate signaling.

    Evidence Co-IP, pulldown, DDX21 knockdown with viral replication quantification, NS1 domain mapping, viral mutant analysis

    PMID:24721576

    Open questions at the time
    • Whether DDX21 restricts other segmented RNA viruses via polymerase binding is unknown
    • Structural basis of PB1–DDX21 interaction unresolved
  8. 2017 High

    Super-resolution imaging revealed DDX21 forms ring-shaped nucleolar structures that suppress Pol I, allosterically relieved by lncRNA SLERT — resolving the paradox of how a ribosome biogenesis factor can also restrain rRNA transcription.

    Evidence Super-resolution microscopy, RNA pulldown, CRISPR deletion, quantitative rRNA transcription assays

    PMID:28475895

    Open questions at the time
    • Molecular basis of ring formation and SLERT-induced allosteric change is unknown
    • Whether other lncRNAs similarly modulate DDX21 rings is untested
  9. 2017 High

    DDX21 was shown to unwind R-loops in vitro and in cells, with activity regulated by opposing acetylation (CBP) and deacetylation (SIRT7), answering what resolves co-transcriptional R-loops and how this resolution is tuned.

    Evidence In vitro R-loop unwinding assay, γH2AX and S9.6 immunofluorescence, SIRT7/CBP epistasis

    PMID:28790157

    Open questions at the time
    • Specific acetylation sites regulating activity were not mapped in this study
    • Whether R-loop resolution and dsRNA unwinding use the same catalytic mechanism is unclear
  10. 2017 High

    Discovery that DDX21 binds and unwinds RNA G-quadruplexes via its C-terminal domain expanded the substrate repertoire beyond canonical duplexes and R-loops.

    Evidence MS-guided pulldown, biochemical binding and unwinding assays, reporter gene expression

    PMID:28472472

    Open questions at the time
    • In vivo G4 targets of DDX21 not comprehensively mapped
    • Structural basis of C-terminal G4 recognition unclear
  11. 2019 High

    PARP-1 was identified as the enzyme that ADP-ribosylates DDX21 in the nucleolus, directly linking snoRNA-activated PARP-1 to DDX21 nucleolar retention and rDNA transcription — answering what post-translational modification anchors DDX21 in the nucleolus.

    Evidence ADP-ribosylation assays, site-directed mutagenesis, PARP inhibitor treatment, xenograft models

    PMID:31351877

    Open questions at the time
    • Interplay between ADP-ribosylation and acetylation on DDX21 activity not studied
    • Whether PARP-1 ADP-ribosylation competes with other nucleolar helicase substrates is unknown
  12. 2020 High

    Crystal structures of DDX21 in apo, pre-hydrolysis, and post-hydrolysis states revealed the open-to-closed conformational cycle and identified key catalytic elements (wedge helix, sensor motif V, DEVD box), providing the first structural framework for DDX21 mechanism.

    Evidence X-ray crystallography (three states), ATPase and unwinding assays, mutagenesis

    PMID:32714761

    Open questions at the time
    • No structure of DDX21 bound to R-loop or G-quadruplex substrate
    • No structure of the full-length dimer
  13. 2020 High

    SAXS analysis established DDX21 functions as a dimer whose dimerization is essential for both ATP-dependent dsRNA unwinding and ATP-independent G4 remodeling, resolving why monomeric constructs showed reduced activity.

    Evidence SAXS, in vitro helicase assays with dimerization domain mutants, RNA binding assays

    PMID:33313488

    Open questions at the time
    • Atomic-resolution structure of the dimer interface not determined
    • How glucose-induced dimer dissociation alters substrate preference in cells is only partially characterized
  14. 2021 High

    Caspase-3/6 cleavage of DDX21 at D126 following viral infection was shown to translocate it to the cytoplasm and suppress DDX1–DDX21–DHX36 complex formation, establishing a negative feedback loop that limits type I IFN signaling.

    Evidence Cleavage site mutagenesis (D126), subcellular fractionation, Co-IP of complex, IFN-β reporter

    PMID:34125604

    Open questions at the time
    • Whether caspase cleavage also affects DDX21 helicase activity is untested
    • In vivo immunological consequences of non-cleavable DDX21 not studied
  15. 2021 High

    Zebrafish genetics revealed a cell-autonomous requirement for Ddx21 in lymphangiogenesis downstream of Vegfc-Flt4 signaling, connecting ribosome biogenesis deficiency to p53/p21 activation and endothelial cell cycle arrest — demonstrating tissue-specific developmental consequences of DDX21 loss.

    Evidence Zebrafish genetic screen, tissue-specific loss-of-function, ribosome biogenesis and cell cycle assays

    PMID:34750583

    Open questions at the time
    • Whether p53 activation is the sole mediator or additional DDX21-dependent pathways contribute is unclear
    • Human relevance for vascular phenotype not established
  16. 2023 High

    Glucose was identified as a direct metabolite ligand of DDX21 that binds the ATP-binding domain, dissociates dimers, and redirects DDX21 to the nucleoplasm to promote splicing of differentiation genes — revealing an unexpected metabolite-sensing function that couples nutrient status to gene expression programs.

    Evidence Azido-glucose click chemistry, helicase assays, eCLIP, splicing assays in differentiating keratinocytes

    PMID:36608661

    Open questions at the time
    • Whether other metabolites similarly regulate DDX21
    • How glucose concentration is sensed in the nucleolus versus nucleoplasm
    • Structural basis of glucose binding to the ATP-binding pocket not determined
  17. 2024 High

    DDX21 was shown to recruit METTL3 to chromatin via R-loop recognition, enabling m6A deposition on nascent RNA that promotes XRN2-mediated transcription termination — answering how R-loop sensing is coupled to epitranscriptomic modification and Pol II termination.

    Evidence ChIP-seq, m6A-seq, Co-IP of DDX21–METTL3, helicase-dead and catalytic mutants, DNA damage assays

    PMID:38569554

    Open questions at the time
    • Whether DDX21–METTL3 coupling operates genome-wide or at specific gene classes is incompletely defined
    • Structural basis of DDX21–METTL3 interaction unknown
  18. 2024 High

    NAT10 was identified as an acetyltransferase that acetylates DDX21 at K236/K573 to enhance helicase activity for nucleolar R-loop resolution, complementing the earlier CBP/SIRT7 acetylation axis and revealing that DDX21 R-loop resolution is tuned by multiple acetyltransferase-deacetylase pairs.

    Evidence MS acetylation site mapping, GST pulldown, in vitro helicase assay with K→R and K→Q mutants, S9.6 and γH2AX assays

    PMID:39394182

    Open questions at the time
    • Whether NAT10 and CBP target the same or different DDX21 residues is not directly compared
    • Physiological stimuli that shift NAT10 versus SIRT7 acetylation balance are not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the full-length dimer structure in complex with R-loop or G-quadruplex substrates; how DDX21 partitioning between nucleolus, nucleoplasm, and cytoplasm is coordinately regulated by its multiple post-translational modifications; and whether DDX21's metabolite-sensing and immune-sensing functions are interconnected in physiological or pathological settings.
  • No full-length DDX21 dimer structure with physiological substrate
  • No integrative model of how ADP-ribosylation, acetylation, glucose binding, and caspase cleavage are prioritized
  • In vivo genetic models linking immune and ribosome biogenesis functions are 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 5 GO:0098772 molecular function regulator activity 4 GO:0140299 molecular sensor activity 3
Localization
GO:0005730 nucleolus 6 GO:0005654 nucleoplasm 4 GO:0005829 cytosol 2 GO:0005694 chromosome 1
Pathway
R-HSA-8953854 Metabolism of RNA 5 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-73894 DNA Repair 3
Partners
DDX1DHX36METTL3NAT10PARP1SIRT7TRIFWDR46
Complex memberships
7SK snRNPDDX1-DDX21-DHX36-TRIF

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 DDX21, DDX1, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in the cytosol of myeloid dendritic cells. DDX21 binds the TIR domain of TRIF via its PRK domain, and knockdown of DDX21 blocks type I IFN and cytokine responses to dsRNA, influenza A virus, and reovirus. poly I:C pulldown/MS identification, domain binding mapping, shRNA knockdown with functional cytokine/IFN readout, subcellular fractionation Immunity High 21703541
2014 DDX21 associates broadly with Pol I- and Pol II-transcribed genes and diverse RNA species. In the nucleolus, DDX21 directly contacts rRNA and snoRNAs and promotes rRNA transcription, processing and modification. In the nucleoplasm, DDX21 binds 7SK RNA as a component of the 7SK snRNP complex and, at Pol II gene promoters encoding ribosomal proteins and snoRNAs, facilitates P-TEFb release from 7SK snRNP in a helicase-activity-dependent manner to promote transcription elongation. ChIP-seq, CLIP-seq, RNA immunoprecipitation, helicase-dead mutant analysis, subcellular fractionation, knockdown with transcriptional readouts Nature High 25470060
2017 DDX21 forms ring-shaped structures surrounding multiple Pol I complexes in the nucleolus and suppresses pre-rRNA transcription. The lncRNA SLERT interacts with DDX21 via a 143-nt non-snoRNA sequence, allosterically alters individual DDX21 molecules, loosens the DDX21 ring, and thereby relieves DDX21-mediated suppression of Pol I transcription. super-resolution microscopy, RNA pulldown, CRISPR deletion, quantitative rRNA transcription 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. PARP inhibition or mutation of DDX21 ADP-ribosylation sites reduces DDX21 nucleolar localization and consequently reduces rDNA transcription, ribosome biogenesis, protein translation, and cell growth. PARP-1 ADP-ribosylation assays, site-directed mutagenesis of ADP-ribosylation sites, nucleolar fractionation, PARP inhibitor treatment, xenograft models Molecular cell High 31351877
2017 DDX21 efficiently unwinds R-loops in vitro and in cells; depletion of DDX21 leads to accumulation of R loops and DNA double-strand breaks. DDX21 helicase activity is regulated by acetylation: CBP-mediated acetylation inhibits DDX21, while SIRT7-mediated deacetylation augments helicase activity, enabling resolution of R-loop-mediated transcription stalling. In vitro R-loop unwinding assay, SIRT7/CBP knockdown, DNA damage markers (γH2AX), R-loop immunofluorescence (S9.6 antibody), epistasis experiments Genes & development High 28790157
2014 DDX21 restricts influenza A virus replication by binding the viral polymerase subunit PB1, inhibiting polymerase assembly and reducing viral RNA and protein synthesis. Later during infection, the viral NS1 protein binds DDX21 and displaces PB1, overcoming this restriction. Sequential interaction of PB1 and NS1 with DDX21 temporally regulates viral gene expression. Co-IP, pulldown, DDX21 knockdown with viral replication readout, NS1 binding domain mapping, viral mutant analysis Cell host & microbe High 24721576
2017 DDX21 binds RNA guanine quadruplexes (G4s) directly; the interaction is mediated via the C-terminus of DDX21. DDX21 can unwind RNA G4 structures and suppresses the expression of a reporter protein containing G4s in its 3' UTR. Mass spectrometry-guided pulldown from cell lysate, biochemical binding assays, nuclease sensitivity assay, reporter gene expression Nucleic acids research High 28472472
2014 DDX21 is required for the association of late-acting snoRNPs (SNORD56, SNORD68) with pre-40S ribosomal particles. DDX21 crosslinking sites on pre-rRNA overlap with basepairing sites of these snoRNAs. Earlier snoRNP associations are not affected, revealing a hierarchical role for DDX21 in ordered snoRNP function during pre-40S maturation. UV crosslinking/CRAC mapping, snoRNA-pre-rRNA co-immunoprecipitation, DDX21 depletion with snoRNP association readout Nucleic acids research High 25477391
2008 c-Jun directly interacts with DDX21 and is required for DDX21 nucleolar localization and rRNA binding. Depletion of c-Jun causes partial translocation of DDX21 from nucleolus to nucleoplasm, inhibits DDX21 binding to rRNA, and reduces 28S and 18S rRNA accumulation; nucleolar localization of DDX21 is rescued by exogenous c-Jun. siRNA knockdown, co-immunoprecipitation, RNA binding assay, immunofluorescence-based localization The Journal of biological chemistry High 18180292
2024 DDX21 recruits the m6A methyltransferase METTL3 to chromatin via recognition of co-transcriptionally formed R-loops. DDX21's helicase activity is required for METTL3-mediated m6A deposition onto nascent RNA. At transcription termination regions, this action promotes XRN2-mediated RNAPII termination, and disruption of DDX21, METTL3, or their enzymatic activities leads to defective termination and DNA damage. ChIP-seq, m6A-seq, Co-IP of DDX21-METTL3, helicase-dead and enzymatic mutants, DNA damage assays, R-loop mapping Molecular cell High 38569554
2023 Glucose binds the ATP-binding domain of DDX21, altering protein conformation, inhibiting helicase activity, and dissociating DDX21 dimers. Glucose elevation during keratinocyte differentiation promotes DDX21 relocalization from the nucleolus to the nucleoplasm, where DDX21 assembles into complexes with RNA splicing factors and promotes splicing of pro-differentiation genes (GRHL3, KLF4, OVOL1, RBPJ) via binding a specific SCUGSDGC motif in mRNA introns. Azido-glucose click chemistry, biochemical helicase assays, conformational analysis, fractionation, eCLIP, splicing assays, loss-of-function Cell High 36608661
2020 Crystal structures of human DDX21 were determined in three states (apo, AMPPNP+ssRNA pre-hydrolysis, ADP post-hydrolysis), revealing open-to-closed conformational change upon RNA binding. The RNA unwinding core includes a wedge helix, sensor motif V, and the DEVD box. DDX21 unwinds dsRNA cooperatively. The influenza NS1 protein inhibits DDX21 ATPase and unwinding activities via small RNAs that cooperatively assemble with DDX21 and NS1. X-ray crystallography, ATPase assays, unwinding assays, Hill coefficient analysis, mutagenesis (D339H/E340G) Advanced science High 32714761
2020 DDX21 is dimeric; its oligomerization is mediated by a central dimerization domain identified by SAXS. The C-terminal Arg/Gly-rich domain maintains high RNA affinity, while an intact dimer is essential for both ATP-dependent dsRNA unwinding and ATP-independent G-quadruplex remodeling activities. SAXS, in vitro helicase assays with dimerization mutants, RNA binding assays iScience High 33313488
2021 Caspase-3/6 cleaves DDX21 at D126 following virus infection or RNA/DNA ligand treatment, promoting DDX21 translocation from the nucleus to the cytoplasm. The cytoplasmic cleaved DDX21 negatively regulates IFN-β signaling by suppressing formation of the DDX1-DDX21-DHX36 complex, acting as a negative feedback regulator of innate immunity. Caspase cleavage site mapping, site-directed mutagenesis (D126), subcellular fractionation, Co-IP of complex formation, IFN-β reporter assay mBio High 34125604
2019 DDX21 binds RNA G-quadruplexes through interaction primarily with the phosphoribose backbone, and recognizes TERRA G-quadruplex. Specificity for TERRA is mediated by interactions with the 2'-OH of loop nucleotides, demonstrated by 2'-OH mutation reducing DDX21 affinity for G-quadruplex. 2D saturation transfer difference NMR, 2'-OH mutagenesis, binding assays Biochimica et biophysica acta. General subjects High 29906500
2014 DDX21 is required for rRNA processing in breast cancer cells and promotes c-Jun phosphorylation at Ser73, which is required for AP-1 transcriptional activity; DDX21 deficiency reduces AP-1 activity and leads to apoptosis. Nuclear (non-nucleolar) localization of DDX21 correlates with AP-1 regulation independently of its nucleolar rRNA processing function. siRNA knockdown, rRNA processing assay, AP-1 luciferase reporter, c-Jun phosphorylation western blot, immunofluorescence localization, xenograft Breast cancer research Medium 25260534
2013 The nucleolar scaffold protein WDR46 is required for proper recruitment of DDX21 (and nucleolin) to the granular component of the nucleolus during cell division. WDR46 knockdown causes mislocalization of DDX21 to the edges of nucleoli in daughter cells. WDR46 directly binds DDX21 through its intrinsically disordered regions. WDR46 knockdown, immunofluorescence localization, Co-IP binding Genes to cells Medium 23848194
1997 DDX21 (RH-II/Gu) is a nucleolar RNA helicase that translocates from the nucleolus to the nucleoplasm in response to cytotoxic drugs (actinomycin D, toyocamycin, mycophenolic acid), with translocation reversible upon drug removal. Immunofluorescence localization in drug-treated MCF-7 cells, drug removal reversal experiments Experimental cell research Medium 9299166
1999 DDX21 (RH-II/Gu) has RNA helicase activity on a 5'-tailed dsRNA substrate in vitro. Adriamycin inhibits DDX21 helicase activity by binding to the RNA substrate (IC50 ~40 µM), not directly to the protein. Baculovirus-expressed recombinant DDX21, in vitro helicase assay, dose-response inhibition, gel electrophoresis binding assay Biochemical and biophysical research communications High 10600508
2019 JMJD3 (KDM6B) interacts with DDX21 (identified by mass spectrometry); upon LPS stimulation, JMJD3 recruits DDX21 to the ENPP2 gene locus in a non-enzymatic manner to resolve aberrant R-loops formed by nascent transcripts, promoting transcription. CRISPR deletion of a distant enhancer reduces JMJD3-DDX21 recruitment and ENPP2 expression. Mass spectrometry, Co-IP, ChIP, R-loop detection (S9.6), CRISPR enhancer deletion Nucleic acids research Medium 31251802
2021 In zebrafish, Ddx21 cell-autonomously regulates lymphatic vessel development downstream of Vegfc-Flt4 signaling. Loss of Ddx21 reduces ribosome biogenesis and activates p53 and p21, causing endothelial cell cycle arrest that blocks lymphangiogenesis. Zebrafish genetic screen, tissue-specific loss-of-function, ribosome biogenesis assays, p53/p21 expression, cell cycle analysis Nature cell biology High 34750583
2020 PRL3 phosphatase binds DDX21 and restricts productive Pol II transcription at MITF-regulated endolysosomal vesicle genes, controlling melanocyte stem cell differentiation. This transcriptional elongation control is a differentiation checkpoint mechanism. Co-IP of PRL3-DDX21, ChIP-seq, zebrafish loss-of-function, transcription elongation assays Developmental cell Medium 32652076
2020 DDX21 acts as a sensor of nucleotide stress; nucleotide depletion (DHODH inhibition with leflunomide) reduces chromatin occupancy of DDX21 in melanoma cells, and nucleotide supplementation reverses DDX21 occupancy changes and gene expression effects. The progesterone receptor (Pgr) binds the RNA helicase Ddx21 (identified by proteomics). In vivo zebrafish chemical suppressor screen, ChIP-seq of DDX21 chromatin occupancy, proteomics (Pgr-Ddx21 interaction), ddx21 morphant/mutant zebrafish Nature cell biology Medium 32231306
2012 DDX21 (Ddx21/Gu) is a direct interactor of protein phosphatase PP1, identified at the mitotic spindle, placing DDX21 in a PP1-containing complex with roles in mitotic chromatin regulation. Affinity purification from mitotic spindle fractions, mass spectrometry, direct PP1-DDX21 interaction validated biochemically PloS one Medium 22761809
2017 DDX21 binds the HIV-1 Rev Response Element (RRE) with high affinity, stimulating ATPase activity. DDX21 has both ATP-dependent and ATP-independent helicase activities. Rev inhibits ATPase and ATP-dependent helicase activity of DDX21 in a dose-dependent manner via interaction with DDX21's DEAD domain (with Rev's nuclear diffusion inhibitory signal motif contributing). DDX21 enhances Rev binding to the RRE, similar to DDX1. In vitro RNA binding assay, ATPase assay, helicase assay, domain mapping by pulldown, Rev dose-response inhibition Journal of molecular biology High 28705764
2019 DDX21 regulates expression of MAGED2 protein through binding to an RNA G-quadruplex in the 5'-UTR of MAGED2 mRNA; loss of DDX21 G-quadruplex binding (M4 mutant) reduces MAGED2 protein levels without affecting mRNA, leading to elevated TRAIL-R2 expression and TRAIL-mediated apoptosis sensitization. Proteomics (label-free MS), rG4-binding deficient mutant (M4), western blot, RT-PCR, TRAIL apoptosis assay RNA Medium 31653714
2024 NAT10 acetylates DDX21 at K236 and K573, enhancing DDX21 helicase activity to unwind nucleolar R-loops. Acetylation-mimicking (K→Q) mutation increases DDX21 helicase activity in vitro and in cells; acetylation-dead (K→R) mutation decreases it. NAT10 and DDX21 cooperate bipartitely (via NAT10's own helicase domain and via DDX21 acetylation) to resolve nucleolar R-loops and prevent DNA damage. Mass spectrometry (acetylation site mapping), Co-IP, GST pulldown, in vitro helicase assay, site-directed mutagenesis (2KR and 2KQ), R-loop immunofluorescence (S9.6), γH2AX assay Cell communication and signaling High 39394182
2022 DDX21 and CDK9 form a complex with nuclear AGO and TNRC6A; this DDX21-CDK9 complex is required for RNA activation (RNAa) of gene transcription by nuclear microRNAs. DDX21 inhibition suppresses RNAa-mediated release of paused Pol II without affecting post-transcriptional regulation. Co-IP of DDX21-CDK9-AGO-TNRC6A complex, DDX21 inhibition with transcriptional and post-transcriptional readout separation Cell reports Medium 35417682
2024 Calmodulin (CaM) interacts with nucleolar DDX21 in a Ca2+-dependent manner and alters DDX21 conformation to liberate DDX21-sequestered RPA194 (catalytic subunit of RNA Pol I), thereby facilitating rDNA transcription in response to neuronal activity-induced Ca2+ influx. Co-IP of CaM-DDX21, Ca2+-dependence assays, conformational analysis, RPA194 release assay, high-throughput small molecule screen, hippocampal neuron axon growth readout The Journal of neuroscience Medium 39060175
2024 U3 snoRNA is the predominant DDX21-binding snoRNA during mitosis; DDX21 and U3 snoRNA co-localize in the perichromosomal region (PR) during mitosis. Their PR distributions are interdependent: DDX21 knockdown causes mitotic catastrophe, and U3 snoRNA maintains DDX21 mobility and PR localization. U3 snoRNA reduces fibrous condensation of DDX21 in vitro at proper molar ratios. CLIP/pulldown, immunofluorescence co-localization, DDX21/U3 depletion with mitotic phenotype, FRAP (mobility assay), in vitro condensate assay with Cy5-U3 snoRNA and His-DDX21 Cell death & disease Medium 38760378
2022 DDX21 interacts with WDR5 to activate CDK1 gene expression by binding to the CDK1 promoter and recruiting WDR5 to enhance H3K4me3 at that locus, promoting CRC cell proliferation. ChIP assay, Co-IP of DDX21-WDR5, H3K4me3 ChIP, gene expression analysis, knockdown proliferation assay Journal of Cancer Medium 35371306
2016 During dengue virus (DENV) infection, DDX21 translocates from the nucleus to the cytoplasm to activate innate immune responses and inhibit DENV replication early in infection. DENV subsequently degrades DDX21 via the viral NS2B-NS3 protease complex to subvert innate immunity. iTRAQ/LC-MS/MS proteomics, subcellular localization assay, DENV replication quantification, NS2B-NS3 protease degradation assay Biochemical and biophysical research communications Medium 27033607
2021 DDX21 knockdown promotes accumulation of R-loops on viral late genes in HCMV-infected cells, preventing viral late gene transcription and impairing HCMV replication, without affecting viral DNA replication or replication compartment formation. R-loop immunofluorescence (S9.6), DNA-RNA immunoprecipitation, DDX21 knockdown, HCMV gene expression assay Journal of virology Medium 31554690
2021 DDX21 inhibits FMDV IRES-dependent translation by associating with FMDV IRES domains 2, 3, and 4. FMDV counteracts this by degrading DDX21 through its non-structural proteins 2B, 2C (caspase pathway) and 3C protease (lysosomal pathway). DDX21 also enhances IFN-β and IL-8 production to restrict viral replication. Pulldown assay, dual-luciferase IRES reporter, knockdown/overexpression, confocal localization, qPCR of innate immune genes Viruses Medium 34578346
2014 DDX21 knockdown results in inhibition of rRNA accumulation and partial translocation of DDX21 from nucleolus to nucleoplasm in a manner dependent on the DDX21-TRIF signaling pathway; DDX21-TRIF signaling is required for S100A9 gene expression during influenza A virus infection. shRNA knockdown, immunofluorescence localization, epistasis with DDX21/TRIF pathway components, cytokine expression assay PLoS pathogens Medium 24391503
2023 DDX21 undergoes liquid-liquid phase separation in vitro and in colorectal cancer cells via its intrinsically disordered region (IDR). Phase-separated DDX21 binds the MCM5 gene locus to drive its expression and CRC metastasis; IDR mutations that disrupt phase separation reduce MCM5 binding and impair metastasis. In vitro phase separation assay, IDR mutagenesis, ChIP, loss-of-function/rescue experiments, in vivo metastasis models Oncogene Medium 37029300
2022 DDX21 interacts with RNase H1 and enhances its endonuclease activity on RNA-DNA hybrids. Purified DDX21 increases RNase H1 cleavage rates in vitro. Reduction of DDX21 decreases antisense oligonucleotide (PS-ASO) activity in cells and increases R-loop levels. BioID proximity labeling, biochemical Co-IP, in vitro RNase H1 cleavage assay with purified DDX21, R-loop quantification Nucleic acid therapeutics Medium 35852833
2021 In mouse preimplantation embryos, DDX21 nucleolar localization is dependent on active p38-MAPK signaling. Clonal Ddx21 knockdown causes cell-autonomous proliferation defects, reduced blastocyst volume, and impairs primitive endoderm (PrE) differentiation (GATA4 expression) while preserving epiblast identity (NANOG expression). siRNA clonal knockdown in mouse embryos, p38-MAPK inhibition, immunofluorescence localization, lineage marker analysis Open biology Medium 34255976
2018 DDX21 suppresses Snail transcription independently of its helicase activity by recruiting the PRC2 subunits SUZ12 and EZH2 to the Snail promoter, establishing a double-negative feedback loop where Snail also represses DDX21 transcription. ChIP of DDX21-SUZ12-EZH2 at Snail promoter, helicase-dead mutant, overexpression/knockdown, luciferase reporter Cancer letters Medium 30165191
2024 DDX21 interacts with TERT protein and regulates rRNA transcription by affecting RNA Pol I binding to rDNA. This interaction is regulated by the BRAF-MEK-ERK-GABP axis, whereby BRAF mutation upregulates DDX21 through the transcription factors GABPA/GABPB1. Co-IP and mass spectrometry of TERT interactors, ChIP (Pol I on rDNA), luciferase reporter of DDX21 promoter, BRAF/MEK inhibitor treatment Thyroid Medium 41817108

Source papers

Stage 0 corpus · 75 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 304 21703541
2014 RNA helicase DDX21 coordinates transcription and ribosomal RNA processing. Nature 263 25470060
2017 SLERT Regulates DDX21 Rings Associated with Pol I Transcription. Cell 234 28475895
2019 Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21. Molecular cell 212 31351877
2017 SIRT7 and the DEAD-box helicase DDX21 cooperate to resolve genomic R loops and safeguard genome stability. Genes & development 192 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 153 24391503
2014 Cellular DDX21 RNA helicase inhibits influenza A virus replication but is counteracted by the viral NS1 protein. Cell host & microbe 98 24721576
2017 Human DDX21 binds and unwinds RNA guanine quadruplexes. Nucleic acids research 84 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 59 36608661
2023 Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway. Oncogene 57 37029300
2008 c-Jun supports ribosomal RNA processing and nucleolar localization of RNA helicase DDX21. The Journal of biological chemistry 56 18180292
2024 DDX21 mediates co-transcriptional RNA m6A modification to promote transcription termination and genome stability. Molecular cell 53 38569554
2016 DDX21 translocates from nucleus to cytoplasm and stimulates the innate immune response due to dengue virus infection. Biochemical and biophysical research communications 47 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
2018 DDX21 promotes gastric cancer proliferation by regulating cell cycle. Biochemical and biophysical research communications 40 30322617
2020 Structural Basis of Human Helicase DDX21 in RNA Binding, Unwinding, and Antiviral Signal Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 39 32714761
2020 PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation. Developmental cell 34 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 31 37072811
2020 The Human RNA Helicase DDX21 Presents a Dimerization Interface Necessary for Helicase Activity. iScience 30 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 26 38387756
2020 Long non-coding RNA ZFAS1 promotes colorectal cancer tumorigenesis and development through DDX21-POLR1B regulatory axis. Aging 26 33202381
2021 Caspase-Dependent Cleavage of DDX21 Suppresses Host Innate Immunity. mBio 24 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
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
2022 DDX21 Interacts with WDR5 to Promote Colorectal Cancer Cell Proliferation by Activating CDK1 Expression. Journal of Cancer 15 35371306
2022 Nuclear microRNAs release paused Pol II via the DDX21-CDK9 complex. Cell reports 15 35417682
2021 DDX21 interacts with nuclear AGO2 and regulates the alternative splicing of SMN2. Bioscience, biotechnology, and biochemistry 11 33604619
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 DDX21 is a p38-MAPK-sensitive nucleolar protein necessary for mouse preimplantation embryo development and cell-fate specification. Open biology 9 34255976
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
2021 Identification of MDM2, YTHDF2 and DDX21 as potential biomarkers and targets for treatment of type 2 diabetes. Biochemical and biophysical research communications 8 34688145
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 TRIP13 regulates progression of gastric cancer through stabilising the expression of DDX21. Cell death & disease 6 39187490
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 DDX21 functions as a potential novel oncopromoter in pancreatic ductal adenocarcinoma: a comprehensive analysis of the DExD box family. Discover oncology 4 39095628
2024 DDX21: The link between m6A and R-loops. Molecular cell 3 38701738
2024 Calmodulin Triggers Activity-Dependent rRNA Biogenesis via Interaction with DDX21. The Journal of neuroscience : the official journal of the Society for Neuroscience 3 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 3 39769343
2023 RRP9 and DDX21 as new biomarkers of colorectal cancer. Medicine 3 37904456
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
2023 Joint effect of RRP9 and DDX21 on development of colorectal cancer and keloid. Aging 2 37988222
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 [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
2025 Epigenetic Silencing of miR-218-5p Modulates BIRC5 and DDX21 Expression to Promote Colorectal Cancer Progression. International journal of molecular sciences 0 40362385
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