DDX6

Summary

DDX6 (DEAD-box helicase 6, HGNC:2747) is a protein-coding gene on chromosome 11q23.3, encoding Probable ATP-dependent RNA helicase DDX6 (P26196). Essential for the formation of P-bodies, cytosolic membrane-less ribonucleoprotein granules involved in RNA metabolism through the coordinated storage of mRNAs encoding regulatory functions. It is a selective cancer dependency (DepMap: 87.1% of cell lines).

This gene encodes a member of the DEAD box protein family. The protein is an RNA helicase found in P-bodies and stress granules, and functions in translation suppression and mRNA degradation. It is required for microRNA-induced gene silencing. Multiple alternatively spliced variants, encoding the same protein, have been identified.

Source: NCBI Gene 1656 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder with impaired language and dysmorphic facies (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 39
• Clinical variants (ClinVar): 112 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): activating (oncogene-like) across 2 cancer types
• Cancer dependency (DepMap): dependent in 87.1% of screened cell lines
• MANE Select transcript: NM_004397

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2747
Approved symbol	DDX6
Name	DEAD-box helicase 6
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	RCK, Rck/p54
Ensembl gene	ENSG00000110367
Ensembl biotype	protein_coding
OMIM	600326
Entrez	1656

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 26 protein_coding, 4 retained_intron

ENST00000525082, ENST00000526070, ENST00000529162, ENST00000531971, ENST00000533239, ENST00000534980, ENST00000620157, ENST00000884920, ENST00000884921, ENST00000884922, ENST00000884923, ENST00000884924, ENST00000884925, ENST00000884926, ENST00000929256, ENST00000929257, ENST00000929258, ENST00000929259, ENST00000929260, ENST00000929261, ENST00000929262, ENST00000929263, ENST00000929264, ENST00000929265, ENST00000929266, ENST00000953095, ENST00000953096, ENST00000953097, ENST00000953098, ENST00000953099

RefSeq mRNA: 12 — MANE Select: NM_004397 NM_001257191, NM_001425145, NM_001425146, NM_001425147, NM_001425148, NM_001425149, NM_001425150, NM_001425151, NM_001425152, NM_001425153, NM_001425154, NM_004397

CCDS: CCDS44751

Canonical transcript exons

ENST00000534980 — 14 exons

Exon	Start	End
ENSE00000498999	118758774	118758902
ENSE00000748309	118759922	118760044
ENSE00000796086	118765209	118765355
ENSE00001053698	118768223	118768352
ENSE00001127237	118763212	118763306
ENSE00001278662	118779632	118779736
ENSE00001278670	118781121	118781184
ENSE00003517690	118786052	118786518
ENSE00003580326	118754705	118754887
ENSE00003601327	118755402	118755503
ENSE00003612108	118757171	118757287
ENSE00003678398	118756260	118756323
ENSE00003844208	118747763	118752097
ENSE00003851056	118791098	118791164

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 97.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 92.2640 / max 1272.0179, expressed in 1817 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122622	68.5542	1814
122620	20.3002	1769
122621	3.4097	1517

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	97.77	gold quality
calcaneal tendon	UBERON:0003701	97.75	gold quality
ventricular zone	UBERON:0003053	97.73	gold quality
cortical plate	UBERON:0005343	97.73	gold quality
middle temporal gyrus	UBERON:0002771	97.63	gold quality
superior vestibular nucleus	UBERON:0007227	97.50	gold quality
amniotic fluid	UBERON:0000173	97.46	gold quality
medial globus pallidus	UBERON:0002477	97.40	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.33	gold quality
vena cava	UBERON:0004087	97.33	gold quality
trigeminal ganglion	UBERON:0001675	97.31	gold quality
globus pallidus	UBERON:0001875	97.20	gold quality
adrenal tissue	UBERON:0018303	97.17	gold quality
colonic epithelium	UBERON:0000397	97.15	gold quality
ventral tegmental area	UBERON:0002691	97.10	gold quality
substantia nigra pars compacta	UBERON:0001965	97.08	gold quality
saphenous vein	UBERON:0007318	97.07	gold quality
subthalamic nucleus	UBERON:0001906	96.96	gold quality
superficial temporal artery	UBERON:0001614	96.91	gold quality
cardia of stomach	UBERON:0001162	96.87	gold quality
tonsil	UBERON:0002372	96.87	gold quality
urethra	UBERON:0000057	96.78	gold quality
inferior vagus X ganglion	UBERON:0005363	96.73	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.69	gold quality
parietal lobe	UBERON:0001872	96.62	gold quality
postcentral gyrus	UBERON:0002581	96.52	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.48	gold quality
gingival epithelium	UBERON:0001949	96.47	gold quality
entorhinal cortex	UBERON:0002728	96.47	gold quality
lateral globus pallidus	UBERON:0002476	96.46	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	16.26
E-CURD-112	yes	4.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RBPJ

miRNA regulators (miRDB)

296 targeting DDX6, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 87.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Rck/p54 protein is possibly involved in the replication of HCV genomes in hepatocytes and in carcinogenesis of hepatocellular carcinoma. (PMID:12823589)
• The Over-expression of RCK-p54 protein in HeLa cells caused growth inhibition and cell cycle arrest at G2/M with down-regulation of c-myc expression. (PMID:16611246)
• Study shows that RCK/p54, a DEAD box helicase, interacts with Ago1 and Ago2, in active siRISC or miRISC from human cells; directly interacts with Ago1 and Ago2 in vivo, facilitates formation of P-bodies, and is a general repressor of translation. (PMID:16756390)
• ataxin-2 interacts with the RNA helicase DDX6 (PMID:17392519)
• DEAD-box helicase rck/p54, is involved in post-transcriptional regulation of APP, as its overexpression in cultured cells results in elevated levels of APP mRNA and protein (PMID:18378046)
• RCK/ p54 might be a determinant of colorectal cancer proliferation by activating the canonical Wnt pathway (PMID:18769115)
• Structural basis for the mutually exclusive anchoring of P body components EDC3 and Tral to the DEAD box protein DDX6/Me31B. (PMID:19285948)
• The role of the p54 helicase activity in translational repression and in P-body formation, was examined. (PMID:19297524)
• In the Australian GWAS, one SNP achieved genomewide significance for comorbid AD/ND, rs1784300 near DDX6 on chromosome 11 (p = 2.60 x 10(-9)). (PMID:20158304)
• DDX6 helicase activity is essential for efficient hepatitis C virus replication, reflecting essential roles for DDX6 in hepatitis C virus genome amplification and/or maintenance of cellular homeostasis. (PMID:20392846)
• data suggest that in premature erythroid cells translational silencing of hr15-LOX mRNA is maintained by DDX6 mediated storage in these RNP granules (PMID:20884783)
• Data show that DDX6 is required for efficient assembly or release of infectious Dengue virus. (PMID:21957497)
• stud finds that DDX6 is required for efficient genome packaging of foamy virus, a spumaretrovirus (PMID:22022269)
• RCK is a functional partner of TTP in promoting TTP-mediated translational repression of AU-rich mRNA (PMID:22203041)
• Rck/p54 recruitment by sequence-specific translational repressors leads to further binding of Rck/p54 along mRNA molecules, resulting in their masking, unwinding, and ultimately recruitment to P-bodies. (PMID:22836354)
• assembling HIV-1 co-opts a preexisting host complex containing cellular facilitators such as DDX6, which the virus uses to catalyze capsid assembly (PMID:22851315)
• We identified several unbalanced aberrations and a t(11;14) involving IGH and DDX6 providing evidence for a contribution of DDX6 to lymphomagenesis by deregulation of BCL6 in NMZL. (PMID:22965301)
• DEAD-box RNA helicase 6 (DDX6) is a cellular modulator of vascular endothelial growth factor expression under hypoxia (PMID:23293030)
• data indicate that P-body assembly occurs in a step-wise manner, where Rck participates in the initial suppression of mRNA translation, whereas Pat1b in a second step triggers P-body assembly and promotes mRNA decapping (PMID:23535175)
• DDX6 and miR-122 modulate HCV through distinct pathways. (PMID:23826300)
• High DDX6 expression is associated with gastric cancer. (PMID:23932921)
• study discovered multiple susceptibility variants for systemic lupus erythematosus in the 11q23.3 region, including variants in/near PHLDB1 (rs11603023), DDX6 (rs638893) and CXCR5 (rs10892301) (PMID:24001599)
• Crystal structures of the DDX6, CNOT1 and CNOT9 complexes. (PMID:24768538)
• Crystal structure of the DDX6, CNOT9 and CNOT1 complex. (PMID:24768540)
• CNOT1 facilitates recruitment of DDX6 to miRNA-targeted mRNAs, placing DDX6 as a downstream effector in the miRNA silencing pathway. (PMID:25035296)
• DDX6 repression complexes are required for P-body assembly. (PMID:25995375)
• Protein Interactome Analysis of DDX6 (PMID:26184334)
• Results indicate that progenitor function is maintained by DDX6 complexes through two distinct pathways that include the degradation of differentiation-inducing transcripts and by promoting the translation of self-renewal and proliferation mRNAs. (PMID:26412305)
• Functional analysis of the 11q23.3 glioma susceptibility locus implicates PHLDB1 and DDX6 in glioma susceptibility. (PMID:26610392)
• DDX6 may have a role in radio- and chemoresistance in glioblastoma (PMID:26783102)
• miRNAs, AGOs, GW182, the CCR4-NOT complex, and DDX6/Me31B repress and degrade polyadenylated mRNA targets that are translated via scanning-independent mechanisms in both human and Drosophila melanogaster cells (PMID:27009120)
• we demonstrate that joint deletion of two short conserved motifs that bind UNR and DDX6 relieves repression of 4E-T-bound mRNA, in part reliant on the 4E-T-DDX6-CNOT1 axis. (PMID:27342281)
• Results provide evidence for a dual mechanisms regulating the nucleocytoplasmic localization of DDX6. First, data show that DDX6 can be transported by 4E-T in a piggyback manner. Furthermore, a novel nuclear targeting mechanism was detected in which DDX6 enters the newly formed nuclei by “hitch-hiking” on mitotic chromosomes with its C-terminal domain during M phase progression. (PMID:28216671)
• DDX6 modulates interaction of miR-122 with the 5’ untranslated region of hepatitis C virus RNA. (PMID:28456022)
• Results showed that DDX6 was overexpressed in gastric cancer (GC) and acted as an oncogene through the regulation of c-Myc mRNA in GC cells. (PMID:29314290)
• Intermediate-sized non-coding RNA 761 could interact with DEAD-box helicase 6 (DDX6) to induce NTERA-2 (NT2 (testicular embryonal carcinoma cell)) cell apoptosis and proliferation inhibition via the p53 pathway. (PMID:29769412)
• These findings imply a novel function for DDX6 as an RNA co-sensor and signaling enhancer for RIG-I. (PMID:29949917)
• Identification of the DEAD box RNA helicase DDX6 as a new partner that acts in cooperation with Tau to increase miRNA activity. (PMID:29966762)
• Results showed that DDX6 protein was overexpressed in gastric cancer (GC) and provided evidence that DDX6 acted as an upstream molecule that positively regulated the expression of HER2 and FGFR2 at the post-transcriptional step in GC cells. (PMID:29987267)
• The abrogation of DDX6 expression inhibited iPSC generation, which was mediated by RNA decay targeting parental mRNAs supporting mesenchymal phenotypes, along with microRNAs, such as miR-302b-3p (PMID:30273347)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddx6	ENSDARG00000061338
mus_musculus	Ddx6	ENSMUSG00000032097
rattus_norvegicus	Ddx6	ENSRNOG00000053932

Paralogs (38): DDX20 (ENSG00000064703), DDX3Y (ENSG00000067048), DDX1 (ENSG00000079785), DDX43 (ENSG00000080007), DDX18 (ENSG00000088205), DDX24 (ENSG00000089737), DDX17 (ENSG00000100201), DDX49 (ENSG00000105671), DDX50 (ENSG00000107625), DDX5 (ENSG00000108654), DDX25 (ENSG00000109832), 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), DDX21 (ENSG00000165732), 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

Probable ATP-dependent RNA helicase DDX6 — P26196 (reviewed: P26196)

Alternative names: ATP-dependent RNA helicase p54, DEAD box protein 6, Oncogene RCK

All UniProt accessions (1): P26196

UniProt curated annotations — full annotation on UniProt →

Function. Essential for the formation of P-bodies, cytosolic membrane-less ribonucleoprotein granules involved in RNA metabolism through the coordinated storage of mRNAs encoding regulatory functions. Plays a role in P-bodies to coordinate the storage of translationally inactive mRNAs in the cytoplasm and prevent their degradation. In the process of mRNA degradation, plays a role in mRNA decapping. Blocks autophagy in nutrient-rich conditions by repressing the expression of ATG-related genes through degradation of their transcripts.

Subunit / interactions. (Microbial infection) Interacts with rotavirus A non-structural protein 2; this interaction probably plays a role in the sequestration of DDX6 in viral factories. Interacts with rotavirus A non-structural protein 5; this interaction probably plays a role in its sequestration in viral factories. Interacts with LSM14A, LSM14B, EIF4ENIF1/4E-T, PATL1, EDC3 and EDC4. Forms a complex with DCP1A, DCP2, EDC3 and EDC4/HEDLS. Interacts with LIMD1, WTIP and AJUBA. Interacts with APOBEC3G in an RNA-dependent manner. Interacts with RC3H1. Interacts with ATXN2L. Interacts with MCRIP1. Interacts with MCRIP2. Interacts with NUFIP2. Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner. Interacts with GIGYF1 and GIGYF2.

Subcellular location. Cytoplasm. P-body. Nucleus. Cytoplasmic ribonucleoprotein granule.

Tissue specificity. Abundantly expressed in most tissues.

Post-translational modifications. Sumoylated.

Disease relevance. Intellectual developmental disorder with impaired language and dysmorphic facies (IDDILF) [MIM:618653] An autosomal dominant disorder characterized by intellectual disability, developmental delay, impaired language development, and dysmorphic features including telecanthus, epicanthus, arched eyebrows and low-set ears. Additional features include feeding difficulties, mild cardiac or genitourinary defects, and distal skeletal anomalies. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving DDX6 may be a cause of hematopoietic tumors such as B-cell lymphomas. Translocation t(11;14)(q23;q32).

Similarity. Belongs to the DEAD box helicase family. DDX6/DHH1 subfamily.

RefSeq proteins (12): NP_001244120, NP_001412074, NP_001412075, NP_001412076, NP_001412077, NP_001412078, NP_001412079, NP_001412080, NP_001412081, NP_001412082, NP_001412083, NP_004388* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000629	RNA-helicase_DEAD-box_CS	Conserved_site
IPR001650	Helicase_C-like	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR014014	RNA_helicase_DEAD_Q_motif	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00270, PF00271

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 (67 total): helix 21, strand 17, mutagenesis site 10, sequence variant 5, turn 3, region of interest 3, domain 2, short sequence motif 2, chain 1, sequence conflict 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
4CRW	X-RAY DIFFRACTION	1.75
1VEC	X-RAY DIFFRACTION	2.01
5ANR	X-RAY DIFFRACTION	2.1
6S8S	X-RAY DIFFRACTION	2.21
2WAX	X-RAY DIFFRACTION	2.3
2WAY	X-RAY DIFFRACTION	2.3
4CT4	X-RAY DIFFRACTION	2.3
4CT5	X-RAY DIFFRACTION	3
6F9S	X-RAY DIFFRACTION	3.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P26196-F1	84.89	0.73

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): 140–147

Post-translational modifications (1): 36

Mutagenesis-validated functional residues (10):

Position	Phenotype
247	abolished helicase activity and ability to regulate rna metabolism.
320	abolishes interaction with edc3; when associated with a-323; a-327 and a-331.
323	abolishes interaction with edc3; when associated with a-320; a-327 and a-331.
324	in cl-aa; abolishes interaction with patl1 and reduces interaction with gigyf1 and gigyf2, but has no affect on interact
327	abolishes interaction with edc3; when associated with a-320; a-323 and a-331.
328	in cl-aa; abolishes interaction with patl1 and reduces interaction with gigyf1 and gigyf2, but has no affect on interact
331	abolishes interaction with edc3; when associated with a-320; a-323 and a-327.
349	in lk-aa; abolishes interaction with patl1 and reduces interaction with gigyf1, gigyf2, edc3, eif4enif1 and lsm14a; when
353	in lk-aa; abolishes interaction with patl1 and reduces interaction with gigyf1, gigyf2, edc3, eif4enif1 and lsm14a; when
386	abolished ability to regulate rna metabolism.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-430039	mRNA decay by 5’ to 3’ exoribonuclease

MSigDB gene sets: 473 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_P_BODY_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, REACTOME_MRNA_DECAY_BY_5_TO_3_EXORIBONUCLEASE, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, GOBP_MALE_GAMETE_GENERATION, LHX3_01, ACTGCAG_MIR173P, CHX10_01, YY1_Q6, SP1_Q2_01

GO Biological Process (11): negative regulation of translation (GO:0017148), viral RNA genome packaging (GO:0019074), stem cell population maintenance (GO:0019827), neuron differentiation (GO:0030182), P-body assembly (GO:0033962), stress granule assembly (GO:0034063), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), negative regulation of neuron differentiation (GO:0045665), spermatid differentiation (GO:0048515), SRP-dependent cotranslational protein targeting to membrane, signal sequence recognition (GO:0006617), spermatogenesis (GO:0007283)

GO Molecular Function (12): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), mRNA binding (GO:0003729), helicase activity (GO:0004386), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), protein domain specific binding (GO:0019904), cadherin binding (GO:0045296), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (17): heterochromatin (GO:0000792), P-body (GO:0000932), outer dense fiber (GO:0001520), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), adherens junction (GO:0005912), cytoplasmic stress granule (GO:0010494), membrane (GO:0016020), RISC complex (GO:0016442), chromatoid body (GO:0033391), cytoplasmic ribonucleoprotein granule (GO:0036464), perinuclear region of cytoplasm (GO:0048471), concave side of sperm head (GO:0061830), sperm annulus (GO:0097227), signal recognition particle, endoplasmic reticulum targeting (GO:0005786)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deadenylation-dependent mRNA decay	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
cytoplasmic ribonucleoprotein granule	3
cytoplasm	3
cell differentiation	2
membraneless organelle assembly	2
developmental process involved in reproduction	2
ATP-dependent activity	2
binding	2
sperm flagellum	2
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
viral genome packaging	1
multicellular organismal process	1
maintenance of cell number	1
generation of neurons	1
negative regulation of translation	1
miRNA-mediated post-transcriptional gene silencing	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
spermatogenesis	1
cellular process involved in reproduction in multicellular organism	1
SRP-dependent cotranslational protein targeting to membrane	1
protein-containing complex assembly	1
male gamete generation	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
RNA binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein binding	1
cell adhesion molecule binding	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

4638 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDX6	EDC3	Q96F86	999
DDX6	DCP2	Q8IU60	998
DDX6	EDC4	Q6P2E9	994
DDX6	LSM14A	Q8ND56	994
DDX6	DCP1A	Q9NPI6	992
DDX6	XRN1	Q8IZH2	991
DDX6	CNOT1	A5YKK6	991
DDX6	AGO2	Q9UKV8	988
DDX6	EIF4ENIF1	Q9NRA8	985
DDX6	TNRC6A	Q8NDV7	979
DDX6	AGO1	Q9UL18	978
DDX6	PATL1	Q86TB9	966
DDX6	ATXN2	Q99700	934
DDX6	CPEB1	Q9BZB8	933
DDX6	PABPC1	P11940	908

IntAct

560 interactions, top by confidence:

A	B	Type	Score
EDC3	DDX6	psi-mi:“MI:0914”(association)	0.960
DDX6	EDC3	psi-mi:“MI:0915”(physical association)	0.960
EDC3	DDX6	psi-mi:“MI:0915”(physical association)	0.960
DDX6	DCP1A	psi-mi:“MI:0403”(colocalization)	0.930
DCP1A	DDX6	psi-mi:“MI:0915”(physical association)	0.930
DDX6	DCP1A	psi-mi:“MI:0915”(physical association)	0.930
DDX6	EIF4ENIF1	psi-mi:“MI:0915”(physical association)	0.880
AGO2	DDX6	psi-mi:“MI:0914”(association)	0.810
AGO2	DDX6	psi-mi:“MI:0407”(direct interaction)	0.810
AGO2	DDX6	psi-mi:“MI:2364”(proximity)	0.810
AGO2	DDX6	psi-mi:“MI:0915”(physical association)	0.810
AGO2	DDX6	psi-mi:“MI:0403”(colocalization)	0.810
GOLGA2	DDX6	psi-mi:“MI:0915”(physical association)	0.780
DDX6	BIRC7	psi-mi:“MI:0915”(physical association)	0.780
DDX6	GOLGA2	psi-mi:“MI:0915”(physical association)	0.780
BIRC7	DDX6	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (724): DDX6 (Two-hybrid), GOLGA2 (Two-hybrid), TRIM37 (Two-hybrid), NONO (Two-hybrid), TRIM27 (Two-hybrid), VPS52 (Two-hybrid), TCF4 (Two-hybrid), ZNF24 (Two-hybrid), CALCOCO2 (Two-hybrid), IKZF1 (Two-hybrid), SDCCAG3 (Two-hybrid), RUNDC3A (Two-hybrid), EIF4ENIF1 (Two-hybrid), BIRC7 (Two-hybrid), EDC3 (Two-hybrid)

ESM2 similar proteins: A1CJ18, A1D8G1, A2QY39, A3LS22, A3LWX3, A4R715, A5DIP0, A6RY31, A6ZXG9, A7TGU7, A7TJT7, A7TLA0, P23128, P26196, P39517, P54823, P54824, Q07478, Q09181, Q0CBE1, Q0IHV9, Q0U7S9, Q109G2, Q1E5R1, Q2U5A2, Q4HW67, Q4WWD3, Q54E49, Q5AAW3, Q5RFQ5, Q5ZKB9, Q6BJX6, Q6C0X2, Q6CDS6, Q6CSZ7, Q6CT49, Q6CT85, Q6FL17, Q6FQU5, Q6H7S2

Diamond homologs: A1C595, A1CJ18, A1CJT5, A1D071, A1D7N3, A1D8G1, A2QEN5, A2QY39, A3GFI4, A3LWX3, A4HRK0, A4QVP2, A4R715, A5DB98, A5DIP0, A5DVM3, A6R3R5, A6RJ45, A6RY31, A6ZQJ1, A6ZXG9, A7EGL7, A7TGU7, A7TK55, O02494, O62591, P0CQ70, P0CQ71, P0CQ80, P0CQ81, P10081, P23128, P26196, P27639, P29562, P39517, P41380, P47943, P54823, P54824

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ATXN2	unknown	DDX6	binding
ATXN2L	unknown	DDX6	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 106 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
Apoptosis	5	12.5×	7e-03
Programmed Cell Death	5	10.9×	7e-03
MITF-M-regulated melanocyte development	6	10.2×	7e-03
TP53 Regulates Metabolic Genes	5	9.7×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
P-body assembly	6	67.2×	2e-07
mRNA stabilization	5	19.5×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 2 cancer types — LMS, MBL.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	62
Likely benign	9
Benign	6

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
694349	NM_004397.6(DDX6):c.1118G>A (p.Arg373Gln)	Pathogenic
694350	NM_004397.6(DDX6):c.1168T>C (p.Cys390Arg)	Pathogenic
694351	NM_004397.6(DDX6):c.1172C>T (p.Thr391Ile)	Pathogenic
694352	NM_004397.6(DDX6):c.1171A>C (p.Thr391Pro)	Pathogenic
694353	NM_004397.6(DDX6):c.1115A>G (p.His372Arg)	Pathogenic
1803958	NM_004397.6(DDX6):c.1052C>T (p.Ala351Val)	Likely pathogenic
3377226	NM_004397.6(DDX6):c.665C>T (p.Thr222Ile)	Likely pathogenic

SpliceAI

2209 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118754661:C:A	donor_gain	1.0000
11:118754684:G:C	donor_gain	1.0000
11:118754703:A:AC	donor_gain	1.0000
11:118754704:C:CC	donor_gain	1.0000
11:118754704:CATG:C	donor_gain	1.0000
11:118754725:T:C	donor_gain	1.0000
11:118754760:CAGG:C	donor_gain	1.0000
11:118754886:ACC:A	acceptor_loss	1.0000
11:118754888:C:CA	acceptor_loss	1.0000
11:118754888:C:CC	acceptor_gain	1.0000
11:118755397:CTCA:C	donor_loss	1.0000
11:118755399:CA:C	donor_loss	1.0000
11:118755400:A:AT	donor_loss	1.0000
11:118755401:C:CT	donor_loss	1.0000
11:118755499:CAGAT:C	acceptor_gain	1.0000
11:118755500:AGAT:A	acceptor_gain	1.0000
11:118755501:GAT:G	acceptor_gain	1.0000
11:118755502:AT:A	acceptor_gain	1.0000
11:118755504:C:CC	acceptor_gain	1.0000
11:118755505:T:C	acceptor_gain	1.0000
11:118755505:T:TC	acceptor_gain	1.0000
11:118756256:TTACC:T	donor_loss	1.0000
11:118756257:TACC:T	donor_loss	1.0000
11:118756258:A:AC	donor_gain	1.0000
11:118756258:AC:A	donor_gain	1.0000
11:118756259:C:CG	donor_gain	1.0000
11:118756259:CC:C	donor_gain	1.0000
11:118756259:CCA:C	donor_gain	1.0000
11:118756259:CCAG:C	donor_gain	1.0000
11:118756259:CCAGT:C	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000024449 (11:118771907 A>G), RS1000110169 (11:118752803 T>C), RS1000138908 (11:118783362 T>C), RS1000190010 (11:118774452 T>G), RS1000284713 (11:118774727 T>A), RS1000511666 (11:118790902 C>T), RS1000605637 (11:118757073 A>G), RS1000713856 (11:118762760 G>A), RS1000737347 (11:118780191 A>G), RS1000748983 (11:118790802 G>A,C), RS1000877276 (11:118790082 A>C), RS1000894228 (11:118784747 G>A), RS1001013453 (11:118786450 G>A), RS1001121753 (11:118789930 A>C), RS1001338947 (11:118753315 C>A)

Disease associations

OMIM: gene MIM:600326 | disease phenotypes: MIM:618653

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual developmental disorder with impaired language and dysmorphic facies	Strong	Autosomal dominant
syndromic intellectual disability	Supportive	Autosomal dominant

Mondo (3): intellectual developmental disorder with impaired language and dysmorphic facies (MONDO:0032851), teratoma (MONDO:0002601), syndromic intellectual disability (MONDO:0000508)

Orphanet (0):

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000076	Vesicoureteral reflux
HP:0000125	Pelvic kidney
HP:0000126	Hydronephrosis
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000270	Delayed cranial suture closure
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000341	Narrow forehead
HP:0000369	Low-set ears
HP:0000396	Overfolded helix
HP:0000486	Strabismus
HP:0000540	Hypermetropia
HP:0000733	Motor stereotypy
HP:0000750	Delayed speech and language development
HP:0000992	Cutaneous photosensitivity
HP:0001182	Tapered finger
HP:0001195	Single umbilical artery
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001513	Obesity
HP:0001545	Anteriorly placed anus
HP:0001562	Oligohydramnios

GWAS associations

39 associations (top):

Study	Trait	p-value
GCST000987_11	Celiac disease or Rheumatoid arthritis	1.000000e-12
GCST001670_2	Vitiligo	2.000000e-09
GCST002702_124	Height	4.000000e-09
GCST003129_24	Primary biliary cholangitis	2.000000e-13
GCST003853_6	Hip minimal joint space width	2.000000e-07
GCST003990_14	Allergy	9.000000e-11
GCST004302_5	Primary biliary cholangitis	3.000000e-13
GCST004867_25	Systemic lupus erythematosus	3.000000e-06
GCST005038_134	Allergic disease (asthma, hay fever or eczema)	5.000000e-18
GCST005523_30	Celiac disease	2.000000e-11
GCST005534_4	Systemic sclerosis	1.000000e-07
GCST005534_5	Systemic sclerosis	3.000000e-06
GCST005535_1	Diffuse cutaneous systemic sclerosis	3.000000e-06
GCST005568_20	Rheumatoid arthritis (ACPA-positive)	5.000000e-07
GCST005568_41	Rheumatoid arthritis (ACPA-positive)	1.000000e-10
GCST005569_15	Rheumatoid arthritis	3.000000e-08
GCST005581_6	Primary biliary cirrhosis	7.000000e-16
GCST005752_133	Systemic lupus erythematosus	2.000000e-06
GCST005990_14	Non-albumin protein levels	2.000000e-08
GCST006048_14	Rheumatoid arthritis (ACPA-positive)	1.000000e-12
GCST006409_32	Allergic rhinitis	2.000000e-23
GCST006585_861	Blood protein levels	6.000000e-06
GCST007797_4	Asthma onset (childhood vs adult)	4.000000e-12
GCST007798_135	Asthma	7.000000e-12
GCST007800_26	Asthma (childhood onset)	4.000000e-30
GCST007994_20	Asthma (age of onset)	4.000000e-14
GCST007995_32	Asthma (childhood onset)	2.000000e-13
GCST008644_3	Celiac disease and Rheumatoid arthritis	2.000000e-11
GCST008916_46	Asthma	9.000000e-09
GCST009131_18	Systemic sclerosis	2.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007873	cartilage thickness measurement
EFO:0004847	age at onset
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013724	Teratoma	C04.557.465.910

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105783 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 912 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2165191	AZD-6482	2	912

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.96	Kd	110.5	nM	CHEMBL5653589
6.96	ED50	110.5	nM	CHEMBL5653589
5.39	Kd	4103	nM	AZD-6482

PubChem BioAssay actives

2 with measured affinity, of 239 total; 2 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148226: Binding affinity to human DDX6 incubated for 45 mins by Kinobead based pull down assay	kd	0.1105	uM
2-[[(1R)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoic acid	1424977: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	4.1030	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	6
trichostatin A	affects cotreatment, decreases expression	3
bisphenol F	increases expression, affects cotreatment	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	decreases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
arsenite	affects methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
nivalenol	increases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Vorinostat	decreases expression	1
Leflunomide	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	1
Furaldehyde	decreases expression, affects cotreatment, affects localization	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991690	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5EF	HEK293T-DDX6-null	Transformed cell line	Female
CVCL_SK72	HAP1 DDX6 (-) 1	Cancer cell line	Male
CVCL_SK73	HAP1 DDX6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00104676	PHASE3	COMPLETED	Combination Chemotherapy in Treating Patients With Stage II or Stage III Germ Cell Tumors
NCT02375204	PHASE3	ACTIVE_NOT_RECRUITING	Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients with Relapsed or Refractory Germ Cell Tumors
NCT00002931	PHASE2	COMPLETED	Combination Chemotherapy Plus Peripheral Stem Cell Transplantation in Treating Patients With Relapsed Germ Cell Cancer
NCT00301782	PHASE2	COMPLETED	Combination Chemotherapy in Treating Male Patients With Germ Cell Tumors
NCT00432094	PHASE2	COMPLETED	Autologous Peripheral Blood Stem Cell Transplant for Germ Cell Tumors
NCT00453232	PHASE2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Men With Metastatic Germ Cell Tumors
NCT00453310	PHASE2	COMPLETED	Sunitinib in Treating Patients With Metastatic Germ Cell Tumors That Have Relapsed or Not Responded to Treatment
NCT00470366	PHASE2	COMPLETED	Combination Chemotherapy and Pegfilgrastim in Treating Patients With Previously Untreated Germ Cell Tumors
NCT02300987	PHASE2	COMPLETED	A Randomized, Blinded, Placebo-controlled, Phase II Trial of LEE011 in Patients With Relapsed, Refractory, Incurable Teratoma With Recent Progression
NCT00003643	PHASE2/PHASE3	UNKNOWN	Combination Chemotherapy in Treating Men With Germ Cell Cancer
NCT00423852	PHASE1/PHASE2	COMPLETED	Paclitaxel, Ifosfamide, and Carboplatin Followed By Autologous Stem Cell Transplant in Treating Patients With Germ Cell Tumors That Did Not Respond to Cisplatin
NCT00687778	Not specified	UNKNOWN	11C-Acetate PET/CT Non-FDG-Avid Tumors
NCT00836121	Not specified	COMPLETED	Anterior Mediastinum Teratoma: A Case Report
NCT05179850	Not specified	UNKNOWN	Computer Aided Diagnostic Tool on Computed Tomography Images for Diagnosis of Retroperitoneal Tumor in Children
NCT05187923	Not specified	UNKNOWN	Computer Aided Tool for Diagnosis of Neck Masses in Children
NCT05564026	Not specified	RECRUITING	Molecular Epidemiology of Pediatric Germ Cell Tumors
NCT06421805	Not specified	RECRUITING	Establishing Prospective Mediastinal Tumor Database of PUMCH
NCT07199699	Not specified	NOT_YET_RECRUITING	Subxiphoid VATS for Giant Mediastinal Teratoma