MTREX

Summary

MTREX (Mtr4 exosome RNA helicase, HGNC:18734) is a protein-coding gene on chromosome 5q11.2, encoding Exosome RNA helicase MTR4 (P42285). Catalyzes the ATP-dependent unwinding of RNA duplexes with a single-stranded 3’ RNA extension. It is a common-essential gene (DepMap: required in 99.6% of cancer cell lines).

Enables ATP binding activity and RNA helicase activity. Involved in DNA damage response; RNA catabolic process; and maturation of 5.8S rRNA. Located in nuclear exosome (RNase complex) and nucleoplasm. Part of TRAMP complex and catalytic step 2 spliceosome. Biomarker of amyotrophic lateral sclerosis.

Source: NCBI Gene 23517 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 155 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_015360

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18734
Approved symbol	MTREX
Name	Mtr4 exosome RNA helicase
Location	5q11.2
Locus type	gene with protein product
Status	Approved
Aliases	Mtr4, Dob1, fSAP118
Ensembl gene	ENSG00000039123
Ensembl biotype	protein_coding
OMIM	618122
Entrez	23517

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 19 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000230640, ENST00000502953, ENST00000503165, ENST00000504388, ENST00000504997, ENST00000505565, ENST00000506750, ENST00000508716, ENST00000518955, ENST00000908194, ENST00000908195, ENST00000908196, ENST00000908197, ENST00000908198, ENST00000908199, ENST00000908200, ENST00000908201, ENST00000929139, ENST00000929140, ENST00000929141, ENST00000929142, ENST00000929143, ENST00000929144, ENST00000962753, ENST00000962754, ENST00000962755

RefSeq mRNA: 1 — MANE Select: NM_015360 NM_015360

CCDS: CCDS3967

Canonical transcript exons

ENST00000230640 — 27 exons

Exon	Start	End
ENSE00001421730	55424720	55425579
ENSE00001607330	55307989	55308147
ENSE00003462238	55343331	55343455
ENSE00003482330	55410524	55410629
ENSE00003501830	55397416	55397526
ENSE00003526604	55353168	55353269
ENSE00003544729	55328699	55328811
ENSE00003551907	55379127	55379195
ENSE00003552705	55378314	55378486
ENSE00003552728	55405425	55405588
ENSE00003554296	55341681	55341771
ENSE00003575413	55350919	55351029
ENSE00003586155	55349573	55349652
ENSE00003590672	55340010	55340184
ENSE00003604791	55345094	55345196
ENSE00003608919	55415970	55416132
ENSE00003612641	55327716	55327778
ENSE00003619216	55387974	55388102
ENSE00003623839	55414182	55414238
ENSE00003633708	55358573	55358698
ENSE00003638721	55400233	55400421
ENSE00003643169	55422878	55422982
ENSE00003649885	55324132	55324198
ENSE00003650639	55344522	55344620
ENSE00003653851	55366725	55366875
ENSE00003658838	55347013	55347144
ENSE00003674204	55322327	55322464

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 97.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 59.4640 / max 1334.8861, expressed in 1821 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56465	45.5608	1817
56464	9.1101	1688
56463	4.6115	1490
56466	0.1816	74

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	97.43	gold quality
sural nerve	UBERON:0015488	96.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	96.27	gold quality
colonic epithelium	UBERON:0000397	95.95	gold quality
ventricular zone	UBERON:0003053	95.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.72	gold quality
ganglionic eminence	UBERON:0004023	94.94	gold quality
tendon	UBERON:0000043	94.78	gold quality
jejunal mucosa	UBERON:0000399	94.76	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.73	gold quality
embryo	UBERON:0000922	94.31	gold quality
cortical plate	UBERON:0005343	94.24	gold quality
islet of Langerhans	UBERON:0000006	94.22	gold quality
biceps brachii	UBERON:0001507	94.19	gold quality
adrenal tissue	UBERON:0018303	94.14	gold quality
heart right ventricle	UBERON:0002080	93.85	gold quality
jejunum	UBERON:0002115	93.63	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.59	gold quality
deltoid	UBERON:0001476	93.34	gold quality
epithelium of nasopharynx	UBERON:0001951	93.02	gold quality
cartilage tissue	UBERON:0002418	92.94	gold quality
skeletal muscle tissue	UBERON:0001134	92.92	gold quality
duodenum	UBERON:0002114	92.90	gold quality
pancreas	UBERON:0001264	92.72	gold quality
tonsil	UBERON:0002372	92.72	gold quality
gastrocnemius	UBERON:0001388	92.71	gold quality
body of pancreas	UBERON:0001150	92.69	gold quality
muscle of leg	UBERON:0001383	92.64	gold quality
popliteal artery	UBERON:0002250	92.58	gold quality
tibial artery	UBERON:0007610	92.57	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	14.41
E-ANND-3	yes	6.20
E-MTAB-4850	no	1500.54

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting MTREX, 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-3924	100.00	72.09	2394
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-7159-3P	99.51	70.17	1920
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-130A-5P	99.33	70.26	2623

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 17)

• Nuclear VCP/p97-like protein 2 might regulate the association/dissociation reaction of DOB1 with pre-ribosomal particles by acting as a molecular chaperone. (PMID:16782053)
• Results are consistent with a role for KIAA052/hMtr4p in the recruitment of the exosome to pre-rRNA to mediate the 3’ end processing of the 5.8S rRNA. (PMID:17412707)
• results suggest that WDR74 is a novel regulatory protein of the MTR4-exsosome complex whose interaction is regulated by NVL2 and is involved in ribosome biogenesis (PMID:26456651)
• We analyzed the interactions of the human TRAMP-like proteins, PAPD5, ZCCHC7, and MTR4, with the nuclear exosome. PAPD5 and ZCCHC7 exhibited mutual interactions in presence of the exosome catalytic subunit RRP6, whereas MTR4 was dispensable for their assembly (PMID:27434818)
• The described is the mRNA degradation poly(A) tail exosome targeting (PAXT) connection, which comprises the ZFC3H1 Zn-knuckle protein as a central link between MTR4 and the nuclear poly(A)-binding protein PABPN1. (PMID:27871484)
• a critical role for Mtr4/ZFC3H1 in nuclear surveillance of naturally unstable lncRNAs to prevent their accumulation, transport to the cytoplasm, and resultant disruption of protein synthesis (PMID:28733371)
• The competition between hMTR4 and ALYREF determines exosome recruitment and functions in creating balanced nuclear RNA pools for degradation and export. (PMID:28801509)
• The cryo-EM structure of the holo-complex shows how obligate nuclear cofactors position the hMTR4 helicase at the entrance of the core complex, suggesting a striking structural conservation from lower to higher eukaryotes. (PMID:30047866)
• NRDE2 interacts with MTR4’s key residues, locks MTR4 in a closed conformation, and inhibits MTR4 interaction with the exosome as well as proteins important for MTR4 recruitment (PMID:30842217)
• Data show that the nuclear exosome adaptors nuclear valosin-containing protein-like (NVL) and zinc finger, CCHC domain containing 8 protein (ZCCHC8) bind the Mtr4 exosome RNA helicase (MTR4) KOW domain on a surface. (PMID:31358741)
• MTR4 is required for the tumorigenesis of the hepatocellular carcinoma cells.MTR4 is a mediator of the functions of c-Myc in cancer metabolism.MTR4 drives cancer metabolism by ensuring correct alternative splicing of pre-mRNAs of critical glycolytic genes such as GLUT1 and PKM2. (PMID:32024842)
• Exploration of Salmonella effector mutant strains on MTR4 and RRP6 degradation. (PMID:32350160)
• Mapping domains of ARS2 critical for its RNA decay capacity. (PMID:32463452)
• Interactome analysis of the Tudor domain-containing protein SPF30 which associates with the MTR4-exosome RNA-decay machinery under the regulation of AAA-ATPase NVL2. (PMID:33422691)
• Mtr4 RNA helicase structures and interactions. (PMID:33857361)
• MTR4 adaptor PICT1 functions in two distinct steps during pre-rRNA processing. (PMID:36403484)
• RNA helicase MTR4 drives tumorigenesis of nasopharyngeal carcinoma by regulating the expression of key cell cycle genes. (PMID:36929008)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtrex	ENSDARG00000013457
mus_musculus	Mtrex	ENSMUSG00000016018
rattus_norvegicus	Mtrex	ENSRNOG00000010125
drosophila_melanogaster	Mtr4	FBGN0001986
caenorhabditis_elegans		WBGENE00012342

Paralogs (8): POLQ (ENSG00000051341), ASCC3 (ENSG00000112249), DDX60 (ENSG00000137628), SNRNP200 (ENSG00000144028), HFM1 (ENSG00000162669), HELQ (ENSG00000163312), DDX60L (ENSG00000181381), SKIC2 (ENSG00000204351)

Protein

Protein identifiers

Exosome RNA helicase MTR4 — P42285 (reviewed: P42285)

Alternative names: ATP-dependent RNA helicase DOB1, ATP-dependent RNA helicase SKIV2L2, Superkiller viralicidic activity 2-like 2, TRAMP-like complex helicase

All UniProt accessions (4): D6REC7, P42285, H0Y8U3, H0YAC4

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the ATP-dependent unwinding of RNA duplexes with a single-stranded 3’ RNA extension. Central subunit of many protein complexes, namely TRAMP-like, nuclear exosome targeting (NEXT) and poly(A) tail exosome targeting (PAXT). NEXT functions as an RNA exosome cofactor that directs a subset of non-coding short-lived RNAs for exosomal degradation. NEXT is involved in surveillance and turnover of aberrant transcripts and non-coding RNAs. PAXT directs a subset of long and polyadenylated poly(A) RNAs for exosomal degradation. The RNA exosome is fundamental for the degradation of RNA in eukaryotic nuclei. Substrate targeting is facilitated by its cofactor ZCCHC8, which links to RNA-binding protein adapters. Associated with the RNA exosome complex and involved in the 3’-processing of the 7S pre-RNA to the mature 5.8S rRNA. May be involved in pre-mRNA splicing. In the context of NEXT complex can also in vitro unwind DNA:RNA heteroduplexes with a 3’ poly (A) RNA tracking strand. Can promote unwinding and degradation of structured RNA substrates when associated with the nuclear exosome and its cofactors. Can displace a DNA strand while translocating on RNA to ultimately degrade the RNA within a DNA/RNA heteroduplex. Plays a role in DNA damage response.

Subunit / interactions. Component of a TRAMP-like complex, an ATP-dependent exosome regulatory complex consisting of a helicase (MTREX), an oligadenylate polymerase (TENT4B or TENT4A), and a substrate specific RNA-binding factor (ZCCHC7 or ZCCHC8). Several TRAMP-like complexes exist with specific compositions and are associated with nuclear, or nucleolar RNA exosomes. Identified in the spliceosome C complex. Component of the poly(A) tail exosome targeting (PAXT) complex made of PABPN1, ZFC3H1 and MTREX that directs a subset of long and polyadenylated poly(A) RNAs for exosomal degradation. Component of the nuclear exosome targeting (NEXT) complex composed of MTREX, ZCCHC8, and RBM7 that directs a subset of non-coding short-lived RNAs for exosomal degradation. Interacts with ZCCHC8; this interaction bridges the interaction between RBM7 and MTREX. Binds to ZFC3H1 and RBM7 in a RNase-insensitive manner. Interacts with EXOSC10; the interaction mediates the association of MTREX with nuclear RNA exosomes. Interacts with isoform 1 of NVL in an ATP-dependent manner; the interaction is required to associate NVL with nuclear RNA exosome. Interacts with WDR74; the interaction dissociation in a late stage of rRNA synthesis is required for appropriate maturation of pre-60S particles and depends on the ATPase activity of NVL. Interacts with MPHOSPH6. Interacts with the RNA cap-binding complex proteins NCBP1 and SRRT. Interacts with NRDE2; the interaction is direct and negatively regulates MTREX function in exosomal degradation by changing its conformation precluding interaction with ZFC3H1, the RNA cap-binding complex proteins NCBP1 and SRRT, and association with the exosome. Associates with the RNA exosome complex.

Subcellular location. Nucleus. Nucleoplasm. Nucleolus. Nucleus speckle.

Activity regulation. Activated when MTREX is incorporated into NEXT complex an the nuclear RNA exosome complex.

Similarity. Belongs to the helicase family. SKI2 subfamily.

RefSeq proteins (1): NP_056175* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001650	Helicase_C-like	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR012961	Ski2/MTR4_C	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR016438	FRH-like	Family
IPR025696	Beta-barrel_MTR4	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR048392	MTR4-like_stalk	Domain
IPR050699	SUPV3-like	Family

Pfam: PF00270, PF00271, PF08148, PF13234, PF21408

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (116 total): helix 46, strand 31, turn 7, binding site 6, mutagenesis site 5, modified residue 4, cross-link 4, sequence conflict 4, domain 2, compositionally biased region 2, initiator methionine 1, chain 1, sequence variant 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
6C90	X-RAY DIFFRACTION	2.2
6IEH	X-RAY DIFFRACTION	2.89
6RO1	X-RAY DIFFRACTION	3.07
7Z52	ELECTRON MICROSCOPY	3.4
6D6Q	ELECTRON MICROSCOPY	3.45
6D6R	ELECTRON MICROSCOPY	3.45
6IEG	X-RAY DIFFRACTION	3.55
7S7C	ELECTRON MICROSCOPY	3.62
7Z4Z	ELECTRON MICROSCOPY	4
7S7B	ELECTRON MICROSCOPY	4.06
7Z4Y	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42285-F1	84.68	0.61

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 (6): 164; 166; 167; 168; 139; 161–168

Post-translational modifications (8): 2, 40, 51, 78, 24, 358, 684, 723

Mutagenesis-validated functional residues (5):

Position	Phenotype
253	abolishes rna helicase activity.
658	decreased interaction with nrde2.
697	decreased interaction with nrde2.
743	decreased interaction with nrde2. impairs the binding of both nvl and nop53.
989–990	loss of interaction with nrde2.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-72163	mRNA Splicing - Major Pathway
R-HSA-9843970	Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex
R-HSA-9930044	Nuclear RNA decay
R-HSA-212165	Epigenetic regulation of gene expression
R-HSA-72172	mRNA Splicing
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-72312	rRNA processing
R-HSA-74160	Gene expression (Transcription)
R-HSA-8868773	rRNA processing in the nucleus and cytosol
R-HSA-8953854	Metabolism of RNA
R-HSA-9842860	Regulation of endogenous retroelements

MSigDB gene sets: 0 (showing top):

GO Biological Process (8): mRNA splicing, via spliceosome (GO:0000398), maturation of 5.8S rRNA (GO:0000460), rRNA processing (GO:0006364), RNA catabolic process (GO:0006401), DNA damage response (GO:0006974), snRNA catabolic process (GO:0016076), mRNA processing (GO:0006397), RNA splicing (GO:0008380)

GO Molecular Function (9): RNA binding (GO:0003723), RNA helicase activity (GO:0003724), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), nuclear speck (GO:0016607), TRAMP complex (GO:0031499), catalytic step 2 spliceosome (GO:0071013), nuclear exosome (RNase complex) (GO:0000176), exosome (RNase complex) (GO:0000178), spliceosomal complex (GO:0005681)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Metabolism of RNA	3
rRNA processing in the nucleus and cytosol	1
mRNA Splicing	1
Regulation of endogenous retroelements	1
Gene expression (Transcription)	1
Processing of Capped Intron-Containing Pre-mRNA	1
rRNA processing	1
Epigenetic regulation of gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	3
nuclear lumen	3
nuclear protein-containing complex	3
ATP-dependent activity	2
binding	2
RNA splicing, via transesterification reactions with bulged adenosine as nucleophile	1
mRNA processing	1
rRNA processing	1
rRNA metabolic process	1
ribosome biogenesis	1
RNA metabolic process	1
nucleic acid catabolic process	1
cellular response to stress	1
RNA catabolic process	1
snRNA metabolic process	1
mRNA metabolic process	1
nucleic acid binding	1
helicase activity	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
intracellular membraneless organelle	1
nuclear ribonucleoprotein granule	1
Prp19 complex	1
spliceosomal complex	1
U5 snRNP	1
catalytic complex	1
exosome (RNase complex)	1
nucleus	1
intracellular anatomical structure	1
exoribonuclease complex	1

Protein interactions and networks

STRING

3413 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTREX	ZCCHC7	Q8N3Z6	998
MTREX	TENT4A	Q5XG87	997
MTREX	ZCCHC8	Q6NZY4	997
MTREX	RBM7	Q9Y580	996
MTREX	PAPOLA	P51003	994
MTREX	PAPOLG	Q9BWT3	994
MTREX	PAPOLB	Q9NRJ5	994
MTREX	EXOSC10	Q01780	982
MTREX	TENT4B	Q8NDF8	969
MTREX	C1D	Q13901	959
MTREX	NOP53	Q9NZM5	959
MTREX	UTP18	Q9Y5J1	954
MTREX	ZFC3H1	O60293	930
MTREX	DIS3	Q9Y2L1	910
MTREX	PABPN1	Q86U42	883

IntAct

211 interactions, top by confidence:

A	B	Type	Score
PPP2R2A	PPP2R1A	psi-mi:“MI:2364”(proximity)	0.970
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
PPP2R1A	STRN	psi-mi:“MI:2364”(proximity)	0.880
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
PPP2R2D	YEATS4	psi-mi:“MI:0914”(association)	0.730
COMMD4	VPS26C	psi-mi:“MI:0914”(association)	0.730
RBM7	MTREX	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MTREX	MPHOSPH6	psi-mi:“MI:0407”(direct interaction)	0.690
MPHOSPH6	MTREX	psi-mi:“MI:0914”(association)	0.690
C1D	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
EXOSC3	MTREX	psi-mi:“MI:0914”(association)	0.640
EXOSC5	ZFC3H1	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
Smc3	RAD21	psi-mi:“MI:0914”(association)	0.600
PPP2R2D	ENSA	psi-mi:“MI:0914”(association)	0.570
PPP2R2D	ENSA	psi-mi:“MI:2364”(proximity)	0.570
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAZ	PIK3C2A	psi-mi:“MI:0914”(association)	0.570

BioGRID (358): SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-MS), SKIV2L2 (Affinity Capture-RNA), ANKMY2 (Co-fractionation), CSE1L (Co-fractionation), DDX5 (Co-fractionation), DHX38 (Co-fractionation)

ESM2 similar proteins: A0A0P0V4R0, A0A1D5PRR9, A4IG62, A9UMG5, B4JNS2, F1R345, F4HQE2, F4KFV7, O75417, P0C928, P42285, Q14527, Q16X92, Q28E61, Q2VPA6, Q43093, Q56YN3, Q5JK52, Q5U2U7, Q5W9E7, Q5ZJT0, Q5ZLV4, Q60446, Q642J4, Q6PCL9, Q6PCN7, Q6PFE3, Q7XT07, Q8CGS6, Q8H2D5, Q8IYB8, Q8IYD8, Q8K394, Q94BR5, Q95216, Q9BWT3, Q9CZU3, Q9DG67, Q9FF61, Q9FT73

Diamond homologs: A3MSA1, B9DFG3, D0KN27, F0LJX3, F0NDL2, F4JAA5, O13799, O14232, O59801, P35207, P42285, P47047, P51979, P9WMR0, P9WMR1, Q15477, Q23223, Q5H9U9, Q6NZR5, Q8IY21, Q97VY9, Q9CZU3, Q9P7T8, Q9XIF2, Q9ZBD8, Q9ZVW2, A2PYH4, A7IB61, B6DMK2, D3Z4R1, E1BNG3, E9PZJ8, F1LNJ2, F1LPQ2, F1NTD6, H2KY86, O48534, O60072, O75417, O75643

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
MTREX	“form complex”	“NEXT complex, TENT4B-ZCCHC7 variant”	binding
MTREX	“form complex”	“NEXT complex, TENT4A-ZCCHC7 variant”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 184 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
KSRP (KHSRP) binds and destabilizes mRNA	8	37.0×	2e-09
Nuclear RNA decay	15	33.8×	4e-17
Activation of BAD and translocation to mitochondria	6	33.3×	6e-07
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	7	32.4×	7e-08
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	7	32.4×	7e-08
mRNA decay by 3’ to 5’ exoribonuclease	6	31.3×	9e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	29.4×	1e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	29.4×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
alternative mRNA splicing, via spliceosome	6	25.4×	1e-05
negative regulation of mRNA splicing, via spliceosome	5	24.1×	1e-04
RNA catabolic process	8	22.9×	3e-07
RNA processing	12	16.5×	4e-09
protein targeting	6	13.8×	2e-04
rRNA processing	14	12.5×	4e-09
positive regulation of interferon-beta production	5	12.3×	2e-03
regulation of alternative mRNA splicing, via spliceosome	8	12.3×	2e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

4130 predictions. Top by Δscore:

Variant	Effect	Δscore
5:55308095:G:GT	donor_gain	1.0000
5:55308146:GG:G	donor_gain	1.0000
5:55308147:GG:G	donor_gain	1.0000
5:55322321:TTTCA:T	acceptor_loss	1.0000
5:55322322:TTCA:T	acceptor_loss	1.0000
5:55322323:TCA:T	acceptor_loss	1.0000
5:55322324:CAG:C	acceptor_loss	1.0000
5:55322325:A:AG	acceptor_gain	1.0000
5:55322325:AG:A	acceptor_gain	1.0000
5:55322326:G:GT	acceptor_gain	1.0000
5:55322326:GG:G	acceptor_gain	1.0000
5:55322326:GGA:G	acceptor_gain	1.0000
5:55322326:GGAA:G	acceptor_gain	1.0000
5:55322326:GGAAA:G	acceptor_gain	1.0000
5:55322461:TAAG:T	donor_loss	1.0000
5:55322462:AAGG:A	donor_loss	1.0000
5:55322463:AGG:A	donor_loss	1.0000
5:55322464:GG:G	donor_loss	1.0000
5:55322465:G:C	donor_loss	1.0000
5:55322466:T:A	donor_loss	1.0000
5:55328807:GCCGA:G	donor_gain	1.0000
5:55328810:GA:G	donor_gain	1.0000
5:55328812:G:GG	donor_gain	1.0000
5:55340182:GAG:G	donor_gain	1.0000
5:55340195:T:TA	donor_gain	1.0000
5:55340196:A:AA	donor_gain	1.0000
5:55341723:G:GT	donor_gain	1.0000
5:55343325:TTTCA:T	acceptor_loss	1.0000
5:55343326:TTCAG:T	acceptor_loss	1.0000
5:55343327:TCAGA:T	acceptor_loss	1.0000

AlphaMissense

6920 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:55328708:T:C	F138L	1.000
5:55328710:C:A	F138L	1.000
5:55328710:C:G	F138L	1.000
5:55328718:A:T	D141V	1.000
5:55328723:T:C	F143L	1.000
5:55328724:T:C	F143S	1.000
5:55328725:T:A	F143L	1.000
5:55328725:T:G	F143L	1.000
5:55328728:A:C	Q144H	1.000
5:55328728:A:T	Q144H	1.000
5:55328735:G:C	A147P	1.000
5:55328766:T:A	V157D	1.000
5:55328769:T:C	L158P	1.000
5:55328774:T:C	S160P	1.000
5:55328777:G:C	A161P	1.000
5:55328778:C:A	A161E	1.000
5:55328780:C:G	H162D	1.000
5:55328782:T:A	H162Q	1.000
5:55328782:T:G	H162Q	1.000
5:55328784:C:T	T163I	1.000
5:55328786:T:C	S164P	1.000
5:55328789:G:C	A165P	1.000
5:55328790:C:A	A165E	1.000
5:55328792:G:A	G166R	1.000
5:55328792:G:C	G166R	1.000
5:55328793:G:A	G166E	1.000
5:55328793:G:C	G166A	1.000
5:55328793:G:T	G166V	1.000
5:55328795:A:C	K167Q	1.000
5:55328796:A:T	K167I	1.000

dbSNP variants (sampled 300 via entrez): RS1000025009 (5:55381308 C>CT), RS1000057517 (5:55390455 T>A), RS1000112600 (5:55377462 A>G), RS1000133028 (5:55345752 C>G), RS1000204665 (5:55321645 G>C,T), RS1000211071 (5:55373754 C>G), RS1000215684 (5:55397841 A>G), RS1000221742 (5:55417860 A>G), RS1000245576 (5:55394216 T>C), RS1000246894 (5:55375543 C>G,T), RS1000268979 (5:55308570 C>T), RS1000273927 (5:55410009 G>T), RS1000289670 (5:55322120 A>G), RS1000365026 (5:55357991 T>C), RS1000372312 (5:55401101 T>G)

Disease associations

OMIM: gene MIM:618122 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008399_7	Cocaine dependence	8.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105889 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 10,636 (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
CHEMBL491473	CEDIRANIB	3	9,098
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.10	Kd	79	nM	MOLIBRESIB
6.77	IC50	170	nM	MOLIBRESIB
6.41	Kd	385.3	nM	CHEMBL3752910
6.41	ED50	385.3	nM	CHEMBL3752910
5.58	Kd	2607	nM	CEDIRANIB

PubChem BioAssay actives

4 with measured affinity, of 252 total; 3 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179127: Binding affinity against SKIV2L2 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0790	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149398: Binding affinity to human SKIV2L2 incubated for 45 mins by Kinobead based pull down assay	kd	0.3853	uM
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline	1425168: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.6070	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
deoxynivalenol	increases expression	2
sodium arsenite	increases reaction, decreases expression, affects binding	2
Valproic Acid	decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression, affects cotreatment	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
salinomycin	decreases expression	1
kojic acid	decreases expression	1
trichostatin A	affects expression	1
perfluorooctanoic acid	decreases expression	1
cupric oxide	decreases expression	1
nivalenol	increases expression	1
beta-methylcholine	affects expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Azacitidine	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	affects expression	1
Ethinyl Estradiol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991881	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Clinical trials (associated diseases)

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