DDX21

Summary

DDX21 (DExD-box helicase 21, HGNC:2744) is a protein-coding gene on chromosome 10q22.1, encoding Nucleolar RNA helicase 2 (Q9NR30). RNA helicase that acts as a sensor of the transcriptional status of both RNA polymerase (Pol) I and II: promotes ribosomal RNA (rRNA) processing and transcription from polymerase II (Pol II). It is a common-essential gene (DepMap: required in 97.4% of cancer cell lines).

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is an antigen recognized by autoimmune antibodies from a patient with watermelon stomach disease. This protein unwinds double-stranded RNA, folds single-stranded RNA, and may play important roles in ribosomal RNA biogenesis, RNA editing, RNA transport, and general transcription.

Source: NCBI Gene 9188 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 100 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.4% of screened cell lines (common-essential)
• MANE Select transcript: NM_004728

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2744
Approved symbol	DDX21
Name	DExD-box helicase 21
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	RH-II/GU, GURDB, Gu-alpha
Ensembl gene	ENSG00000165732
Ensembl biotype	protein_coding
OMIM	606357
Entrez	9188

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 13 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000354185, ENST00000620315, ENST00000684824, ENST00000685106, ENST00000685513, ENST00000686366, ENST00000686528, ENST00000687162, ENST00000688593, ENST00000690316, ENST00000690650, ENST00000692943, ENST00000897110, ENST00000913483, ENST00000913484, ENST00000913485, ENST00000913486, ENST00000971836

RefSeq mRNA: 3 — MANE Select: NM_004728 NM_001256910, NM_001410932, NM_004728

CCDS: CCDS31211, CCDS73144, CCDS91249

Canonical transcript exons

ENST00000354185 — 15 exons

Exon	Start	End
ENSE00000707138	68971891	68972052
ENSE00000707145	68978842	68978976
ENSE00000834213	68970201	68970350
ENSE00000834217	68974670	68974743
ENSE00000834221	68981537	68981581
ENSE00000986288	68967018	68967203
ENSE00000986296	68965377	68965494
ENSE00000986298	68968976	68969121
ENSE00000986299	68973545	68973664
ENSE00001026814	68962082	68962157
ENSE00001095934	68977529	68977688
ENSE00001095955	68963291	68963469
ENSE00001372127	68959806	68960249
ENSE00001420901	68982543	68985068
ENSE00001460795	68956170	68956312

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 98.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 113.8875 / max 1950.0620, expressed in 1824 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105273	102.3855	1824
105274	9.3421	1633
105276	1.5242	808
105275	0.4715	242
205884	0.1642	52

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pericardium	UBERON:0002407	98.81	gold quality
cartilage tissue	UBERON:0002418	98.61	gold quality
mucosa of urinary bladder	UBERON:0001259	98.37	gold quality
pharyngeal mucosa	UBERON:0000355	98.24	gold quality
gingival epithelium	UBERON:0001949	98.19	gold quality
vena cava	UBERON:0004087	98.09	gold quality
lower lobe of lung	UBERON:0008949	97.98	gold quality
nipple	UBERON:0002030	97.93	gold quality
gingiva	UBERON:0001828	97.89	gold quality
mammary duct	UBERON:0001765	97.70	gold quality
penis	UBERON:0000989	97.57	gold quality
superior surface of tongue	UBERON:0007371	97.48	gold quality
pylorus	UBERON:0001166	97.42	gold quality
epithelium of mammary gland	UBERON:0003244	97.39	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.39	gold quality
mammalian vulva	UBERON:0000997	97.11	gold quality
body of tongue	UBERON:0011876	97.01	gold quality
upper arm skin	UBERON:0004263	96.98	gold quality
cardia of stomach	UBERON:0001162	96.81	gold quality
tongue	UBERON:0001723	96.74	gold quality
type B pancreatic cell	CL:0000169	96.68	gold quality
squamous epithelium	UBERON:0006914	96.65	gold quality
tibialis anterior	UBERON:0001385	96.60	gold quality
epithelium of nasopharynx	UBERON:0001951	96.42	gold quality
synovial joint	UBERON:0002217	96.30	gold quality
esophagus squamous epithelium	UBERON:0006920	96.28	gold quality
islet of Langerhans	UBERON:0000006	96.24	gold quality
cervix squamous epithelium	UBERON:0006922	96.19	gold quality
endometrium epithelium	UBERON:0004811	96.07	gold quality
colonic mucosa	UBERON:0000317	95.87	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-8	yes	684.59
E-HCAD-4	yes	30.56
E-MTAB-9467	yes	21.25
E-MTAB-6379	no	722.63
E-CURD-112	no	2.16
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN

miRNA regulators (miRDB)

107 targeting DDX21, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-548AZ-3P	99.82	70.56	3549

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.4% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• RNA helicase II/Gualpha silencing inhibits mammalian ribosomal RNA production (PMID:14559904)
• the function of Gu(alpha)in rRNA processing is at least partially dependent on its ability to interact with ribosomal protein L4. (PMID:16045751)
• in addition to its transcriptional effects, c-Jun regulates rRNA processing and nucleolar compartmentalization of the rRNA processing protein DDX21 (PMID:18180292)
• Studies indicated that DDX21, HNRNPC, and RCC2 were isolated from Ku86 multicomponent complex in response to DNA damage. (PMID:20873769)
• Data indicate that DDX21, a nucleolar protein, was confirmed to associate with SET8. (PMID:23419719)
• As sequential interaction of PB1 and NS1 with DDX21 leads to temporal regulation of viral gene expression, influenza A virus likely uses the DDX21-NS1 interaction not only to overcome restriction, but also to regulate the viral life cycle. (PMID:24721576)
• DDX21 expression in breast cancer cells can promote AP-1 activity and rRNA processing, and thus, promote tumorigenesis by two independent mechanisms. (PMID:25260534)
• results uncover the multifaceted role of DDX21 in multiple steps of ribosome biogenesis, and provide evidence implicating a mammalian RNA helicase in RNA modification and Pol II elongation control (PMID:25470060)
• Identification of several late-acting snoRNAs that bind pre-40S particles in human cells and show that their association and function in pre-40S complexes is regulated by the RNA helicase DDX21. (PMID:25477391)
• In dengue virus infected cells, DDX21 translocates from nucleus to cytoplasm to active the innate immune response and thus inhibits DENV replication in the early stages of infection. (PMID:27033607)
• DDX21 can suppress the expression of proteins with G4 qudruplexes in the 3 UTR of its mRNA. (PMID:28472472)
• Results report the biogenesis and function of a box H/ACA snoRNA-ended sno-lncRNA, referred to SLERT (snoRNA-ended lncRNA enhances pre-ribosomal RNA transcription). SLERT is different from Prader-Willi Syndrome (PWS) sno-lncRNAs and plays a crucial role in rRNA biogenesis by dislodging a previously unknown clamp of DDX21 ring-shaped arrangements on Pol I complexes, thereby liberating Pol I for active rRNA transcription. (PMID:28475895)
• DDX21 is both an ATP-dependent and ATP-independent helicase, and both ATPase and ATP-dependent helicase activities are inhibited by Rev in a dose-dependent manner, although ATP-independent helicase activity is not. A conserved binding interaction between DDX protein’s DEAD domain and Rev was identified, with Rev’s nuclear diffusion inhibitory signal motif playing a significant role in binding. (PMID:28705764)
• Knockdown of SIRT7 leads to the same phenotype as depletion of DDX21 (i.e., increased formation of R loops and DNA double-strand breaks), indicating that SIRT7 and DDX21 cooperate to prevent R-loop accumulation, thus safeguarding genome integrity. (PMID:28790157)
• can drastically reduce DDX21’s affinity for quadruplex, indicating that the recognition of quadruplex and specificity for telomeric repeat containing RNA quadruplex is mediated by interactions with the 2’OH of loop nucleotides (PMID:29906500)
• Data indicate that DEAD-box helicase 21 (DDX21) regulated Snail transcription factors (Snail) expression independent of its helicase activity. (PMID:30165191)
• DDX21 induced gastric cancer cell growth by up-regulating levels of Cyclin D1 and CDK2. (PMID:30322617)
• The findings revealed that enhancer-mediated enrichment of novel JMJD3-DDX21 interaction at ENPP2 locus is necessary for nascent transcript synthesis via the resolution of aberrant R-loops formation in response to inflammatory stimulus. (PMID:31251802)
• Activation of PARP-1 by snoRNAs Controls Ribosome Biogenesis and Cell Growth via the RNA Helicase DDX21. (PMID:31351877)
• DDX21 knockdown prevented viral late gene transcription and consequently impaired HCMV replication. (PMID:31554690)
• Our work identifies the role of DDX21 in regulation at the translational level through biologically relevant RNA G-quadruplex (rG4) and shows that MAGED2 protein levels are regulated, at least in part, by the potential to form rG4 in their 5’-UTRs. (PMID:31653714)
• RNA helicase DDX21 mediates nucleotide stress responses in neural crest and melanoma cells. (PMID:32231306)
• PRL3-DDX21 Transcriptional Control of Endolysosomal Genes Restricts Melanocyte Stem Cell Differentiation. (PMID:32652076)
• DEAD-box RNA helicase protein DDX21 as a prognosis marker for early stage colorectal cancer with microsatellite instability. (PMID:33328538)
• The RNA-helicase DDX21 upregulates CEP55 expression and promotes neuroblastoma. (PMID:33497018)
• DDX21 interacts with nuclear AGO2 and regulates the alternative splicing of SMN2. (PMID:33604619)
• Identification of Prognostic RBPs in Osteosarcoma. (PMID:33754909)
• Caspase-Dependent Cleavage of DDX21 Suppresses Host Innate Immunity. (PMID:34125604)
• lncRNA SLERT controls phase separation of FC/DFCs to facilitate Pol I transcription. (PMID:34326237)
• DDX21, a Host Restriction Factor of FMDV IRES-Dependent Translation and Replication. (PMID:34578346)
• Identification of MDM2, YTHDF2 and DDX21 as potential biomarkers and targets for treatment of type 2 diabetes. (PMID:34688145)
• 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). (PMID:34903139)
• The Roles of RNA Helicases in DNA Damage Repair and Tumorigenesis Reveal Precision Therapeutic Strategies. (PMID:34987058)
• Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation. (PMID:36608661)
• Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway. (PMID:37029300)
• LINC00240 in the 6p22.1 risk locus promotes gastric cancer progression through USP10-mediated DDX21 stabilization. (PMID:37072811)
• RRP9 and DDX21 as new biomarkers of colorectal cancer. (PMID:37904456)
• Joint effect of RRP9 and DDX21 on development of colorectal cancer and keloid. (PMID:37988222)
• Lnc-PLCB1 is stabilized by METTL14 induced m6A modification and inhibits Helicobacter pylori mediated gastric cancer by destabilizing DDX21. (PMID:38387756)
• DDX21 mediates co-transcriptional RNA m[6]A modification to promote transcription termination and genome stability. (PMID:38569554)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddx21	ENSDARG00000063626
mus_musculus	Ddx21	ENSMUSG00000020075
rattus_norvegicus	Ddx21	ENSRNOG00000043099

Paralogs (38): DDX20 (ENSG00000064703), DDX3Y (ENSG00000067048), DDX1 (ENSG00000079785), DDX43 (ENSG00000080007), DDX18 (ENSG00000088205), DDX24 (ENSG00000089737), DDX17 (ENSG00000100201), DDX49 (ENSG00000105671), DDX50 (ENSG00000107625), DDX5 (ENSG00000108654), DDX25 (ENSG00000109832), DDX6 (ENSG00000110367), DDX55 (ENSG00000111364), DDX59 (ENSG00000118197), DDX54 (ENSG00000123064), DDX39A (ENSG00000123136), DDX27 (ENSG00000124228), DDX31 (ENSG00000125485), DDX56 (ENSG00000136271), EIF4A3 (ENSG00000141543), DDX46 (ENSG00000145833), DDX4 (ENSG00000152670), EIF4A2 (ENSG00000156976), DDX19B (ENSG00000157349), EIF4A1 (ENSG00000161960), DDX19A (ENSG00000168872), TDRD12 (ENSG00000173809), DDX23 (ENSG00000174243), DDX10 (ENSG00000178105), DDX28 (ENSG00000182810), DDX41 (ENSG00000183258), DDX53 (ENSG00000184735), DDX51 (ENSG00000185163), DDX42 (ENSG00000198231), DDX39B (ENSG00000198563), DDX47 (ENSG00000213782), DDX3X (ENSG00000215301), DDX52 (ENSG00000278053)

Protein

Protein identifiers

Nucleolar RNA helicase 2 — Q9NR30 (reviewed: Q9NR30)

Alternative names: DEAD box protein 21, Gu-alpha, Nucleolar RNA helicase Gu, Nucleolar RNA helicase II, RH II/Gu

All UniProt accessions (5): A0A8I5KND9, A0A8I5KNN2, A0A8I5KNP3, Q9NR30, A0A8I5KYZ4

UniProt curated annotations — full annotation on UniProt →

Function. RNA helicase that acts as a sensor of the transcriptional status of both RNA polymerase (Pol) I and II: promotes ribosomal RNA (rRNA) processing and transcription from polymerase II (Pol II). Binds various RNAs, such as rRNAs, snoRNAs, 7SK and, at lower extent, mRNAs. In the nucleolus, localizes to rDNA locus, where it directly binds rRNAs and snoRNAs, and promotes rRNA transcription, processing and modification. Required for rRNA 2’-O-methylation, possibly by promoting the recruitment of late-acting snoRNAs SNORD56 and SNORD58 with pre-ribosomal complexes. In the nucleoplasm, binds 7SK RNA and is recruited to the promoters of Pol II-transcribed genes: acts by facilitating the release of P-TEFb from inhibitory 7SK snRNP in a manner that is dependent on its helicase activity, thereby promoting transcription of its target genes. Functions as a cofactor for JUN-activated transcription: required for phosphorylation of JUN at ‘Ser-77’. Can unwind double-stranded RNA (helicase) and can fold or introduce a secondary structure to a single-stranded RNA (foldase). Together with SIRT7, required to prevent R-loop-associated DNA damage and transcription-associated genomic instability: deacetylation by SIRT7 activates the helicase activity, thereby overcoming R-loop-mediated stalling of RNA polymerases. Involved in rRNA processing. May bind to specific miRNA hairpins. Component of a multi-helicase-TICAM1 complex that acts as a cytoplasmic sensor of viral double-stranded RNA (dsRNA) and plays a role in the activation of a cascade of antiviral responses including the induction of pro-inflammatory cytokines via the adapter molecule TICAM1.

Subunit / interactions. Homodimer; homodimerizes via its N-terminus. Found in a multi-helicase-TICAM1 complex at least composed of DHX36, DDX1, DDX21 and TICAM1; this complex exists in resting cells with or without poly(I:C) RNA ligand stimulation. Interacts (via C-terminus) with TICAM1 (via TIR domain). Interacts with DHX36 (via C-terminus); this interaction serves as bridges to TICAM1. Interacts (via C-terminus) with DDX1 (via B30.2/SPRY domain); this interaction serves as bridges to TICAM1. Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21. Interacts with C1QBP. Interacts with JUN. Interacts with WDR46. Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21. Interacts with C1QBP. Interacts with JUN. Interacts with WDR46. Interacts with MCM3AP isoform GANP. Interacts with WDR43. Interacts with KPNA3. Interacts with GID4.

Subcellular location. Nucleus. Nucleolus. Nucleoplasm. Cytoplasm. Cytosol. Mitochondrion.

Post-translational modifications. Acetylation by CREBBP/CBP inhibits the helicase activity. Deacetylation by SIRT7 promotes the helicase activity and overcomes R-loop-mediated stalling of RNA polymerases.

Activity regulation. Acetylation inhibits the helicase activity.

Domain organisation. The helicase and foldase activities reside in two separate domains, the helicase in the N-terminus and the foldase in the C-terminus. The 3 X 5 AA repeats seem to be critical for the RNA folding activity.

Miscellaneous. Autoantibodies against DDX21 are found in patients with watermelon stomach disease, which is characterized by prominent stripes of ectatic vascular tissue in the stomach similar to stripes on a watermelon.

Similarity. Belongs to the DEAD box helicase family. DDX21/DDX50 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NR30-1	1	yes
Q9NR30-2	2

RefSeq proteins (3): NP_001243839, NP_001397861, NP_004719* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR012562	GUCT	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR050079	DEAD_box_RNA_helicase	Family
IPR059027	DD_DDX21-DDX50	Domain

Pfam: PF00270, PF00271, PF08152, PF26142

Enzyme classification (BRENDA):

• EC 3.6.4.13 — RNA helicase (BRENDA: 3 organisms, 3 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (88 total): helix 23, strand 20, modified residue 16, mutagenesis site 5, compositionally biased region 4, repeat 3, turn 3, region of interest 3, domain 2, short sequence motif 2, cross-link 2, chain 1, binding site 1, splice variant 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6L5O	X-RAY DIFFRACTION	1.8
6L5N	X-RAY DIFFRACTION	2.24
6L5M	X-RAY DIFFRACTION	2.7
6L5L	X-RAY DIFFRACTION	3.1
2M3D	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR30-F1	71.07	0.31

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 230–237

Post-translational modifications (18): 7, 13, 18, 71, 89, 121, 137, 147, 164, 171, 173, 296, 567, 600, 779, 116, 116, 1

Mutagenesis-validated functional residues (5):

Position	Phenotype
18	mimics acetylation; impaired ability to resolve r-loops; when associated with q-137 and q-600.
137	mimics acetylation; impaired ability to resolve r-loops; when associated with q-18 and q-600.
339–340	in mutant dev; loss of helicase activity. defects in release of p-tefb from inhibitory 7sk snrnp.
375–376	in mutant sat; atpase defective. defects in release of p-tefb from inhibitory 7sk snrnp.
600	mimics acetylation; impaired ability to resolve r-loops; when associated with q-18 and q-137.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5250924	B-WICH complex positively regulates rRNA expression
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol

MSigDB gene sets: 342 (showing top): MODULE_52, FUNG_IL2_SIGNALING_2, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, MORF_UBE2N, GOBP_TRANSCRIPTION_BY_RNA_POLYMERASE_III, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, BROWNE_HCMV_INFECTION_16HR_UP, MODULE_16, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, PUJANA_CHEK2_PCC_NETWORK

GO Biological Process (18): osteoblast differentiation (GO:0001649), positive regulation of myeloid dendritic cell cytokine production (GO:0002735), chromatin remodeling (GO:0006338), rRNA processing (GO:0006364), transcription by RNA polymerase II (GO:0006366), negative regulation of transcription by RNA polymerase I (GO:0016479), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), response to exogenous dsRNA (GO:0043330), innate immune response (GO:0045087), positive regulation of transcription by RNA polymerase I (GO:0045943), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of transcription by RNA polymerase III (GO:0045945), defense response to virus (GO:0051607), R-loop processing (GO:0062176), immune system process (GO:0002376), response to virus (GO:0009615), regulation of gene expression (GO:0010468), positive regulation of macromolecule biosynthetic process (GO:0010557)

GO Molecular Function (17): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), double-stranded RNA binding (GO:0003725), mRNA binding (GO:0003729), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), rRNA binding (GO:0019843), snoRNA binding (GO:0030515), miRNA binding (GO:0035198), identical protein binding (GO:0042802), 7SK snRNA binding (GO:0097322), RNA polymerase inhibitor activity (GO:0140870), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (9): nucleoplasm (GO:0005654), chromosome (GO:0005694), nucleolus (GO:0005730), mitochondrion (GO:0005739), cytosol (GO:0005829), membrane (GO:0016020), B-WICH complex (GO:0110016), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Positive epigenetic regulation of rRNA expression	1
rRNA processing in the nucleus and cytosol	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA binding	4
cellular anatomical structure	4
positive regulation of DNA-templated transcription	3
regulation of transcription by RNA polymerase I	2
transcription by RNA polymerase I	2
regulation of macromolecule biosynthetic process	2
ATP-dependent activity	2
binding	2
nuclear lumen	2
intracellular membraneless organelle	2
cytoplasm	2
intracellular membrane-bounded organelle	2
ossification	1
cell differentiation	1
myeloid dendritic cell cytokine production	1
positive regulation of dendritic cell cytokine production	1
regulation of myeloid dendritic cell cytokine production	1
positive regulation of myeloid leukocyte mediated immunity	1
positive regulation of myeloid leukocyte cytokine production involved in immune response	1
chromatin organization	1
RNA processing	1
rRNA metabolic process	1
ribosome biogenesis	1
DNA-templated transcription	1
negative regulation of DNA-templated transcription	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
response to dsRNA	1
immune response	1
defense response to symbiont	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
regulation of transcription by RNA polymerase III	1
transcription by RNA polymerase III	1
defense response	1
response to virus	1
chromatin remodeling	1
biological_process	1
response to other organism	1

Protein interactions and networks

STRING

4625 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDX21	DHX36	Q9H2U1	997
DDX21	DDX1	Q92499	991
DDX21	SSRP1	Q08945	871
DDX21	EBNA1BP2	Q99848	826
DDX21	DHX9	Q08211	808
DDX21	HNRNPC	P07910	778
DDX21	WDR46	O15213	772
DDX21	DHX8	Q14562	770
DDX21	MYBBP1A	Q9BQG0	732
DDX21	SIRT7	Q9NRC8	729
DDX21	SRPK1	Q96SB4	721
DDX21	TLE5	Q08117	707
DDX21	SRSF2	Q01130	697
DDX21	RIGI	O95786	684
DDX21	FBL	P22087	677

IntAct

322 interactions, top by confidence:

A	B	Type	Score
HEXIM1	CDK9	psi-mi:“MI:0914”(association)	0.940
MOV10	N	psi-mi:“MI:0914”(association)	0.910
DDX21	N	psi-mi:“MI:0914”(association)	0.870
N	DDX21	psi-mi:“MI:0915”(physical association)	0.870
DDX21	N	psi-mi:“MI:0403”(colocalization)	0.870
NOP58	FBL	psi-mi:“MI:0914”(association)	0.800
DDX21	HNRNPC	psi-mi:“MI:0915”(physical association)	0.750
DDX21	KPNA3	psi-mi:“MI:0915”(physical association)	0.740
XPC	CETN3	psi-mi:“MI:0914”(association)	0.730
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DDX21	LARP7	psi-mi:“MI:0915”(physical association)	0.670
DDX21	DKC1	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
DDX21	CDK9	psi-mi:“MI:0915”(physical association)	0.560
HNRNPA1	DDX21	psi-mi:“MI:0915”(physical association)	0.560
DDX21	H1-2	psi-mi:“MI:0915”(physical association)	0.560
DDX21	MAPT	psi-mi:“MI:0915”(physical association)	0.560
DDX21	LITAF	psi-mi:“MI:0915”(physical association)	0.560
DDX21	CARF	psi-mi:“MI:0915”(physical association)	0.560
HTT	DDX21	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (988): DDX21 (Affinity Capture-MS), DDX21 (Affinity Capture-MS), DDX21 (Two-hybrid), DDX21 (Affinity Capture-MS), DDX21 (Affinity Capture-MS), DDX21 (Affinity Capture-MS), DDX21 (Biochemical Activity), DDX21 (Affinity Capture-MS), DDX21 (Reconstituted Complex), DDX21 (Affinity Capture-MS), DDX21 (Affinity Capture-MS), DDX21 (Affinity Capture-MS), DDX21 (Affinity Capture-MS), DDX21 (Affinity Capture-MS), DDX21 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D6GDY8, A0A1D6LAB7, A1CHL3, A1CX72, A6RJA2, A7EGG4, O22907, P0CQ88, P0CQ89, P16381, P19109, P46942, Q0CLX0, Q0D8N0, Q0DM51, Q0ILZ4, Q0INC5, Q1DMX8, Q2HEB0, Q39189, Q3B8Q1, Q3MSQ8, Q41382, Q4I7F9, Q4WPE9, Q5BCU6, Q5N7W4, Q5VQL1, Q5W5U4, Q61496, Q62095, Q64060, Q650T9, Q6CCZ1, Q6GVM6, Q6H601, Q6H6R9, Q750Q4, Q7ZY47, Q8H136

Diamond homologs: A0A1D6GDY8, A0A1D6LAB7, A0R8U6, A1C5V3, A1DG51, A1DGZ7, A5DL80, A5DS77, A6ZRX0, A6ZUA1, B9XXL6, O25029, P0A4D7, P0A4D8, P0A9P6, P0A9P7, P0A9P8, P20447, P24783, P25888, P33906, P42305, P44586, P46942, P57453, P96614, P9WH04, P9WH05, Q0CL13, Q0D8N0, Q0DM51, Q0ILZ4, Q10202, Q1DP69, Q2FF45, Q2FWH5, Q2U070, Q2YUH3, Q39189, Q3B8Q1

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
DDX21	“up-regulates activity”	JUN	binding
DDX21	“form complex”	“B-WICH complex”	binding
DDX1	“up-regulates activity”	DDX21	binding
DDX21	“up-regulates activity”	TICAM1	binding
SIRT7	“up-regulates activity”	DDX21	deacetylation
CREBBP	“down-regulates activity”	DDX21	acetylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 197 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
The NLRP3 inflammasome	5	23.8×	6e-05
TRAF6 mediated NF-kB activation	5	16.2×	4e-04
Purinergic signaling in leishmaniasis infection	5	15.0×	6e-04
HIV Transcription Elongation	5	11.9×	2e-03
TAK1-dependent IKK and NF-kappa-B activation	5	10.7×	2e-03
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	12	10.0×	9e-07
Formation of HIV-1 elongation complex containing HIV-1 Tat	5	9.2×	4e-03
Tat-mediated elongation of the HIV-1 transcript	5	9.2×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of telomere maintenance via telomerase	6	25.1×	4e-05
non-canonical NF-kappaB signal transduction	5	24.1×	2e-04
alternative mRNA splicing, via spliceosome	5	19.3×	6e-04
stress granule assembly	5	17.2×	1e-03
cytoplasmic translation	12	12.7×	2e-07
canonical NF-kappaB signal transduction	5	10.5×	6e-03
mRNA stabilization	5	10.5×	6e-03
rRNA processing	12	9.7×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

100 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	77
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2069 predictions. Top by Δscore:

Variant	Effect	Δscore
10:68956285:G:T	donor_gain	1.0000
10:68956310:G:GT	donor_gain	1.0000
10:68956338:G:GT	donor_gain	1.0000
10:68956342:G:T	donor_gain	1.0000
10:68959792:T:G	acceptor_gain	1.0000
10:68959792:T:TA	acceptor_gain	1.0000
10:68959801:TTTA:T	acceptor_loss	1.0000
10:68959804:A:AC	acceptor_loss	1.0000
10:68959804:A:AG	acceptor_gain	1.0000
10:68959805:G:GA	acceptor_gain	1.0000
10:68959805:GA:G	acceptor_gain	1.0000
10:68959805:GAA:G	acceptor_gain	1.0000
10:68959805:GAAA:G	acceptor_gain	1.0000
10:68960226:GAAA:G	donor_gain	1.0000
10:68960227:A:T	donor_gain	1.0000
10:68960230:G:GG	donor_gain	1.0000
10:68960236:G:GG	donor_gain	1.0000
10:68960246:GCAG:G	donor_gain	1.0000
10:68960247:CAG:C	donor_loss	1.0000
10:68960249:GGT:G	donor_loss	1.0000
10:68960250:G:A	donor_loss	1.0000
10:68961396:G:GG	donor_gain	1.0000
10:68963289:A:AG	acceptor_gain	1.0000
10:68963290:G:GG	acceptor_gain	1.0000
10:68963322:A:G	acceptor_gain	1.0000
10:68963448:G:GT	donor_gain	1.0000
10:68963465:CTCAG:C	donor_loss	1.0000
10:68963466:TCAGG:T	donor_loss	1.0000
10:68963467:CAGGT:C	donor_loss	1.0000
10:68963468:AG:A	donor_loss	1.0000

AlphaMissense

5159 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:68963380:G:A	G233R	1.000
10:68963380:G:C	G233R	1.000
10:68963381:G:A	G233E	1.000
10:68963386:G:A	G235R	1.000
10:68963386:G:C	G235R	1.000
10:68963386:G:T	G235W	1.000
10:68963387:G:A	G235E	1.000
10:68963387:G:T	G235V	1.000
10:68963389:A:C	K236Q	1.000
10:68965393:C:A	P268H	1.000
10:68965399:G:C	R270T	1.000
10:68965399:G:T	R270I	1.000
10:68965400:A:C	R270S	1.000
10:68965400:A:T	R270S	1.000
10:68965401:G:A	E271K	1.000
10:68965405:T:C	L272S	1.000
10:68965405:T:G	L272W	1.000
10:68965470:G:C	G294R	1.000
10:68965470:G:T	G294C	1.000
10:68965471:G:A	G294D	1.000
10:68965474:G:A	G295E	1.000
10:68967053:G:A	G314R	1.000
10:68967053:G:C	G314R	1.000
10:68967054:G:A	G314E	1.000
10:68967062:G:C	G317R	1.000
10:68967062:G:T	G317C	1.000
10:68967063:G:A	G317D	1.000
10:68967065:C:A	R318S	1.000
10:68967065:C:G	R318G	1.000
10:68967066:G:C	R318P	1.000

dbSNP variants (sampled 300 via entrez): RS1000029965 (10:68957702 G>A), RS1000051705 (10:68964445 A>G), RS1000322128 (10:68964218 T>A,C), RS1000376753 (10:68969652 C>T), RS1000567999 (10:68984471 C>G), RS1000585140 (10:68976663 G>T), RS1000609921 (10:68962864 A>G,T), RS1000612893 (10:68977006 C>A,G), RS1000918457 (10:68962574 C>A), RS1001053857 (10:68963075 T>A), RS1001156878 (10:68967807 A>G), RS1001232761 (10:68964740 G>A), RS1001349169 (10:68955772 T>C), RS1001446336 (10:68962037 G>T), RS1001476010 (10:68961578 C>T)

Disease associations

OMIM: gene MIM:606357 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000779_1	Depression (quantitative trait)	9.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296016 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.42	Kd	384	nM	CHEMBL3752910
6.42	ED50	384	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148223: Binding affinity to human DDX21 incubated for 45 mins by Kinobead based pull down assay	kd	0.3840	uM

CTD chemical–gene interactions

80 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, increases expression, decreases expression	4
Estradiol	increases expression	4
Tetrachlorodibenzodioxin	decreases expression, increases expression	4
sodium arsenite	decreases expression, increases abundance, increases expression	3
Valproic Acid	increases expression, affects expression, decreases expression	3
afimoxifene	decreases reaction, increases expression, decreases expression	2
cobaltous chloride	decreases expression, decreases reaction	2
chloropicrin	decreases expression	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Arsenic	decreases expression, increases abundance, increases expression	2
Lipopolysaccharides	affects cotreatment, decreases expression, increases expression, affects response to substance	2
Plant Extracts	affects cotreatment, increases expression	2
Tretinoin	decreases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	increases expression	2
aristolochic acid I	decreases expression	1
afuresertib	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
TL8-506	affects cotreatment, increases expression	1
2,4,6-tribromophenol	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
decabromobiphenyl ether	increases expression	1
zinc chloride	decreases expression, decreases reaction	1
tetrabromobisphenol A	increases expression	1
ochratoxin A	decreases acetylation, decreases expression	1
coumarin	decreases phosphorylation	1
nivalenol	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4155371	Binding	Binding affinity to nucleolar RNA helicase 2 in human A549 cells at 0.15 mM after 4 hrs by HPLC-MS based pull down assay relative to control	Synthesis, cytotoxic evaluation and target identification of thieno[2,3-d]pyrimidine derivatives with a dithiocarbamate side chain at C2 position. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D9D2	Ubigene HEK293 DDX21 KO	Transformed cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.