DHX36

Summary

DHX36 (DEAH-box helicase 36, HGNC:14410) is a protein-coding gene on chromosome 3q25.2, encoding ATP-dependent DNA/RNA helicase DHX36 (Q9H2U1). Multifunctional ATP-dependent helicase that unwinds G-quadruplex (G4) structures. It is a selective cancer dependency (DepMap: 78.8% of cell lines).

This gene is a member of the DEAH-box family of RNA-dependent NTPases which are named after the conserved amino acid sequence Asp-Glu-Ala-His in motif II. The protein encoded by this gene has been shown to enhance the deadenylation and decay of mRNAs with 3’-UTR AU-rich elements (ARE-mRNA). The protein has also been shown to resolve into single strands the highly stable tetramolecular DNA configuration (G4) that can form spontaneously in guanine-rich regions of DNA. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 170506 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 126 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 78.8% of screened cell lines
• MANE Select transcript: NM_020865

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14410
Approved symbol	DHX36
Name	DEAH-box helicase 36
Location	3q25.2
Locus type	gene with protein product
Status	Approved
Aliases	MLEL1, KIAA1488, RHAU
Ensembl gene	ENSG00000174953
Ensembl biotype	protein_coding
OMIM	612767
Entrez	170506

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 7 retained_intron, 1 nonsense_mediated_decay

ENST00000308361, ENST00000329463, ENST00000460695, ENST00000460875, ENST00000462464, ENST00000469977, ENST00000477549, ENST00000479934, ENST00000481332, ENST00000481941, ENST00000491011, ENST00000495598, ENST00000496811, ENST00000932391, ENST00000964933, ENST00000964934

RefSeq mRNA: 2 — MANE Select: NM_020865 NM_001114397, NM_020865

CCDS: CCDS3171, CCDS54657

Canonical transcript exons

ENST00000496811 — 25 exons

Exon	Start	End
ENSE00000779787	154277598	154277718
ENSE00000779795	154292551	154292694
ENSE00000779796	154293748	154293812
ENSE00001125776	154300594	154300696
ENSE00001182676	154306216	154306295
ENSE00001182678	154303329	154303410
ENSE00001182681	154309653	154309823
ENSE00001224560	154283188	154283271
ENSE00001224568	154284583	154284669
ENSE00001224573	154284814	154284987
ENSE00001224619	154295284	154295339
ENSE00001224627	154299838	154299925
ENSE00001224644	154300987	154301127
ENSE00001224666	154305094	154305168
ENSE00001224688	154311636	154311674
ENSE00001224697	154315046	154315280
ENSE00001342318	154324174	154324487
ENSE00001935300	154272546	154276356
ENSE00003496133	154288866	154288964
ENSE00003555734	154316039	154316163
ENSE00003578920	154280763	154280862
ENSE00003595443	154304806	154304972
ENSE00003626762	154280579	154280669
ENSE00003629076	154276747	154276899
ENSE00003632580	154289709	154289826

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 98.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.8529 / max 588.4982, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45208	38.3613	1818
45207	5.4480	1491
45206	0.0354	15
45209	0.0082	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	98.45	gold quality
kidney epithelium	UBERON:0004819	97.70	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.64	gold quality
lower lobe of lung	UBERON:0008949	97.54	gold quality
pancreatic ductal cell	CL:0002079	97.41	gold quality
cauda epididymis	UBERON:0004360	97.41	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.35	gold quality
caput epididymis	UBERON:0004358	97.27	gold quality
upper arm skin	UBERON:0004263	97.25	gold quality
trigeminal ganglion	UBERON:0001675	97.02	gold quality
tendon of biceps brachii	UBERON:0008188	96.99	gold quality
pons	UBERON:0000988	96.98	gold quality
lateral globus pallidus	UBERON:0002476	96.93	gold quality
corpus epididymis	UBERON:0004359	96.89	gold quality
superficial temporal artery	UBERON:0001614	96.76	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.73	gold quality
dorsal root ganglion	UBERON:0000044	96.71	gold quality
mammary duct	UBERON:0001765	96.63	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.63	gold quality
epithelium of mammary gland	UBERON:0003244	96.51	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.51	gold quality
substantia nigra pars compacta	UBERON:0001965	96.39	gold quality
superior surface of tongue	UBERON:0007371	96.32	gold quality
superior vestibular nucleus	UBERON:0007227	96.30	gold quality
biceps brachii	UBERON:0001507	96.29	gold quality
ventricular zone	UBERON:0003053	96.29	gold quality
nipple	UBERON:0002030	96.24	gold quality
ganglionic eminence	UBERON:0004023	96.23	gold quality
medulla oblongata	UBERON:0001896	96.21	gold quality
corpus callosum	UBERON:0002336	96.16	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.90
E-MTAB-9689	no	192.04
E-MTAB-7303	no	51.11

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
YY1

miRNA regulators (miRDB)

50 targeting DHX36, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-4528	99.18	69.77	1936
HSA-MIR-10399-5P	99.17	69.87	2610

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 78.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 30)

• DHX36 protein is responsible for the majority of tetramolecular G4-DNA resolvase activity (PMID:16150737)
• RHAU has a dual function, being involved in both the synthesis and degradation of mRNA in different subcellular compartments. (PMID:18279852)
• the RNA quadruplex resolving enzymatic activity associated with G4R1/RHAU and its exceptional binding affinity, suggesting a potential novel role for G4R1/RHAU in targeting in vivo RNA quadruplex structures (PMID:18842585)
• RHAU is the fourth RNA helicase detected in SGs, after rck/p54, DDX3, and eIF4A, and its association with SGs is dynamic and mediated by an RHAU-specific RNA-binding domain (PMID:18854321)
• The amino-terminal region of RHAU is essential for RHAU to bind G4 structures and within this region the evolutionary conserved RSM (RHAU-specific motif) domain is a major affinity and specificity determinant (PMID:20472641)
• DHX9/DHX36 represent the MyD88-dependent DNA sensors in the cytosol of plasmacytoid dendritic cells and suggest a much broader role for DHX helicases in viral sensing (PMID:20696886)
• The helicase domain of DHX36 does not mediate telomerase RNA (hTR) binding; instead, hTR interacts with the N-terminal accessory domain of DHX36 known to bind specifically to the parallel-strand G-quadruplex substrates resolved by the helicase domain. (PMID:21149580)
• Data show that hnRNPA1/A2, HuR and DAZAP1 splicing factors and DHX36 RNA helicase bind to the ISE, with hnRNPA1 acting negatively and DAZAP1 positively on splicing selection (PMID:21858080)
• Data supports a helicase function of RHAU on an intramolecular RNA quadruplex and show that the enzyme is capable of completely converting quadruplex RNA to a stable duplex. (PMID:22238380)
• Used an integrated approach that includes small angle x-ray scattering, nuclear magnetic resonance spectroscopy, circular dichroism, and dynamic light scattering methods to demonstrate the recognition of G-quadruplexes by the N-terminal domain of RHAU. (PMID:24151078)
• we identify a novel function of DHX36 to facilitate viral RNA recognition (PMID:24651521)
• present a model showing that a replication fork disrupting a T-loop could create a 5’ quadruplex with an opened 3’tail structure that is recognized by G4R1 (PMID:26172836)
• biophysical analysis provides evidence that the RNA G-quadruplex, but not its DNA counterpart, can adopt a parallel orientation, and that only the RNA can interact with N-terminal domain of RHAU via the tetrad face of the G-quadruplex. This work extends our insight into how the N-terminal region of RHAU recognizes parallel G-quadruplexes. (PMID:26649896)
• RHAU binds to an adenosine-rich region near the 3’-end of the long non-coding RNA BC200. (PMID:26740632)
• Data show that helicases RHAU, BLM, and WRN exhibit distinct G-quadruplex (GQ) conformation specificity, but use a common mechanism of repetitive unfolding that leads to disrupting GQ structure multiple times in succession. (PMID:27407146)
• RHAU mediates the unfolding of DNA and RNA quadruplexes. (PMID:28065761)
• The study provides the first evidence that the unfolding kinetics of a G-quadruplex can be modulated by different nucleotide-bound states of the RHAU helicase. (PMID:28069994)
• DHX36 has striking 3’-extension sequence preferences that differ for G4 disruption and dsDNA unwinding, most likely arising from differences in the rate-limiting step for the two activities. (PMID:29269411)
• RNA G-quadruplex folding, controlled by the two DEAH-box helicases DHX36 and DHX9, impedes the scanning of the 43S preinitiation complex, promotes 80S ribosome formation within 5’-UTRs and consequently represses the translation of transcripts involved in key biological pathways. (PMID:30591072)
• Study demonstrated that unlike on G4-DNA, DHX36 displays ATP-independent unfolding of G4-RNA followed by ATP-dependent refolding, generating a highly asymmetric pattern of activity. DHX36 refolds G4-RNA in several steps, reflecting the discrete steps in forming the G4 structure. The ATP-dependent activity of DHX36 arises from the RNA tail rather than the G4. (PMID:31015431)
• Considering that DHX36 targets, harboring G4s, preferentially localize in stress granules, and that DHX36 KO results in increased SG formation and protein kinase R (PKR/EIF2AK2) phosphorylation, we speculate that DHX36 is involved in resolution of rG4 induced cellular stress. (PMID:31160600)
• Recognition of different base tetrads by RHAU (DHX36): X-ray crystal structure of the G4 recognition motif bound to the 3’-end tetrad of a DNA G-quadruplex. (PMID:31586599)
• DHX36, BAX, and ARPC1B May Be Critical for the Diagnosis and Treatment of Tuberculosis. (PMID:32774561)
• The DEAH helicase DHX36 and its role in G-quadruplex-dependent processes. (PMID:33021960)
• The DHX36-specific-motif (DSM) enhances specificity by accelerating recruitment of DNA G-quadruplex structures. (PMID:33857359)
• The RNA helicase DHX36-G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat-associated translation. (PMID:34174288)
• G4-PROTAC: targeted degradation of a G-quadruplex binding protein. (PMID:34783801)
• G-Quadruplexes and the DNA/RNA helicase DHX36 in health, disease, and aging. (PMID:34862880)
• DHX36 maintains genomic integrity by unwinding G-quadruplexes. (PMID:37632696)
• Differential Gene Expression following DHX36/G4R1 Knockout Is Associated with G-Quadruplex Content and Cancer. (PMID:38339029)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	dhx36	ENSDARG00000101059
mus_musculus	Dhx36	ENSMUSG00000027770
rattus_norvegicus	Dhx36	ENSRNOG00000014599
drosophila_melanogaster	Rhau	FBGN0032883

Paralogs (18): DHX33 (ENSG00000005100), YTHDC2 (ENSG00000047188), DHX29 (ENSG00000067248), DHX8 (ENSG00000067596), DHX32 (ENSG00000089876), DHX35 (ENSG00000101452), DHX40 (ENSG00000108406), DHX15 (ENSG00000109606), HELB (ENSG00000127311), DHX30 (ENSG00000132153), DHX34 (ENSG00000134815), DHX9 (ENSG00000135829), DHX38 (ENSG00000140829), DQX1 (ENSG00000144045), DHX37 (ENSG00000150990), TDRD9 (ENSG00000156414), DHX57 (ENSG00000163214), DHX16 (ENSG00000204560)

Protein

Protein identifiers

ATP-dependent DNA/RNA helicase DHX36 — Q9H2U1 (reviewed: Q9H2U1)

Alternative names: DEAD/H box polypeptide 36, DEAH-box protein 36, G4-resolvase-1, MLE-like protein 1, RNA helicase associated with AU-rich element protein

All UniProt accessions (4): Q9H2U1, E7EWK3, H7C514, H7C5F5

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional ATP-dependent helicase that unwinds G-quadruplex (G4) structures. Plays a role in many biological processes such as genomic integrity, gene expression regulations and as a sensor to initiate antiviral responses. G4 structures correspond to helical structures containing guanine tetrads. Binds with high affinity to and unwinds G4 structures that are formed in nucleic acids (G4-DNA and G4-RNA). Plays a role in genomic integrity. Converts the G4-RNA structure present in telomerase RNA template component (TREC) into a double-stranded RNA to promote P1 helix formation that acts as a template boundary ensuring accurate reverse transcription. Plays a role in transcriptional regulation. Resolves G4-DNA structures in promoters of genes, such as YY1, KIT/c-kit and ALPL and positively regulates their expression. Plays a role in post-transcriptional regulation. Unwinds a G4-RNA structure located in the 3’-UTR polyadenylation site of the pre-mRNA TP53 and stimulates TP53 pre-mRNA 3’-end processing in response to ultraviolet (UV)-induced DNA damage. Binds to the precursor-microRNA-134 (pre-miR-134) terminal loop and regulates its transport into the synapto-dendritic compartment. Involved in the pre-miR-134-dependent inhibition of target gene expression and the control of dendritic spine size. Plays a role in the regulation of cytoplasmic mRNA translation and mRNA stability. Binds to both G4-RNA structures and alternative non-quadruplex-forming sequence within the 3’-UTR of the PITX1 mRNA regulating negatively PITX1 protein expression. Binds to both G4-RNA structure in the 5’-UTR and AU-rich elements (AREs) localized in the 3’-UTR of NKX2-5 mRNA to either stimulate protein translation or induce mRNA decay in an ELAVL1-dependent manner, respectively. Also binds to ARE sequences present in several mRNAs mediating exosome-mediated 3’-5’ mRNA degradation. Involved in cytoplasmic urokinase-type plasminogen activator (uPA) mRNA decay. 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. Required for early embryonic development and hematopoiesis. Involved in the regulation of cardioblast differentiation and proliferation during heart development. Involved in spermatogonia differentiation. May play a role in ossification.

Subunit / interactions. 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 dsRNA poly(I:C) ligand stimulation. Interacts (via C-terminus) with TICAM1 (via TIR domain). Interacts (via C-terminus) with DDX21; this interaction serves as bridges to TICAM1. Interacts with TERT; this interaction is dependent on the ability of DHX36 to bind to the G-quadruplex RNA (G4-RNA) structure present in the telomerase RNA template component (TERC). Interacts with DKC1; this interaction is dependent on the ability of DHX36 to bind to the G4-RNA structure present in TERC. Interacts with PARN; this interaction stimulates PARN to enhance uPA mRNA decay. Interacts with EXOSC3; this interaction occurs in a RNase-insensitive manner. Interacts with EXOSC10; this interaction occurs in a RNase-insensitive manner. Interacts with ILF3; this interaction occurs in a RNA-dependent manner. Interacts with ELAVL1; this interaction occurs in an RNA-dependent manner. Interacts with DDX5; this interaction occurs in a RNA-dependent manner. Interacts with DDX17; this interaction occurs in a RNA-dependent manner. Interacts with HDAC1; this interaction occurs in a RNA-dependent manner. Interacts with HDAC3; this interaction occurs in a RNA-dependent manner. Interacts with HDAC4. Interacts with AGO1. Interacts with AGO2. Interacts with ERCC6.

Subcellular location. Nucleus. Cytoplasm. Cytosol. Stress granule. Nucleus speckle. Chromosome. Telomere. Mitochondrion. Perikaryon. Cell projection. Dendrite. Axon Nucleus. Cytoplasm Nucleus.

Tissue specificity. Highly expressed in testis.

Activity regulation. ATPase activity is enhanced in the presence of homomeric poly(U) RNAs, but not by double-stranded DNA (dsDNA), double-stranded RNA (dsRNA) and tRNA.

Domain organisation. The DHX36-specific motif (DSM) form folds into a DNA-binding-induced alpha-helix that together with the oligonucleotide and oligosaccharide-binding-fold-like (OB-fold-like) subdomain, selectively bind to Myc-promoter G4-DNA-containing structure in an ATP-dependent manner. Upon G4-DNA-binding, DHX36 pulls on DSM in the 3’-direction, inducing rearrangement of the RecA-like 1 and 2 and the degenerate-winged-helix (WH) regions; these rearrangements are propbably responsible for the ATP-independent repetitive G4-DNA unfolding activity, one residue at a time. Upon resolving of G4-DNA into separate nucleotide strands, and ATP hydrolysis, the apoprotein of DHX36 seems incompatible with G4-DNA-binding. The N-terminus is necessary for its recruitment to cytoplasmic stress granules (SGs) upon arsenite-induced treatment.

Miscellaneous. More unstable than isoform 1.

Similarity. Belongs to the DEAD box helicase family. DEAH subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9H2U1-1	1, Nuclear isoform	yes
Q9H2U1-2	2, Cytoplasmic isoform, RHAU-delta 14
Q9H2U1-3	3

RefSeq proteins (2): NP_001107869, NP_065916* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR002464	DNA/RNA_helicase_DEAH_CS	Conserved_site
IPR007502	Helicase-assoc_dom	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR011709	DEAD-box_helicase_OB_fold	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR048333	HA2_WH	Domain
IPR059023	RNA_hel_CTD	Domain

Pfam: PF00270, PF00271, PF04408, PF07717, PF21010, PF26026

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (49 total): region of interest 15, mutagenesis site 13, binding site 5, modified residue 3, sequence variant 3, domain 2, short sequence motif 2, splice variant 2, chain 1, coiled-coil region 1, compositionally biased region 1, helix 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6Q6R	X-RAY DIFFRACTION	1.5
2N16	SOLUTION NMR
2N21	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H2U1-F1	82.77	0.58

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 (5): 233–238; 335; 337; 557; 602–605

Post-translational modifications (3): 161, 947, 963

Mutagenesis-validated functional residues (13):

Position	Phenotype
54	reduces g4-rna binding; when associated with a-57, a-59, a-62 and a-63.
55	inhibits g4-dna-binding; when associated with l-59 and l-63.
57	reduces g4-rna-binding; when associated with g-54, a-59, a-62 and a-63.
59	reduces g4-rna-binding; when associated with g-54, a-57, a-62 and a-63.
59	inhibits g4-dna-binding; when associated with l-55 and l-63.
59	greatly reduces g4-rna-binding; when associated with p-63.
62	reduces g4-rna-binding; when associated with g-54, a-57, a-59 and a-63.
63	reduces g4-rna-binding; when associated with g-54, a-57, a-59 and a-62.
63	inhibits g4-dna-binding; when associated with l-55 and l-59.
63	greatly reduces g4-rna-binding; when associated with p-59.
65	does not inhibit g4-dna-binding; when associated with a-66.
66	does not inhibit g4-dna-binding; when associated with a-65.
335	loss of atpase activity; results in an increased in g4-dna- and g4-rna-binding stabilities, increases localization in cy

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3134963	DEx/H-box helicases activate type I IFN and inflammatory cytokines production

MSigDB gene sets: 329 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOBP_DENDRITE_DEVELOPMENT, GOBP_CHROMOSOME_ORGANIZATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GCM_GSPT1, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_POSITIVE_REGULATION_OF_MRNA_PROCESSING, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS

GO Biological Process (34): ossification (GO:0001503), positive regulation of myeloid dendritic cell cytokine production (GO:0002735), regulation of transcription by RNA polymerase III (GO:0006359), spermatogenesis (GO:0007283), positive regulation of gene expression (GO:0010628), negative regulation of translation (GO:0017148), cell differentiation (GO:0030154), positive regulation of mRNA 3’-end processing (GO:0031442), positive regulation of telomere maintenance (GO:0032206), positive regulation of interferon-alpha production (GO:0032727), cellular response to heat (GO:0034605), cellular response to UV (GO:0034644), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), response to exogenous dsRNA (GO:0043330), regulation of mRNA stability (GO:0043488), innate immune response (GO:0045087), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of embryonic development (GO:0045995), defense response to virus (GO:0051607), positive regulation of cardioblast differentiation (GO:0051891), positive regulation of transcription initiation by RNA polymerase II (GO:0060261), positive regulation of dendritic spine morphogenesis (GO:0061003), 3’-UTR-mediated mRNA destabilization (GO:0061158), telomerase RNA stabilization (GO:0090669), positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay (GO:1900153), positive regulation of hematopoietic progenitor cell differentiation (GO:1901534), cellular response to arsenite ion (GO:1903843), positive regulation of telomere maintenance via telomere lengthening (GO:1904358), positive regulation of intracellular mRNA localization (GO:1904582), positive regulation of cytoplasmic translation (GO:2000767), immune system process (GO:0002376), regulation of translation (GO:0006417), response to virus (GO:0009615), positive regulation of translation (GO:0045727)

GO Molecular Function (27): magnesium ion binding (GO:0000287), transcription cis-regulatory region binding (GO:0000976), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), G-quadruplex RNA binding (GO:0002151), DNA helicase activity (GO:0003678), single-stranded DNA binding (GO:0003697), RNA binding (GO:0003723), RNA helicase activity (GO:0003724), double-stranded RNA binding (GO:0003725), mRNA 3’-UTR binding (GO:0003730), ATP binding (GO:0005524), ATP-dependent activity, acting on DNA (GO:0008094), ATP hydrolysis activity (GO:0016887), mRNA 3’-UTR AU-rich region binding (GO:0035925), histone deacetylase binding (GO:0042826), mRNA 5’-UTR binding (GO:0048027), G-quadruplex DNA binding (GO:0051880), telomerase RNA binding (GO:0070034), pre-miRNA binding (GO:0070883), catalytic activity, acting on a nucleic acid (GO:0140640), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (15): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), nuclear speck (GO:0016607), axon (GO:0030424), dendrite (GO:0030425), perikaryon (GO:0043204), extracellular exosome (GO:0070062), chromosome (GO:0005694), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cytosolic sensors of pathogen-associated DNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
RNA binding	4
helicase activity	2
DNA binding	2
mRNA binding	2
ATP-dependent activity	2
intracellular membrane-bounded organelle	2
cytoplasm	2
neuron projection	2
multicellular organismal process	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
regulation of DNA-templated transcription	1
transcription by RNA polymerase III	1
developmental process involved in reproduction	1
male gamete generation	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
translation	1
regulation of translation	1
negative regulation of gene expression	1
negative regulation of protein metabolic process	1
cellular developmental process	1
mRNA 3’-end processing	1
regulation of mRNA 3’-end processing	1
positive regulation of mRNA processing	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
positive regulation of type I interferon production	1
interferon-alpha production	1
regulation of interferon-alpha production	1
response to heat	1
cellular response to stress	1
response to UV	1

Protein interactions and networks

STRING

3238 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHX36	DDX21	Q9NR30	997
DHX36	DDX1	Q92499	997
DHX36	DDX56	Q9NY93	996
DHX36	MYD88	P78397	747
DHX36	DDX41	Q9UJV9	736
DHX36	DDX17	Q92841	708
DHX36	LRRFIP1	Q32MZ4	700
DHX36	DDX60	Q8IY21	692
DHX36	DDX3X	O00571	676
DHX36	ELAVL4	P26378	675
DHX36	FAM98A	Q8NCA5	657
DHX36	DDX6	P26196	654
DHX36	WRN	Q14191	644
DHX36	HNRNPH1	P31943	627
DHX36	IGHV4-38-2	P0DP08	611

IntAct

176 interactions, top by confidence:

A	B	Type	Score
BYSL	PARN	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
GATA1	TRIP6	psi-mi:“MI:0914”(association)	0.570
N	RBM47	psi-mi:“MI:0914”(association)	0.530
FGF3	GTPBP10	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
MAGEB2	POLRMT	psi-mi:“MI:0914”(association)	0.530
PDGFB	DKC1	psi-mi:“MI:0914”(association)	0.530
ZBTB38	IPO7	psi-mi:“MI:0914”(association)	0.530
RBM3	AARS2	psi-mi:“MI:0914”(association)	0.530
ILF2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
GSPT2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
RPS2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
KRR1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
ABT1	ZNF316	psi-mi:“MI:0914”(association)	0.530
SRSF3	CASC3	psi-mi:“MI:0914”(association)	0.530
FUS	DDX3X	psi-mi:“MI:0914”(association)	0.430
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
Mbd2	MTA3	psi-mi:“MI:0914”(association)	0.350
Cep85l	CLK2	psi-mi:“MI:0914”(association)	0.350
Max	PABPN1	psi-mi:“MI:0914”(association)	0.350
Vps28	UMAD1	psi-mi:“MI:0914”(association)	0.350
CCDC93	VPS26C	psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
DUX4		psi-mi:“MI:0914”(association)	0.350
PA	RBMX	psi-mi:“MI:0914”(association)	0.350

BioGRID (361): DHX36 (Two-hybrid), DHX36 (Two-hybrid), DHX36 (Affinity Capture-MS), DHX36 (Affinity Capture-MS), DHX36 (Affinity Capture-MS), DHX36 (Affinity Capture-MS), DHX36 (Affinity Capture-MS), DHX36 (Affinity Capture-MS), DHX36 (Affinity Capture-MS), DHX36 (Affinity Capture-RNA), DHX36 (Co-fractionation), DHX36 (Co-fractionation), DHX36 (Affinity Capture-MS), DHX36 (Affinity Capture-MS), DHX36 (Affinity Capture-MS)

ESM2 similar proteins: A0PG75, A2A3N6, A7T1N0, A8XKF2, B3H5L1, D4A2Z8, E9PU17, E9PX95, F1S5L4, F4IM84, O08619, O15162, O42857, O75386, P00488, P34751, P41879, P47140, P58195, P58196, P97564, Q05187, Q05B79, Q09306, Q0KHU5, Q28C60, Q3UW68, Q3ZBG9, Q5GJ77, Q5XI69, Q69RI8, Q6DCK1, Q6DNF3, Q6QBQ4, Q6S5G3, Q84M24, Q8IJH8, Q8VHK9, Q9DCW2, Q9FHK8

Diamond homologs: A1Z9L3, A2A4P0, B4GEU5, B4JT42, B4K5R2, B4RC48, D4A2Z8, F4HYJ7, F4IE66, F4IJV4, F4ILR7, F4IM84, F4JMJ3, F4JRJ6, F4K2E9, F4KGU4, O17438, O22243, O22899, O35286, O42643, O42945, O43143, O45244, O46072, O51767, O60114, O60231, O70133, O94536, P0C7L7, P0CE10, P15938, P20095, P24384, P34305, P34498, P36009, P37024, P43329

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MYD88	“up-regulates activity”	DHX36	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 209 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
SARS-CoV-1 modulates host translation machinery	12	28.3×	2e-13
Eukaryotic Translation Initiation	11	25.9×	6e-12
Cap-dependent Translation Initiation	11	25.9×	6e-12
Eukaryotic Translation Elongation	11	23.4×	2e-11
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	11	22.8×	2e-11
Nonsense-Mediated Decay (NMD)	12	21.4×	6e-12
SARS-CoV-2 modulates host translation machinery	11	18.8×	2e-10
Peptide chain elongation	19	18.4×	3e-17

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of cytoplasmic translation	5	27.7×	1e-04
negative regulation of mRNA splicing, via spliceosome	6	25.7×	2e-05
alternative mRNA splicing, via spliceosome	6	22.6×	3e-05
cytoplasmic translation	20	20.7×	5e-18
regulation of alternative mRNA splicing, via spliceosome	14	19.1×	5e-12
ribosomal small subunit biogenesis	12	15.3×	5e-09
RNA processing	11	13.4×	1e-07
translation	23	13.2×	1e-16

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	87
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3501 predictions. Top by Δscore:

Variant	Effect	Δscore
3:154276187:T:TA	donor_gain	1.0000
3:154276742:GTCA:G	donor_loss	1.0000
3:154276745:ACC:A	donor_loss	1.0000
3:154276751:A:C	donor_gain	1.0000
3:154276796:T:C	donor_gain	1.0000
3:154276848:C:CT	acceptor_gain	1.0000
3:154276895:TATAT:T	acceptor_gain	1.0000
3:154276896:ATAT:A	acceptor_gain	1.0000
3:154276897:TAT:T	acceptor_gain	1.0000
3:154276897:TATC:T	acceptor_loss	1.0000
3:154276899:TC:T	acceptor_loss	1.0000
3:154276900:C:A	acceptor_loss	1.0000
3:154276900:C:CC	acceptor_gain	1.0000
3:154277591:CACT:C	donor_loss	1.0000
3:154277592:A:AC	donor_gain	1.0000
3:154277592:ACTT:A	donor_loss	1.0000
3:154277593:C:CC	donor_gain	1.0000
3:154277595:TACAC:T	donor_loss	1.0000
3:154277596:A:AC	donor_gain	1.0000
3:154277596:A:T	donor_loss	1.0000
3:154277597:C:CA	donor_gain	1.0000
3:154277597:CA:C	donor_gain	1.0000
3:154277597:CACT:C	donor_gain	1.0000
3:154277597:CACTG:C	donor_gain	1.0000
3:154277612:T:C	donor_gain	1.0000
3:154277717:CC:C	acceptor_gain	1.0000
3:154277717:CCCT:C	acceptor_loss	1.0000
3:154277717:CCCTT:C	acceptor_gain	1.0000
3:154277718:CCT:C	acceptor_gain	1.0000
3:154277718:CCTT:C	acceptor_loss	1.0000

AlphaMissense

6657 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:154277668:G:A	S873F	1.000
3:154277676:A:C	H870Q	1.000
3:154277676:A:T	H870Q	1.000
3:154277677:T:C	H870R	1.000
3:154277678:G:C	H870D	1.000
3:154280615:G:T	A844D	1.000
3:154283207:A:G	L786P	1.000
3:154284611:T:G	D755A	1.000
3:154284612:C:G	D755H	1.000
3:154284613:A:C	S754R	1.000
3:154284613:A:T	S754R	1.000
3:154284615:T:G	S754R	1.000
3:154284640:T:A	R745S	1.000
3:154284640:T:G	R745S	1.000
3:154284826:A:C	F731L	1.000
3:154284826:A:T	F731L	1.000
3:154284828:A:G	F731L	1.000
3:154284835:T:A	K728N	1.000
3:154284835:T:G	K728N	1.000
3:154284836:T:A	K728I	1.000
3:154284950:C:A	G690V	1.000
3:154284950:C:T	G690E	1.000
3:154284951:C:G	G690R	1.000
3:154284951:C:T	G690R	1.000
3:154288876:A:G	L674P	1.000
3:154292551:C:G	R605T	1.000
3:154292557:G:T	A603D	1.000
3:154292560:C:G	R602P	1.000
3:154292561:G:C	R602G	1.000
3:154292568:T:A	R599S	1.000

dbSNP variants (sampled 300 via entrez): RS1000052768 (3:154312990 A>G), RS1000173588 (3:154274625 G>C), RS1000226651 (3:154318772 T>C), RS1000282571 (3:154286519 T>C), RS1000308855 (3:154305609 G>A), RS1000333829 (3:154289067 C>T), RS1000407878 (3:154324867 C>G,T), RS1000625895 (3:154304867 A>G), RS1000760611 (3:154294562 G>T), RS1000868093 (3:154280583 TTC>T), RS1000929364 (3:154300507 G>A,T), RS1000982284 (3:154281001 G>C), RS1001019879 (3:154314156 T>C), RS1001054023 (3:154314421 T>C), RS1001082819 (3:154317586 GAAGA>G)

Disease associations

OMIM: gene MIM:612767 | 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
GCST008129_12	Body mass index	2.000000e-13
GCST008360_4	Response to cognitive-behavioural therapy in anxiety disorder	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007820	cognitive behavioural therapy

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2040704 (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
5.02	Kd	9559	nM	CHEMBL5653589
5.02	ED50	9559	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 9 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148237: Binding affinity to human DHX36 incubated for 45 mins by Kinobead based pull down assay	kd	9.5586	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
sodium arsenite	affects cotreatment, increases abundance, increases expression, increases activity	2
Doxorubicin	decreases expression, affects phosphorylation, affects response to substance	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
methylparaben	increases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects 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
ICG 001	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Vorinostat	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Dinitrochlorobenzene	affects binding	1
Haloperidol	decreases expression	1
Ivermectin	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2043709	Binding	Inhibition of human DHX36/RHAU ATPase activity using [32Pgamma]ATP as substrate for 30 mins in the presence of poly(U)RNA	Inhibition of hepatitis C virus NS3 helicase by manoalide. — J Nat Prod

Clinical trials (associated diseases)

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