DDX5

Summary

DDX5 (DEAD-box helicase 5, HGNC:2746) is a protein-coding gene on chromosome 17q23.3, encoding Probable ATP-dependent RNA helicase DDX5 (P17844). Involved in the alternative regulation of pre-mRNA splicing; its RNA helicase activity is necessary for increasing tau exon 10 inclusion and occurs in a RBM4-dependent manner. It is a selective cancer dependency (DepMap: 74.1% of cell lines).

This gene encodes a member of the DEAD box family of RNA helicases that are involved in a variety of cellular processes as a result of its role as an adaptor molecule, promoting interactions with a large number of other factors. This protein is involved in pathways that include the alteration of RNA structures, plays a role as a coregulator of transcription, a regulator of splicing, and in the processing of small noncoding RNAs. Members of this family contain nine conserved motifs, including the conserved Asp-Glu-Ala-Asp (DEAD) motif, important to ATP binding and hydrolysis as well as RNA binding and unwinding activities. Dysregulation of this gene may play a role in cancer development. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1655 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 68 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 74.1% of screened cell lines
• MANE Select transcript: NM_004396

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2746
Approved symbol	DDX5
Name	DEAD-box helicase 5
Location	17q23.3
Locus type	gene with protein product
Status	Approved
Aliases	p68
Ensembl gene	ENSG00000108654
Ensembl biotype	protein_coding
OMIM	180630
Entrez	1655

Gene structure

Transcript identifiers

Ensembl transcripts: 61 — 35 protein_coding, 16 retained_intron, 8 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000225792, ENST00000450599, ENST00000540698, ENST00000577787, ENST00000577922, ENST00000578190, ENST00000578400, ENST00000578491, ENST00000578758, ENST00000578804, ENST00000579091, ENST00000579461, ENST00000579996, ENST00000580026, ENST00000581230, ENST00000581237, ENST00000581551, ENST00000581693, ENST00000581697, ENST00000581806, ENST00000582326, ENST00000583201, ENST00000583212, ENST00000583239, ENST00000583894, ENST00000584500, ENST00000584549, ENST00000585060, ENST00000585111, ENST00000585317, ENST00000676575, ENST00000676581, ENST00000676601, ENST00000676785, ENST00000676969, ENST00000677726, ENST00000678110, ENST00000678757, ENST00000678810, ENST00000678814, ENST00000678890, ENST00000874381, ENST00000874382, ENST00000874383, ENST00000874384, ENST00000874385, ENST00000874386, ENST00000874387, ENST00000874388, ENST00000874389, ENST00000874390, ENST00000874391, ENST00000874392, ENST00000937086, ENST00000937087, ENST00000937088, ENST00000937089, ENST00000937090, ENST00000937091, ENST00000942655, ENST00000942656

RefSeq mRNA: 4 — MANE Select: NM_004396 NM_001320595, NM_001320596, NM_001320597, NM_004396

CCDS: CCDS11659, CCDS82190

Canonical transcript exons

ENST00000225792 — 13 exons

Exon	Start	End
ENSE00003458688	64500549	64500773
ENSE00003466024	64506076	64506289
ENSE00003468939	64504222	64504318
ENSE00003499827	64504677	64504842
ENSE00003532332	64503983	64504116
ENSE00003554917	64503188	64503348
ENSE00003558396	64502162	64502223
ENSE00003584302	64502926	64503098
ENSE00003585557	64502010	64502069
ENSE00003596319	64498254	64500326
ENSE00003621662	64502439	64502549
ENSE00003635634	64503803	64503868
ENSE00003689615	64503430	64503571

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1021.8454 / max 8064.5851, expressed in 1828 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167586	998.3219	1828
167589	7.0485	1667
167579	3.3018	1376
167578	2.6648	1211
167587	2.4042	1111
167588	1.9715	1163
167590	1.8346	1060
167576	1.4478	773
167584	0.9756	604
167583	0.7053	333

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.76	gold quality
bone marrow cell	CL:0002092	99.74	gold quality
granulocyte	CL:0000094	99.70	gold quality
adenohypophysis	UBERON:0002196	99.67	gold quality
right adrenal gland cortex	UBERON:0035827	99.66	gold quality
smooth muscle tissue	UBERON:0001135	99.65	gold quality
right adrenal gland	UBERON:0001233	99.64	gold quality
monocyte	CL:0000576	99.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.63	gold quality
colonic epithelium	UBERON:0000397	99.63	gold quality
cortical plate	UBERON:0005343	99.63	gold quality
right lobe of thyroid gland	UBERON:0001119	99.62	gold quality
left lobe of thyroid gland	UBERON:0001120	99.62	gold quality
left adrenal gland	UBERON:0001234	99.62	gold quality
right lung	UBERON:0002167	99.62	gold quality
leukocyte	CL:0000738	99.61	gold quality
lower esophagus	UBERON:0013473	99.61	gold quality
left adrenal gland cortex	UBERON:0035825	99.61	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.61	gold quality
embryo	UBERON:0000922	99.59	gold quality
left uterine tube	UBERON:0001303	99.59	gold quality
gall bladder	UBERON:0002110	99.59	gold quality
ganglionic eminence	UBERON:0004023	99.59	gold quality
right uterine tube	UBERON:0001302	99.58	gold quality
body of uterus	UBERON:0009853	99.58	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.58	gold quality
mucosa of stomach	UBERON:0001199	99.56	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.56	gold quality
vermiform appendix	UBERON:0001154	99.55	gold quality
upper lobe of left lung	UBERON:0008952	99.55	gold quality

Single-cell (SCXA)

Detected in 25 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	2579.62
E-HCAD-1	yes	87.32
E-CURD-122	yes	42.15
E-CURD-88	yes	41.52
E-MTAB-9543	yes	28.90
E-MTAB-8410	yes	26.56
E-HCAD-9	yes	22.97
E-MTAB-6678	yes	11.29
E-MTAB-10042	yes	9.72
E-GEOD-125970	yes	7.79
E-CURD-112	yes	6.89
E-MTAB-6379	no	10592.30
E-GEOD-76312	no	6214.45
E-MTAB-10137	no	2903.62
E-MTAB-11011	no	2767.93

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
CDKN1A	Activation
H19	Unknown
IGF2	Unknown

Upstream regulators (CollecTRI, top): AR, FOXO1, MYC, MYOD1, NFAT5, ZNF331

miRNA regulators (miRDB)

120 targeting DDX5, 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-8485	100.00	77.57	4731
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-3910	99.95	71.13	2227

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 74.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Essential for pre-mrna splicing in vitro; may function in destabilizing the U1-5’ss interaction. Depletion of p68 RNA helicase arrested spliceosome assembly at the prespliceosome stage (PMID:12101238)
• synergism with transcriptional coactivators CBP and p300 (PMID:12527917)
• role in c-H-ras alternative splicing regulation (PMID:12665590)
• p68 is an important transcriptional regulator, functioning as a co-activator and/or co-repressor depending on the context of the promoter & the transcriptional complex. AA 1-478 of p68 can repress transcription as well as the full-length protein. (PMID:15298701)
• there is a tightly controlled expression and nucleolar localization of p68 in keratinocytes in vitro and during skin repair in vivo that functionally contributes to keratinocyte proliferation and gene expression (PMID:15304501)
• mechanism by which p68 may act as a tumour cosuppressor in governing p53 transcriptional activity (PMID:15660129)
• data suggest that function(s) of p68 RNA helicase may be subjected to the regulation of multiple cell signal pathways (PMID:15927448)
• In addition, it could be demonstrated that increasing the Tlk1 activity in HT1080 cells by forced Tlk1 overexpression leads to an increased phosphorylation of endogenous p68. (PMID:15950181)
• Patient with chronic hepatitis C carrying DDX5 haplotypes are at an increased risk of developing advanced liver fibrosis. (PMID:16697732)
• Data show that P68 RNA helicase mediates platelet-derived growth factor-induced epithelial mesenchymal transition by displacing Axin from beta-catenin. (PMID:17018282)
• SUMO modification of the DEAD box protein p68 modulates its transcriptional activity and promotes its interaction with HDAC1 (PMID:17369852)
• A mutant that carries mutations at the phosphorylation sites (Y593/595F) dramatically sensitizes TRAIL-resistant cells to TRAIL-induced apoptosis, suggesting a potential therapeutic strategy to overcome TRAIL resistance. (PMID:17384675)
• The percentage correlation between Q-RT-PCR and microarray were 70% and 48% by using DDX5 and GAPDH as internal controls, respectively. (PMID:17540040)
• p68/p72 may contribute to colon cancer formation by directly up-regulating proto-oncogenes and indirectly by down-regulating the growth suppressor p21(WAF1/CIP1). (PMID:17699760)
• P68 RNA helicase is an essential component of the let-7 microRNA pathway (PMID:17724023)
• The DEAD-box proteins p68(Ddx5) and p72(Ddx17) were used as models for this coexpression frequency analysis as there are defined functions for these proteins in splicing and transcription. (PMID:18005418)
• DEAD-box RNA helicase p68 is not required for nuclear translocation of beta-catenin in colon cancer cells. (PMID:18239468)
• A ubiquitously expressed, androgen-insensitive gene, DDX5, fused in frame with ETV4, leading to the expression of a DDX5-ETV4 fusion protein was identified in prostate cancer. (PMID:18794152)
• p68 is a novel AR transcriptional coactivator that is significantly overexpressed in PCa with a possible role in progression to hormone-refractory disease. (PMID:18829551)
• Upregulated in at least 50% of multiple myeloma cases tested. (PMID:19171422)
• the Ddx5 (Asp-Glu-Ala-Asp box polypeptide 5) protein showed specific interaction with SARS-CoV helicase. (PMID:19224332)
• Distinct but important roles for both p68 and p72 in regulating ERalpha activity in breast cancer. (PMID:19718048)
• DDX5 is a repressor of fibrogenic genes in HSCs through interaction with transcriptional complexes. (PMID:20022962)
• crystallization and preliminary diffraction analysis of N-terminal region of DDX5 is reported.X-ray diffraction data were processed to a resolution of 2.7 A. (PMID:20124720)
• Pleiotropic effects of p300-mediated acetylation on p68 and p72 RNA helicase. (PMID:20663877)
• a striking inverse association of p68 and delta133p53 expression in primary breast cancers was identified. (PMID:20818423)
• DEAD-box RNA helicase p68 (DDX5) and its associated noncoding RNA, steroid receptor RNA activator (SRA), form a complex with CTCF that is essential for insulator function (PMID:20966046)
• Using an RNA affinity pulldown-coupled mass spectrometry approach the study identified DDX5/RNA helicase p68 as an activator of TAU exon 10 splicing. (PMID:21343338)
• High DDX5 is associated with basal breast cancer cells. (PMID:22086602)
• Data indicate that transcriptional coregulator ddx5/ddx17 RNA helicases can simultaneously regulate the transcriptional activity and alternative splicing of NFAT5 transcription factor. (PMID:22266867)
• The DEAD box RNA helicase p68, also referred to as DDX5, directly interacts with VDR. (PMID:22476084)
• there is a direct interaction between DDX5 and NS5B and DDX5 has two independent NS5B-binding sites (PMID:22640416)
• Results show a novel role for DDX5 in cancer cell proliferation and suggest DDX5 as a therapeutic target in breast cancer treatment. (PMID:22750847)
• High p68 RNA helicase expression is associated with glioma. (PMID:22810421)
• RNA helicases Ddx17 and Ddx5 contribute to tumor-cell invasiveness by regulating alternative splicing of several DNA- and chromatin-binding factors, including the macroH2A1 histone. (PMID:23022728)
• DDX5 might be critical for NOTCH1-mediated T-ALL pathogenesis and thus is a potential new target for modulating the Notch signaling in leukemia (PMID:23108395)
• p68, in the presence of Ca-calmodulin, can function as a microtubule motor. (PMID:23322042)
• Data show that p68/DdX5 immunoprecipitated with RNA polymerase II (RNAP II) and suggest p68 is important in facilitating beta-catenin and androgen receptor (AR) transcriptional activity in prostate cancer cells. (PMID:23349811)
• Results suggest that distinct DDX DEAD-box RNA helicases DDX3 and DDX5 cooperate to modulate the HIV-1 Rev function. (PMID:23608157)
• DDX5 facilitates HIV-1 replication as a cellular co-factor of Rev. (PMID:23741449)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddx5	ENSDARG00000038068
mus_musculus	Ddx5	ENSMUSG00000020719
rattus_norvegicus	Ddx5	ENSRNOG00000030680

Paralogs (38): DDX20 (ENSG00000064703), DDX3Y (ENSG00000067048), DDX1 (ENSG00000079785), DDX43 (ENSG00000080007), DDX18 (ENSG00000088205), DDX24 (ENSG00000089737), DDX17 (ENSG00000100201), DDX49 (ENSG00000105671), DDX50 (ENSG00000107625), 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), 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 DDX5 — P17844 (reviewed: P17844)

Alternative names: DEAD box protein 5, RNA helicase p68

All UniProt accessions (19): P17844, A0A0G2JLI4, A0A7I2V2S0, A0A7I2V507, A0A7I2V5F5, J3KRZ1, J3KTA4, J3KTQ4, J3QKN9, J3QLG9, J3QR02, J3QR62, J3QRN5, J3QRQ7, J3QS79, J3QS97, J3QSF1, K7EKV0, X6RLV5

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the alternative regulation of pre-mRNA splicing; its RNA helicase activity is necessary for increasing tau exon 10 inclusion and occurs in a RBM4-dependent manner. Binds to the tau pre-mRNA in the stem-loop region downstream of exon 10. The rate of ATP hydrolysis is highly stimulated by single-stranded RNA. Involved in transcriptional regulation; the function is independent of the RNA helicase activity. Transcriptional coactivator for androgen receptor AR but probably not ESR1. Synergizes with DDX17 and SRA1 RNA to activate MYOD1 transcriptional activity and involved in skeletal muscle differentiation. Transcriptional coactivator for p53/TP53 and involved in p53/TP53 transcriptional response to DNA damage and p53/TP53-dependent apoptosis. Transcriptional coactivator for RUNX2 and involved in regulation of osteoblast differentiation. Acts as a transcriptional repressor in a promoter-specific manner; the function probably involves association with histone deacetylases, such as HDAC1. As component of a large PER complex is involved in the inhibition of 3’ transcriptional termination of circadian target genes such as PER1 and NR1D1 and the control of the circadian rhythms.

Subunit / interactions. Identified in the spliceosome C complex. Component of a ribonucleoprotein complex containing mRNAs and RNA-binding proteins including DDX5, HNRNPH2 and SRSF1 as well as splicing regulator ARVCF. Interacts with RBM4; the interaction occurs in an RNA-independent manner. Interacts with AGO1 and AGO2. Interacts with ESR1, AR, EP300, CREBBP, POLR2A, TP53, RUNX2 and HDAC1. Self-associates. Interacts with DDX17. Interacts with BRDT. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). Interacts with DHX36; this interaction occurs in a RNA-dependent manner. Interacts with NUPR1. Interacts with ERCC6. Interacts with DDX3X in the cytoplasm; this interaction may be more efficient when both proteins are unphosphorylated.

Subcellular location. Nucleus. Nucleolus. Nucleus speckle. Cytoplasm.

Post-translational modifications. Arg-502 is dimethylated, probably to asymmetric dimethylarginine. Sumoylated; sumoylation, promoted by PIAS1, promotes interaction with HDAC1 and transcriptional repression activity. Sumoylation also significantly increases stability, and reduces polyubiquitination. Polyubiquitinated, leading to proteasomal degradation. Weakly phosphorylated in the G1/S phase of the cell cycle and much more at G2/M, especially at Thr and Tyr residues.

Similarity. Belongs to the DEAD box helicase family. DDX5/DBP2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P17844-1	1	yes
P17844-2	2

RefSeq proteins (4): NP_001307524, NP_001307525, NP_001307526, NP_004387* (*=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
IPR012587	P68_rpt	Repeat
IPR014001	Helicase_ATP-bd	Domain
IPR014014	RNA_helicase_DEAD_Q_motif	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00270, PF00271, PF08061

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 (64 total): cross-link 14, helix 11, strand 9, modified residue 8, mutagenesis site 4, binding site 3, region of interest 3, turn 3, domain 2, short sequence motif 2, compositionally biased region 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3FE2	X-RAY DIFFRACTION	2.6
4A4D	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17844-F1	76.74	0.48

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 (3): 114–116; 121; 138–145

Post-translational modifications (22): 24, 32, 33, 40, 236, 297, 480, 520, 32, 45, 53, 53, 53, 340, 343, 388, 391, 411, 437, 451 …

Mutagenesis-validated functional residues (4):

Position	Phenotype
53	abolishes sumoylation, abolishes interaction with hdac1, increases tp53 coactivation and promotes polyubiquitination.
55	abolishes sumoylation.
144	abolishes rna helicase activity.
403	binds to the tau stem-loop-containing rna. inhibits tau exon 10 inclusion and rna cleavage. does not inhibit interaction

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-9682706	Replication of the SARS-CoV-1 genome
R-HSA-9694686	Replication of the SARS-CoV-2 genome
R-HSA-9770562	mRNA Polyadenylation
R-HSA-9918481	Dengue Virus-Host Interactions

MSigDB gene sets: 466 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GOBP_POSITIVE_REGULATION_OF_DNA_DAMAGE_RESPONSE_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GNF2_BNIP2, GOBP_REGULATION_OF_SKELETAL_MUSCLE_CELL_DIFFERENTIATION, GCM_MSN, GOBP_CELLULAR_RESPONSE_TO_LIPID, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_ALTERNATIVE_MRNA_SPLICING_VIA_SPLICEOSOME, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, ACTGCAG_MIR173P, MODULE_229

GO Biological Process (23): negative regulation of transcription by RNA polymerase II (GO:0000122), alternative mRNA splicing, via spliceosome (GO:0000380), regulation of alternative mRNA splicing, via spliceosome (GO:0000381), mRNA splicing, via spliceosome (GO:0000398), nuclear-transcribed mRNA catabolic process (GO:0000956), epithelial to mesenchymal transition (GO:0001837), regulation of transcription by RNA polymerase II (GO:0006357), mRNA transcription (GO:0009299), BMP signaling pathway (GO:0030509), estrogen receptor signaling pathway (GO:0030520), androgen receptor signaling pathway (GO:0030521), primary miRNA processing (GO:0031053), positive regulation of DNA damage response, signal transduction by p53 class mediator (GO:0043517), regulation of viral genome replication (GO:0045069), myoblast differentiation (GO:0045445), regulation of osteoblast differentiation (GO:0045667), rhythmic process (GO:0048511), regulation of androgen receptor signaling pathway (GO:0060765), miRNA transcription (GO:0061614), intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332), regulation of skeletal muscle cell differentiation (GO:2001014), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (22): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), mRNA binding (GO:0003729), mRNA 3’-UTR binding (GO:0003730), calmodulin binding (GO:0005516), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), enzyme binding (GO:0019899), MH2 domain binding (GO:0035500), pre-mRNA binding (GO:0036002), ribonucleoprotein complex binding (GO:0043021), SMAD binding (GO:0046332), calcium-dependent protein binding (GO:0048306), nuclear androgen receptor binding (GO:0050681), R-SMAD binding (GO:0070412), primary miRNA binding (GO:0070878), promoter-specific chromatin binding (GO:1990841), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear speck (GO:0016607), extracellular exosome (GO:0070062), catalytic step 2 spliceosome (GO:0071013), ribonucleoprotein complex (GO:1990904), spliceosomal complex (GO:0005681)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	1
mRNA Splicing	1
ESR-mediated signaling	1
SARS-CoV-1 Genome Replication and Transcription	1
SARS-CoV-2 Genome Replication and Transcription	1
mRNA 3’-end processing	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
cellular anatomical structure	4
RNA binding	3
transcription by RNA polymerase II	2
DNA-templated transcription	2
nuclear receptor-mediated steroid hormone signaling pathway	2
ATP-dependent activity	2
nuclear lumen	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
mRNA splicing, via spliceosome	1
alternative mRNA splicing, via spliceosome	1
regulation of mRNA splicing, via spliceosome	1
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
mRNA catabolic process	1
mesenchymal cell differentiation	1
regulation of DNA-templated transcription	1
mRNA metabolic process	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
miRNA processing	1
DNA damage response, signal transduction by p53 class mediator	1
regulation of DNA damage response, signal transduction by p53 class mediator	1
positive regulation of signal transduction by p53 class mediator	1
viral genome replication	1
regulation of viral life cycle	1
cell differentiation	1
muscle structure development	1
osteoblast differentiation	1
regulation of cell differentiation	1
biological_process	1
androgen receptor signaling pathway	1
regulation of intracellular steroid hormone receptor signaling pathway	1
miRNA metabolic process	1
signal transduction by p53 class mediator	1
intrinsic apoptotic signaling pathway	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on RNA	1

Protein interactions and networks

STRING

4932 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDX5	DROSHA	Q9NRR4	998
DDX5	DGCR8	Q8WYQ5	990
DDX5	TP53	P04637	987
DDX5	DDX17	Q92841	949
DDX5	DHX9	Q08211	935
DDX5	SMAD3	P84022	926
DDX5	AGO2	Q9UKV8	865
DDX5	SMAD5	Q99717	836
DDX5	HNRNPC	P07910	827
DDX5	DDX3X	O00571	810
DDX5	CTNNB1	P35222	804
DDX5	MATR3	P43243	803
DDX5	MYOD1	P15172	802
DDX5	SRA1	Q9HD15	794
DDX5	HNRNPK	P61978	790

IntAct

447 interactions, top by confidence:

A	B	Type	Score
ESR1	ESR1	psi-mi:“MI:0914”(association)	0.870
EGFR	HSP90AA1	psi-mi:“MI:0914”(association)	0.820
DROSHA	DDX5	psi-mi:“MI:0915”(physical association)	0.740
DROSHA	DDX5	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
DROSHA	TP53	psi-mi:“MI:0914”(association)	0.680
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
DDX5	SMAD1	psi-mi:“MI:0915”(physical association)	0.610
SMAD1	DDX5	psi-mi:“MI:0914”(association)	0.610
DDX5	SMAD1	psi-mi:“MI:0914”(association)	0.610
DDX5	SMAD5	psi-mi:“MI:0915”(physical association)	0.560
SMAD5	DDX5	psi-mi:“MI:0914”(association)	0.560
DDX5	TARDBP	psi-mi:“MI:0915”(physical association)	0.560
DAPK1	SVIL	psi-mi:“MI:0914”(association)	0.530
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
DDX5	PB1	psi-mi:“MI:0915”(physical association)	0.510
MAEA	HTRA2	psi-mi:“MI:0914”(association)	0.510
RANBP9	DDX5	psi-mi:“MI:0914”(association)	0.510
RMND5A	DDX5	psi-mi:“MI:0914”(association)	0.510
YPEL5	SYNCRIP	psi-mi:“MI:0914”(association)	0.510

BioGRID (847): DDX5 (Affinity Capture-MS), DDX5 (Affinity Capture-MS), DDX5 (Affinity Capture-Western), MAPKAPK2 (Affinity Capture-Western), DDX5 (Biochemical Activity), DDX5 (Affinity Capture-Western), DROSHA (Affinity Capture-Western), DDX5 (Biochemical Activity), EP300 (Affinity Capture-Western), ESR1 (Affinity Capture-Western), DDX5 (Affinity Capture-Western), DDX5 (Affinity Capture-Western), DDX5 (Affinity Capture-Western), DDX5 (Affinity Capture-RNA), DDX5 (Affinity Capture-MS)

ESM2 similar proteins: A1C6C4, A1DGZ7, A2QC74, A3LQW7, A4QSS5, A4RHF1, A5A6J2, A5DL80, A5DS77, A6RGE3, A6SFW7, A6ZP47, A6ZRX0, A7E449, A7TTT5, G0SFM2, P06634, P0CQ76, P0CQ77, P17844, P24782, P24783, Q1DP69, Q2H720, Q2U070, Q4I7K4, Q4IF76, Q4PHU9, Q4R6M5, Q4X195, Q501J6, Q59LU0, Q5B0J9, Q5QMN3, Q5R4I9, Q61656, Q6BY27, Q6C4D4, Q6CB69, Q6CIV2

Diamond homologs: A1C5V3, A1C6C4, A1DG51, A1DGZ7, A2QC74, A2QFL3, A3LQ01, A3LQW7, A3LRW2, A4QSS5, A5A6J2, A5DAC8, A5DL80, A5DS77, A5DZE6, A5E1W4, A6QXC1, A6RGE3, A6SCT6, A6SFW7, A6ZP47, A6ZRX0, A6ZUA1, A6ZWD3, A7E449, A7EYW0, A7TJ36, A7TKR8, G0SFM2, O22907, P06634, P0CQ78, P0CQ79, P17844, P19109, P20447, P24782, P24783, P24784, P46942

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
DDX5	up-regulates	TP53	binding
DDX5	“form complex”	“RNA helicases DDX5/DDX17”	binding
ABL1	up-regulates	DDX5	phosphorylation
DDX5	up-regulates	HDAC1	binding
PIAS1	up-regulates	DDX5	sumoylation
DDX5	up-regulates	AR	binding
rep	“up-regulates activity”	DDX5	binding
PAK5	“up-regulates quantity by stabilization”	DDX5	phosphorylation
CBP/p300	up-regulates	DDX5	binding
DDX5	up-regulates	RUNX2	binding
PRKCA	“down-regulates activity”	DDX5	phosphorylation
DDX5	“up-regulates activity”	“Microprocessor complex”	binding
DDX5	“up-regulates quantity”	mir-10b	“post transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 200 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
DNA Damage Recognition in GG-NER	5	10.7×	7e-03
Signaling by ALK fusions and activated point mutants	7	7.9×	3e-03
Potential therapeutics for SARS	8	6.9×	3e-03
Processing of Capped Intron-Containing Pre-mRNA	10	6.2×	9e-04
SARS-CoV Infections	13	5.4×	4e-04
Neddylation	13	4.6×	9e-04
Viral Infection Pathways	17	3.9×	4e-04
Infectious disease	21	3.9×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
SMAD protein signal transduction	5	22.3×	3e-04
spliceosomal complex assembly	5	18.4×	6e-04
mRNA stabilization	7	15.6×	9e-05
intrinsic apoptotic signaling pathway	7	15.3×	9e-05
extrinsic apoptotic signaling pathway via death domain receptors	5	12.2×	3e-03
mitophagy	6	11.6×	1e-03
mRNA export from nucleus	6	10.8×	1e-03
autophagosome maturation	5	10.7×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	40
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2089 predictions. Top by Δscore:

Variant	Effect	Δscore
17:64500825:C:CT	acceptor_gain	1.0000
17:64500834:C:CT	acceptor_gain	1.0000
17:64500839:C:CT	acceptor_gain	1.0000
17:64500840:A:T	acceptor_gain	1.0000
17:64502145:T:TA	donor_gain	1.0000
17:64502157:TTTA:T	donor_loss	1.0000
17:64502158:TTA:T	donor_loss	1.0000
17:64502159:TAC:T	donor_loss	1.0000
17:64502160:ACCAT:A	donor_loss	1.0000
17:64502161:C:CA	donor_loss	1.0000
17:64502220:CCAC:C	acceptor_gain	1.0000
17:64502221:CAC:C	acceptor_gain	1.0000
17:64502221:CACC:C	acceptor_gain	1.0000
17:64502222:ACCT:A	acceptor_loss	1.0000
17:64502223:CCTA:C	acceptor_loss	1.0000
17:64502225:T:A	acceptor_loss	1.0000
17:64502438:CCCAT:C	donor_gain	1.0000
17:64502442:T:C	donor_gain	1.0000
17:64502446:T:A	donor_gain	1.0000
17:64502919:AACTT:A	donor_loss	1.0000
17:64502920:ACTT:A	donor_loss	1.0000
17:64502922:TTAC:T	donor_loss	1.0000
17:64502923:TA:T	donor_loss	1.0000
17:64502924:A:AC	donor_gain	1.0000
17:64502924:A:T	donor_loss	1.0000
17:64502925:C:CT	donor_gain	1.0000
17:64502925:CT:C	donor_gain	1.0000
17:64502925:CTT:C	donor_gain	1.0000
17:64502925:CTTT:C	donor_gain	1.0000
17:64502925:CTTTT:C	donor_gain	1.0000

AlphaMissense

4066 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:64500578:A:C	L471W	1.000
17:64500578:A:G	L471S	1.000
17:64500595:T:A	Q465H	1.000
17:64500595:T:G	Q465H	1.000
17:64500596:T:G	Q465P	1.000
17:64500602:G:T	A463D	1.000
17:64500603:C:G	A463P	1.000
17:64500611:A:G	L460P	1.000
17:64500611:A:T	L460H	1.000
17:64500614:A:T	V459E	1.000
17:64500623:A:G	L456P	1.000
17:64500623:A:T	L456H	1.000
17:64500656:A:G	F445S	1.000
17:64500659:A:G	F444S	1.000
17:64500666:A:C	Y442D	1.000
17:64500668:G:T	A441E	1.000
17:64500669:C:G	A441P	1.000
17:64500674:C:A	G439V	1.000
17:64500674:C:T	G439D	1.000
17:64500675:C:A	G439C	1.000
17:64500675:C:G	G439R	1.000
17:64500675:C:T	G439S	1.000
17:64500690:G:T	R434S	1.000
17:64500692:G:A	A433V	1.000
17:64500692:G:T	A433D	1.000
17:64500695:G:A	T432I	1.000
17:64500697:T:A	R431S	1.000
17:64500697:T:G	R431S	1.000
17:64500698:C:A	R431I	1.000
17:64500698:C:G	R431T	1.000

dbSNP variants (sampled 300 via entrez): RS1000057115 (17:64500456 C>G), RS1000267629 (17:64507534 C>T), RS1000479703 (17:64504972 C>T), RS1000677464 (17:64506917 C>A,G,T), RS1000748155 (17:64507756 A>C), RS1000775758 (17:64503659 T>C,G), RS1001585107 (17:64497962 G>A), RS1002275595 (17:64506292 C>A,G,T), RS1002450072 (17:64502274 C>T), RS1003032195 (17:64505684 G>A,T), RS1004148326 (17:64508045 C>A,G,T), RS1004179190 (17:64508224 T>C), RS1004296563 (17:64504995 T>A), RS1004480684 (17:64507081 C>T), RS1004505374 (17:64499386 A>G)

Disease associations

OMIM: gene MIM:180630 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007429_133	Lung function (FVC)	3.000000e-09
GCST010002_128	Refractive error	2.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295722 (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: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.80	Kd	15.73	nM	CHEMBL5653589
7.80	ED50	15.73	nM	CHEMBL5653589
7.46	Kd	34.4	nM	CHEMBL307794
6.27	Kd	535	nM	MOLIBRESIB
6.04	IC50	920	nM	MOLIBRESIB
5.94	Kd	1157	nM	CHEMBL3752910
5.94	ED50	1157	nM	CHEMBL3752910

PubChem BioAssay actives

5 with measured affinity, of 13 total; 4 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	2148225: Binding affinity to human DDX5 incubated for 45 mins by Kinobead based pull down assay	kd	0.0157	uM
(5S)-5-ethyl-5-hydroxy-7,18,20-trioxa-11,24-diazahexacyclo[11.11.0.02,11.04,9.015,23.017,21]tetracosa-1(13),2,4(9),14,16,21,23-heptaene-6,10-dione	2025452: Binding affinity to human recombinant DDX5 assessed as dissociation constant	kd	0.0344	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179141: Binding affinity against DDX5 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.5350	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148225: Binding affinity to human DDX5 incubated for 45 mins by Kinobead based pull down assay	kd	1.1574	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment	4
Valproic Acid	decreases expression, affects cotreatment	4
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Rotenone	decreases expression	2
Cadmium Chloride	increases expression, decreases expression, increases abundance	2
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects oxidation, increases abundance, affects cotreatment, affects expression	1
deoxynivalenol	increases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	increases expression	1
gossypol acetic acid	decreases expression	1
cupric oxide	increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, affects expression, affects oxidation	1
cyclic 3’,5’-uridine monophosphate	affects binding	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	decreases expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118566	Binding	Binding affinity to DDX5 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1661	ZR-75-30	Cancer cell line	Female
CVCL_B8UR	Abcam MCF-7 DDX5 KO	Cancer cell line	Female
CVCL_SK69	HAP1 DDX5 (-) 1	Cancer cell line	Male
CVCL_XN21	HAP1 DDX5 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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