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): 127 total
• GTEx eGene: eQTL in 40 tissues, sQTL in 8 (q < 0.05)
• Cancer dependency (DepMap): dependent in 78.8% of screened cell lines
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.40 (moderately constrained)
• MANE Select transcript: NM_020865
• Interaction hub: 2,034 STRING partners (top 7% of genes corpus-wide)
• Notable: 127 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 21 — 10 protein_coding, 7 retained_intron, 4 nonsense_mediated_decay

MANE Select: ENST00000496811

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 6, TSL 3: 2, TSL 5: 2

ENST00000496811, ENST00000308361, ENST00000329463, ENST00000460695, ENST00000460875, ENST00000462464, ENST00000469977, ENST00000477549, ENST00000479934, ENST00000481332, ENST00000481941, ENST00000491011, ENST00000495598, ENST00000932391, ENST00000964933, ENST00000964934, ENST00001073505, ENST00001073506, ENST00001111178, ENST00001124049, ENST00001141284

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.

Highest expression (Bgee): sperm, kidney epithelium, lateral nuclear group of thalamus, lower lobe of lung, pancreatic ductal cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DHX36 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 40 tissues and its splicing (sQTL) in 8 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 48 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	2.5e-32	-0.30	3:154245184:T:C
Esophagus Muscularis	eqtl	4.1e-27	-0.28	3:154357733:A:G
Spleen	eqtl	4.6e-26	-0.44	3:154260500:C:T
Brain Cerebellum	eqtl	1.6e-23	-0.64	3:154260500:C:T
Nerve Tibial	eqtl	2.9e-23	-0.29	3:154337010:T:C
Brain Cerebellar Hemisphere	eqtl	1.7e-18	-0.38	3:154260500:C:T
Esophagus Gastroesophageal Junction	eqtl	4.1e-17	-0.29	3:154298846:A:G
Colon Sigmoid	eqtl	7.3e-17	-0.28	3:154357733:A:G
Colon Transverse	eqtl	7.4e-16	-0.29	3:154357733:A:G
Heart Left Ventricle	eqtl	9.5e-14	-0.25	3:154264650:T:G
Adipose Visceral Omentum	sqtl	1.9e-12	+0.49	3:154253813:T:C
Adipose Subcutaneous	eqtl	2.0e-12	-0.21	3:154260649:C:CAT
Lung	sqtl	1.0e-10	+0.41	3:154238161:C:T
Prostate	eqtl	1.1e-10	-0.28	3:154260500:C:T
Heart Atrial Appendage	eqtl	3.5e-10	-0.23	3:154337010:T:C
Stomach	eqtl	4.1e-10	-0.24	3:154357733:A:G
Brain Cortex	eqtl	4.1e-10	-0.37	3:154260500:C:T
Artery Aorta	eqtl	7.1e-10	-0.23	3:154282823:T:C
Lung	eqtl	7.6e-10	-0.20	3:154282823:T:C
Adipose Visceral Omentum	eqtl	9.8e-10	-0.18	3:154337010:T:C

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

showing 100 of 260 tissues 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
oral cavity	UBERON:0000167	96.14	gold quality
pericardium	UBERON:0002407	96.14	gold quality
right testis	UBERON:0004534	96.11	gold quality
globus pallidus	UBERON:0001875	96.10	gold quality
cortical plate	UBERON:0005343	96.04	gold quality
pylorus	UBERON:0001166	96.03	gold quality
trabecular bone tissue	UBERON:0002483	95.99	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.98	gold quality
medial globus pallidus	UBERON:0002477	95.97	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.93	gold quality
inferior vagus X ganglion	UBERON:0005363	95.91	gold quality
subthalamic nucleus	UBERON:0001906	95.89	gold quality
visceral pleura	UBERON:0002401	95.86	gold quality
mammalian vulva	UBERON:0000997	95.83	gold quality
left testis	UBERON:0004533	95.81	gold quality
ventral tegmental area	UBERON:0002691	95.79	gold quality
gastrocnemius	UBERON:0001388	95.77	gold quality
parietal pleura	UBERON:0002400	95.76	gold quality
urethra	UBERON:0000057	95.73	gold quality
pigmented layer of retina	UBERON:0001782	95.70	gold quality
penis	UBERON:0000989	95.64	gold quality
tendon	UBERON:0000043	95.54	gold quality
nasal cavity epithelium	UBERON:0005384	95.53	gold quality
cardia of stomach	UBERON:0001162	95.48	gold quality
adrenal tissue	UBERON:0018303	95.48	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.46	gold quality
calcaneal tendon	UBERON:0003701	95.43	gold quality
bone marrow	UBERON:0002371	95.28	gold quality
cerebellar vermis	UBERON:0004720	95.27	gold quality
skeletal muscle tissue	UBERON:0001134	95.20	gold quality
endometrium	UBERON:0001295	95.09	gold quality
testis	UBERON:0000473	95.04	gold quality
adult organism	UBERON:0007023	95.04	gold quality
tongue	UBERON:0001723	94.97	gold quality
muscle of leg	UBERON:0001383	94.96	gold quality
layer of synovial tissue	UBERON:0007616	94.95	gold quality
skeletal muscle organ	UBERON:0014892	94.93	gold quality
body of tongue	UBERON:0011876	94.90	gold quality
pharyngeal mucosa	UBERON:0000355	94.88	gold quality
mucosa of stomach	UBERON:0001199	94.84	gold quality
jejunum	UBERON:0002115	94.83	gold quality
deltoid	UBERON:0001476	94.80	gold quality
cartilage tissue	UBERON:0002418	94.77	gold quality
vena cava	UBERON:0004087	94.67	gold quality
muscle tissue	UBERON:0002385	94.65	gold quality
jejunal mucosa	UBERON:0000399	94.56	gold quality
vastus lateralis	UBERON:0001379	94.53	gold quality
bone marrow cell	CL:0002092	94.47	gold quality
parietal lobe	UBERON:0001872	94.47	gold quality
saphenous vein	UBERON:0007318	94.42	gold quality
pituitary gland	UBERON:0000007	94.41	gold quality
synovial joint	UBERON:0002217	94.40	gold quality
bronchus	UBERON:0002185	94.39	gold quality
bronchial epithelial cell	CL:0002328	94.32	gold quality
islet of Langerhans	UBERON:0000006	94.26	gold quality
myocardium	UBERON:0002349	94.20	gold quality
quadriceps femoris	UBERON:0001377	94.18	gold quality
skin of hip	UBERON:0001554	94.18	gold quality
postcentral gyrus	UBERON:0002581	94.18	gold quality
adenohypophysis	UBERON:0002196	94.17	gold quality
renal medulla	UBERON:0000362	94.13	gold quality
tibial nerve	UBERON:0001323	94.11	gold quality
mammary gland	UBERON:0001911	93.93	gold quality
thoracic mammary gland	UBERON:0005200	93.93	gold quality
trachea	UBERON:0003126	93.92	gold quality
uterus	UBERON:0000995	93.89	gold quality
tibialis anterior	UBERON:0001385	93.89	gold quality
urinary bladder	UBERON:0001255	93.85	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.68	gold quality
left ovary	UBERON:0002119	93.66	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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Superior colliculi	tissue	48.3
Cerebellum	tissue	48.0	high
Thalamus	tissue	46.8
Pons	tissue	45.0
Midbrain	tissue	44.4
Putamen	tissue	40.9
Hippocampal formation	tissue	39.0
Caudate putamen	tissue	37.8
Septum	tissue	37.7
Olfactory bulb	tissue	37.4
Cerebral cortex	tissue	36.5	high
Somatosensory cortex	tissue	36.5
Ventral forebrain	tissue	36.3
Occipital cortex	tissue	36.0
Motor cortex	tissue	34.7
Substantia nigra	tissue	34.6
Hypothalamus	tissue	34.5
Medulla oblongata	tissue	34.1
Nucleus accumbens	tissue	33.6
Basal ganglia	tissue	33.3	high
Retrosplenial and cingulate cortex	tissue	33.0
Spinal cord	tissue	32.8
Prefrontal cortex	tissue	32.7
Frontal cortex	tissue	32.3
Testis	tissue	32.2	high
Temporal cortex	tissue	32.2
Entorhinal cortex	tissue	31.7
Corpus callosum	tissue	31.3
Periaqueductal gray	tissue	31.3
Retrosplenial cortex	tissue	30.6
Locus coeruleus	tissue	30.0
Tongue	tissue	29.5
Amygdala	tissue	29.4
Choroid plexus	tissue	29.2
Postcentral gyrus	tissue	28.2
Insular cortex	tissue	27.6
Parathyroid gland	tissue	27.4	high
Hippocampus	tissue	24.3	medium
Thyroid gland	tissue	21.6	medium
Lymph node	tissue	20.3	medium
Skeletal muscle	tissue	20.3	medium
Thymus	tissue	20.2
Tonsil	tissue	19.2	high
Liver	tissue	18.7	medium
Placenta	tissue	17.8	high
Kidney	tissue	17.4	high
Endometrium 1	tissue	17.1	high
Adipose tissue	tissue	16.6	low
Appendix	tissue	16.3	high
Prostate	tissue	16.2	medium
Urinary bladder	tissue	16.1	medium
Smooth muscle	tissue	16.0	high
Heart muscle	tissue	15.8	high
Retina	tissue	15.7
Seminal vesicle	tissue	15.5	high
Ovary	tissue	15.4	low
Bone marrow	tissue	15.4	medium
Breast	tissue	15.3	high
Stomach 1	tissue	15.1	high
Pancreas	tissue	15.1	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal hippocampus (39.0), Parieto-temporal junction (white matter) (35.1), Corpus callosum, splenium (white matter) (34.8), Corpus callosum, genu (white matter) (34.3), Cerebellar cortex (34.2).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets:

Target	Regulation
YY1

miRNA regulators (miRDB)

Targeting DHX36 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 50 miRNAs:

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

gnomAD constraint: pLI 1, LOEUF 0.401, missense Z 2.32 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000496811 splits into 4 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:154,276,174–154,299,923	470 / 616.2	0.76	no
3:154,299,924–154,303,346	115 / 105.6	1.09	no
3:154,303,347–154,309,800	146 / 215.0	0.68	no
3:154,309,801–154,324,416	293 / 274.4	1.07	no
DepMap (CRISPR cell-line fitness): dependent in 78.8% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): DK-MG (-2.15), SCC-9 (-1.684), OV-90 (-1.411), OCI-AML3 (-1.4), SKM-1 (-1.267), Set-2 (-1.256), DB (-1.225), SU-DHL-10 (-1.217), NOMO-1 (-1.207), COLO 201 (-1.161), OUMS-23 (-1.156), COV362 (-1.154), KP-N-RT-BM-1 (-1.142), MOLM-13 (-1.137), TF-1 (-1.128).

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1919412) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 26 distinct phenotype terms.

Mouse phenotype (MP)	Records
enlarged liver	1
pale liver	1
enlarged spleen	1
anemia	1
hemolytic anemia	1
thymus hypoplasia	1
abnormal proerythroblast morphology	1
increased mean corpuscular volume	1
reticulocytosis	1
spherocytosis	1
decreased hemoglobin content	1
decreased erythrocyte cell number	1
abnormal cell cycle	1
abnormal erythrocyte physiology	1
pallor	1
increased hematopoietic stem cell number	1
pale kidney	1
abnormal leukopoiesis	1
intermingled spleen red and white pulp	1
embryonic lethality between implantation and somite formation, complete penetrance	1
increased erythroblast number	1
decreased erythroblast number	1
decreased granulocyte monocyte progenitor cell number	1
increased megakaryocyte-erythroid progenitor cell number	1
impaired erythropoiesis	1

+1 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pongo abelii	Q5RAZ4	100.0%	Diamond
Pan troglodytes	Q7YR39	99.6%	Diamond
Bos taurus	Q2NKY8	97.9%	Diamond
Sus scrofa	Q767K6	96.5%	Diamond
Drosophila persimilis	B4GEU5	95.0%	Diamond
Drosophila pseudoobscura pseudoobscura	Q296Q5	95.0%	Diamond
Arabidopsis thaliana	F4I9Q5	93.4%	Diamond
Drosophila sechellia	B4HLH4	92.5%	Diamond
Drosophila erecta	B3P3W1	89.5%	Diamond
Drosophila yakuba	B4PRJ9	89.5%	Diamond
Strongylocentrotus purpuratus	O17438	87.3%	Diamond
Drosophila mojavensis	B4K5R2	83.1%	Diamond
Drosophila virilis	B4LX81	83.1%	Diamond
Xenopus laevis	Q68FK8	81.3%	Diamond
Drosophila grimshawi	B4JT42	79.1%	Diamond
Gallus gallus	Q5ZI74	76.2%	Diamond
Culex quinquefasciatus	B0XDC4	74.6%	Diamond
Aedes aegypti	Q16JS8	74.6%	Diamond
Schizosaccharomyces pombe 972h-	O42945	72.3%	Diamond
Saccharomyces cerevisiae S288C	P53131	72.3%	Diamond
Escherichia coli K-12	P43329	70.0%	Diamond
Haemophilus influenzae Rd KW20	P45018	70.0%	Diamond
Drosophila ananassae	B3M383	69.7%	Diamond
Caenorhabditis elegans	P34498	67.3%	Diamond
Dictyostelium discoideum	Q54F05	66.4%	Diamond
Drosophila willistoni	B4NBB0	65.5%	Diamond
Anopheles gambiae	Q7QCW2	53.2%	Diamond
Mycosarcoma maydis	P0C7L7	38.6%	Diamond
Trypanosoma brucei brucei TREU927	Q581T1	36.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
GPR149	protein-coding	344758
ARHGEF26	protein-coding	26084
ARHGEF26-AS1	ncRNA	100507524

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): E7EWK3, Q9H2U1, 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

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)

• 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 by resolution:

PDB	Title	Method	Resolution (Å)
6Q6R	Recognition of different base tetrads by RHAU: X-ray crystal structure of G4 recognition …	X-RAY DIFFRACTION	1.5
2N16	Solution structure of G-quadruplex recognition domain of RHAU	SOLUTION NMR
2N21	Solution structure of complex between DNA G-quadruplex and G-quadruplex recognition …	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Predicted membrane proteins, Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm

Antibody reliability (HPA): IH approved · IF supported

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)

Position	Role
233–238	ATP
335	Mg(2+)
337	Mg(2+)
557	ATP
602–605	ATP

Post-translational modifications (3)

Type	Positions
Phosphoserine	161, 963
N6-acetyllysine	947

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 cytoplasmic stress …

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-3134963	DEx/H-box helicases activate type I IFN and inflammatory cytokines production	curated
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—

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 (33): ossification (GO:0001503), positive regulation of myeloid dendritic cell cytokine production (GO:0002735), DNA-templated transcription (GO:0006351), 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), 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), 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), G-quadruplex unwinding activity (GO:0160225), 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 (12): 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)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Cytosolic sensors of pathogen-associated DNA	1
Immune System	1
Innate Immune System	1

GO top-level categories

showing 60 of 86 GO namespaces:

Category	Terms
RNA binding	4
cellular anatomical structure	4
gene expression	2
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
RNA biosynthetic process	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase III	1
developmental process involved in reproduction	1
male gamete generation	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
cellular response to light stimulus	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
regulation of RNA stability	1
regulation of mRNA catabolic process	1
immune response	1
defense response to symbiont	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
embryo development	1
regulation of multicellular organismal development	1
defense response	1
response to virus	1
cardioblast differentiation	1
regulation of cardioblast differentiation	1
positive regulation of cardiocyte differentiation	1
positive regulation of stem cell differentiation	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 38 of 72 annotations. The rest are phylogenetic / computational / electronic (IEA).

38 experimentally-supported GO terms:

GO term	NS	Evidence
3’-UTR-mediated mRNA destabilization	BP	mutant phenotype
cellular response to UV	BP	mutant phenotype
cellular response to arsenite ion	BP	direct assay
cellular response to heat	BP	direct assay
negative regulation of translation	BP	direct assay
positive regulation of cytoplasmic translation	BP	mutant phenotype
positive regulation of interferon-alpha production	BP	mutant phenotype
positive regulation of mRNA 3’-end processing	BP	mutant phenotype
positive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	BP	mutant phenotype
positive regulation of telomere maintenance	BP	mutant phenotype
positive regulation of telomere maintenance via telomere lengthening	BP	mutant phenotype
positive regulation of transcription initiation by RNA polymerase II	BP	mutant phenotype
regulation of mRNA stability	BP	mutant phenotype
regulation of transcription by RNA polymerase III	BP	mutant phenotype
telomerase RNA stabilization	BP	direct assay
chromosome, telomeric region	CC	direct assay
cytoplasm	CC	direct assay
cytoplasmic stress granule	CC	direct assay
cytosol	CC	direct assay
extracellular exosome	CC	high-throughput assay
nuclear speck	CC	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
ATP-dependent activity, acting on DNA	MF	direct assay
DNA helicase activity	MF	direct assay
G-quadruplex DNA binding	MF	direct assay
G-quadruplex RNA binding	MF	direct assay
G-quadruplex unwinding activity	MF	direct assay
RNA binding	MF	direct assay
RNA helicase activity	MF	direct assay
RNA polymerase II cis-regulatory region sequence-specific DNA binding	MF	direct assay
double-stranded RNA binding	MF	direct assay
mRNA 3’-UTR AU-rich region binding	MF	direct assay
mRNA 3’-UTR binding	MF	direct assay
mRNA 5’-UTR binding	MF	direct assay
magnesium ion binding	MF	direct assay
single-stranded DNA binding	MF	direct assay
telomerase RNA binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,034 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DHX36	DDX1	Q92499	823
DHX36	DDX21	Q9NR30	807
DHX36	DDX41	Q9UJV9	763
DHX36	DDX56	Q9NY93	745
DHX36	LRRFIP1	Q32MZ4	703
DHX36	DDX60	Q8IY21	677
DHX36	DDX3X	O00571	666
DHX36	DDX24	Q9GZR7	635
DHX36	IGHV4-38-2	P0DP08	623
DHX36	PIF1	Q9H611	601
DHX36	BRIP1	Q9BX63	570
DHX36	DDX17	Q92841	555
DHX36	DHX58	Q96C10	550
DHX36	RIGI	O95786	547
DHX36	IFI16	Q16666	540

IntAct

Human interaction partners of DHX36 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

11 partners by confidence:

Partner	Interaction type	MIscore	Records
AGO2	association	0.350	1
ATG12	physical association	0.000	1
CBFB	physical association	0.000	1
CDK5RAP3	physical association	0.000	1
DISC1	physical association	0.000	1
GSK3B	physical association	0.000	1
ILK	physical association	0.000	1
PANK2	physical association	0.000	1
PARVA	physical association	0.000	1
PHB1	physical association	0.000	1
PRKAB1	physical association	0.000	1

BioGRID (365 interactions; top human partners by supporting records): GATA1 (Affinity Capture-MS; 4 records), BYSL (Affinity Capture-MS; 3 records), ERCC6 (Affinity Capture-MS; 3 records), MYC (Affinity Capture-MS; 3 records), ZBTB38 (Affinity Capture-MS; 3 records), ANLN (Affinity Capture-MS; 2 records), CIAO1 (Proximity Label-MS; 2 records), FGF3 (Affinity Capture-MS; 2 records), FGF8 (Affinity Capture-MS; 2 records), FUBP1 (Affinity Capture-MS; 2 records), HNRNPA1 (Affinity Capture-MS; 2 records), KRAS (Negative Genetic; 2 records), LARP4B (Proximity Label-MS; 2 records), LIN28A (Affinity Capture-MS; 2 records), MEN1 (Affinity Capture-MS; 2 records)

SIGNOR signaling

1 signaling interactions:

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

Disease & clinical

Genetic variants

Variant evidence for DHX36: 127 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	88
Likely benign	4
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 37 predictions of 1,896):

Position(s)	Effect	Δscore	Sites
3:154276745–154276746	donor_loss	1.0000	5
3:154276751	donor_gain	1.0000
3:154276796	donor_gain	1.0000
3:154276900–154276901	acceptor_loss	1.0000	5
3:154277596–154277597	donor_loss	1.0000	5
3:154277612	donor_gain	1.0000
3:154277719–154277721	acceptor_gain	1.0000	3
3:154283186–154283187	donor_loss	1.0000	5
3:154284812–154284813	donor_loss	1.0000	5
3:154284988–154284989	acceptor_loss	1.0000	6

AlphaMissense

2,796 missense substitutions predicted likely pathogenic (of 6,657 scored), across 632 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M365	9	0.954	0.997
M797	9	0.881	0.990
M892	9	0.850	0.991
D334	8	0.999	1.000
D755	8	0.999	1.000
H525	8	0.998	1.000
H337	8	0.995	0.998
D344	8	0.995	0.999
F494	8	0.994	1.000
H870	8	0.993	1.000
F537	8	0.992	0.999
D901	8	0.992	0.998
F731	8	0.989	1.000
D729	8	0.987	0.997
F936	8	0.977	0.999
S268	8	0.976	1.000
S366	8	0.976	1.000
S557	8	0.965	1.000
D568	8	0.964	0.996
H756	8	0.959	0.997

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	7.62e-06
Kidney Chromophobe (TCGA)	unfavorable	0.000248
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000655

Disease associations

OMIM: gene MIM:612767 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST008129_54	Body mass index	2e-13
GCST008360_4	Response to cognitive-behavioural therapy in anxiety disorder	4e-6

EFO canonical traits (from GWAS)

2 canonical traits:

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 (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

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	increases abundance, increases expression, increases activity, affects cotreatment	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	affects cotreatment, increases abundance, increases expression	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	increases abundance, increases expression, affects cotreatment	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)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for DHX36 across ~30M SureChEMBL compounds — explore on Sugi Predict.