TUT4

Summary

TUT4 (terminal uridylyl transferase 4, HGNC:28981) is a protein-coding gene on chromosome 1p32.3, encoding Terminal uridylyltransferase 4 (Q5TAX3). Uridylyltransferase that mediates the terminal uridylation of mRNAs with short (less than 25 nucleotides) poly(A) tails, hence facilitating global mRNA decay.

Enables RNA uridylyltransferase activity. Involved in RNA metabolic process; stem cell population maintenance; and transposable element silencing by mRNA destabilization. Located in cytoplasmic ribonucleoprotein granule; cytosol; and nucleolus. Implicated in liver benign neoplasm. Biomarker of breast cancer.

Source: NCBI Gene 23318 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 231 total
• MANE Select transcript: NM_001009881

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28981
Approved symbol	TUT4
Name	terminal uridylyl transferase 4
Location	1p32.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0191, PAPD3, TENT3A
Ensembl gene	ENSG00000134744
Ensembl biotype	protein_coding
OMIM	613692
Entrez	23318

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 6 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000257177, ENST00000355809, ENST00000371541, ENST00000371544, ENST00000466440, ENST00000469810, ENST00000470212, ENST00000470626, ENST00000471623, ENST00000473856, ENST00000474453, ENST00000481133, ENST00000481528, ENST00000484723, ENST00000494469, ENST00000497120, ENST00000524582, ENST00000527941, ENST00000528457, ENST00000528642, ENST00000531722, ENST00000938125, ENST00000938126, ENST00000938127, ENST00000938128, ENST00000938129

RefSeq mRNA: 2 — MANE Select: NM_001009881 NM_001009881, NM_015269

CCDS: CCDS30715, CCDS30716

Canonical transcript exons

ENST00000257177 — 30 exons

Exon	Start	End
ENSE00000915847	52425349	52425507
ENSE00000915848	52431013	52431460
ENSE00000915851	52438220	52438335
ENSE00000915853	52445957	52446004
ENSE00000915859	52461712	52461769
ENSE00001455481	52436755	52436978
ENSE00001821943	52423275	52424002
ENSE00002149925	52525563	52526373
ENSE00002192828	52552931	52553092
ENSE00003468222	52446590	52446667
ENSE00003491109	52474832	52475535
ENSE00003494946	52490732	52490801
ENSE00003503931	52468181	52468267
ENSE00003506818	52465070	52465173
ENSE00003517431	52458336	52458449
ENSE00003521522	52471952	52472102
ENSE00003564973	52488909	52489035
ENSE00003564980	52461134	52461223
ENSE00003601932	52461513	52461616
ENSE00003611953	52515891	52516054
ENSE00003636807	52493611	52493662
ENSE00003645025	52495427	52495515
ENSE00003645652	52481804	52481923
ENSE00003657221	52477708	52477882
ENSE00003657662	52435365	52435465
ENSE00003668290	52497006	52497183
ENSE00003669075	52509596	52509712
ENSE00003671240	52481423	52481635
ENSE00003694136	52446265	52446442
ENSE00003787004	52445787	52445869

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 96.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.1475 / max 527.1046, expressed in 1785 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12368	21.0846	1671
12369	8.8473	1672
12365	0.1854	36
12361	0.0301	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	96.43	gold quality
cerebellar hemisphere	UBERON:0002245	96.38	gold quality
right testis	UBERON:0004534	96.33	gold quality
cerebellar cortex	UBERON:0002129	96.30	gold quality
left testis	UBERON:0004533	96.18	gold quality
adrenal tissue	UBERON:0018303	96.13	gold quality
left ovary	UBERON:0002119	95.97	gold quality
right ovary	UBERON:0002118	95.74	gold quality
adenohypophysis	UBERON:0002196	95.69	gold quality
ventricular zone	UBERON:0003053	95.68	gold quality
right uterine tube	UBERON:0001302	95.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.12	gold quality
endocervix	UBERON:0000458	95.10	gold quality
colonic epithelium	UBERON:0000397	94.92	gold quality
calcaneal tendon	UBERON:0003701	94.91	gold quality
cerebellum	UBERON:0002037	94.78	gold quality
right lobe of thyroid gland	UBERON:0001119	94.74	gold quality
sural nerve	UBERON:0015488	94.65	gold quality
tibial nerve	UBERON:0001323	94.62	gold quality
pituitary gland	UBERON:0000007	94.61	gold quality
ganglionic eminence	UBERON:0004023	94.61	gold quality
testis	UBERON:0000473	94.50	gold quality
gastrocnemius	UBERON:0001388	94.28	gold quality
cortical plate	UBERON:0005343	94.24	gold quality
left lobe of thyroid gland	UBERON:0001120	94.21	gold quality
skin of abdomen	UBERON:0001416	94.21	gold quality
body of uterus	UBERON:0009853	94.17	gold quality
muscle of leg	UBERON:0001383	94.01	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.95	gold quality
left uterine tube	UBERON:0001303	93.65	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.54
E-HCAD-10	yes	3.91
E-MTAB-8060	no	82.21
E-GEOD-93593	no	6.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

122 targeting TUT4, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4666A-3P	99.96	71.71	3434

Literature-anchored findings (GeneRIF, showing 18)

• We propose that ZCCHC11 is a unique TLR signal regulator, which interacts with TIFA after LPS treatment and suppresses the TRAF6-dependent activation of NF-kappaB. (PMID:16643855)
• Zcchc11 fine tunes IL-6 production by uridylating miR-26a. (PMID:19701194)
• TUT4 adds an oligouridine tail to the pre-let-7, which blocks Dicer processing. Knockdown of TUT4 and Lin28 reduces the level of stem cell markers (PMID:19703396)
• This study uncovers the role of TUT4 and Lin28 as specific suppressors of microRNA biogenesis, which has implications for stem cell research and cancer biology. (PMID:19703396)
• Terminal uridyltransferase enzyme Zcchc11 promotes cell proliferation independent of its uridyltransferase activity (PMID:22006926)
• Lin28 uses two different TUTases to control let-7 expression . (PMID:22898984)
• Study identified TUT7, TUT4, and TUT2 as novel components of the miRNA biogenesis pathway. (PMID:23063654)
• miR-26a directly targets Lin28B and Zcchc11-two critical repressors of let-7 maturation. (PMID:24056962)
• Study identified TUT4 and TUT7 as uridylyl transferases for poly(A)+ mRNAs in humans and delineated in detail the action mechanism and molecular function of uridylation in the mRNA decay pathway. (PMID:25480299)
• Data indicate that some of the small molecules were validated as specific inhibitors of 3’ terminal uridylyl transferase (TUTase) Zcchc11 (TUT4) activity. (PMID:26114892)
• For overall breast cancer risk, three single-nucleotide polymorphisms (SNPs) in miRNA biogenesis genes DROSHA rs78393591 (OR = 0.69, 95 % CI: 0.55-0.88, P = 0.003), ESR1 rs523736 (OR = 0.88, 95 % CI: 0.82-0.95, P = 3.99 x 10(-4)), and ZCCHC11 rs114101502 (OR = 1.33, 95 % CI: 1.11-1.59, P = 0.002), and one SNP in primary miRNA sequence (rs116159732 in miR-6826, OR = 0.74, 95 % CI: 0.63-0.89, P = 0.001) were found to have s (PMID:27380242)
• The authors found that TUT4(7) utilize two multidomain functional modules during the switch from either promoting expression of let-7 microRNA (monoU) or marking it for degradation (oligoU). (PMID:28671666)
• Uridylation by TUT4, which is enriched in cytoplasmic foci, destabilizes LINE-1 mRNAs. (PMID:30122351)
• This tail-U-mediated repression (TUMR) is abolished in cells lacking the uridylation enzymes TUT4 and TUT7, indicating that uridylation alters miRNA function by modulating target recognition. We identified a set of non-canonical targets in human cells that are specifically regulated by uridylated miR-27a. (PMID:31178353)
• Identification of novel targets of miR-622 in hepatocellular carcinoma reveals common regulation of cooperating genes and outlines the oncogenic role of zinc finger CCHC-type containing 11. (PMID:33901943)
• RNA uridyl transferases TUT4/7 differentially regulate miRNA variants depending on the cancer cell type. (PMID:34949722)
• TENT2, TUT4, and TUT7 selectively regulate miRNA sequence and abundance. (PMID:36071058)
• Terminal Uridylyltransferases TUT4/7 Regulate microRNA and mRNA Homeostasis. (PMID:36497000)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	tut4	ENSDARG00000070271
danio_rerio		ENSDARG00000101404
mus_musculus	Tut4	ENSMUSG00000034610
rattus_norvegicus	Tut4	ENSRNOG00000052062
caenorhabditis_elegans	gld-2	WBGENE00001596
caenorhabditis_elegans		WBGENE00011131
caenorhabditis_elegans		WBGENE00019628
caenorhabditis_elegans		WBGENE00019629
caenorhabditis_elegans	T08B2.4	WBGENE00020345
caenorhabditis_elegans		WBGENE00021338
caenorhabditis_elegans		WBGENE00194706

Paralogs (4): TUT7 (ENSG00000083223), MTPAP (ENSG00000107951), TUT1 (ENSG00000149016), TENT2 (ENSG00000164329)

Protein

Protein identifiers

Terminal uridylyltransferase 4 — Q5TAX3 (reviewed: Q5TAX3)

Alternative names: Zinc finger CCHC domain-containing protein 11

All UniProt accessions (13): E9PJN7, E9PKX1, E9PKY2, E9PQS7, E9PRG2, Q5TAX3, H0YCX5, H0YDJ1, H0YDZ6, H0YEE8, H0YEY0, H0YF28, X6R5G7

UniProt curated annotations — full annotation on UniProt →

Function. Uridylyltransferase that mediates the terminal uridylation of mRNAs with short (less than 25 nucleotides) poly(A) tails, hence facilitating global mRNA decay. Essential for both oocyte maturation and fertility. Through 3’ terminal uridylation of mRNA, sculpts, with TUT7, the maternal transcriptome by eliminating transcripts during oocyte growth. Involved in microRNA (miRNA)-induced gene silencing through uridylation of deadenylated miRNA targets. Also functions as an integral regulator of microRNA biogenesis using 3 different uridylation mechanisms. Acts as a suppressor of miRNA biogenesis by mediating the terminal uridylation of some miRNA precursors, including that of let-7 (pre-let-7), miR107, miR-143 and miR-200c. Uridylated miRNAs are not processed by Dicer and undergo degradation. Degradation of pre-let-7 contributes to the maintenance of embryonic stem (ES) cell pluripotency. Also catalyzes the 3’ uridylation of miR-26A, a miRNA that targets IL6 transcript. This abrogates the silencing of IL6 transcript, hence promoting cytokine expression. In the absence of LIN28A, TUT7 and TUT4 monouridylate group II pre-miRNAs, which includes most of pre-let7 members, that shapes an optimal 3’ end overhang for efficient processing. Adds oligo-U tails to truncated pre-miRNAS with a 5’ overhang which may promote rapid degradation of non-functional pre-miRNA species. May also suppress Toll-like receptor-induced NF-kappa-B activation via binding to T2BP. Does not play a role in replication-dependent histone mRNA degradation. Due to functional redundancy between TUT4 and TUT7, the identification of the specific role of each of these proteins is difficult. TUT4 and TUT7 restrict retrotransposition of long interspersed element-1 (LINE-1) in cooperation with MOV10 counteracting the RNA chaperonne activity of L1RE1. TUT7 uridylates LINE-1 mRNAs in the cytoplasm which inhibits initiation of reverse transcription once in the nucleus, whereas uridylation by TUT4 destabilizes mRNAs in cytoplasmic ribonucleoprotein granules.

Subunit / interactions. Interacts with LIN28A in the presence of pre-let-7 RNA. Interacts with T2BP. Interacts with MOV10; the interaction is RNA-dependent.

Subcellular location. Nucleus. Cytoplasm. Cytoplasmic ribonucleoprotein granule.

Domain organisation. Utilizes two multidomain functional modules during the switch from monouridylation to oligouridylation. The catalytic module (containing the 3 CCHC-type Zinc finger domains) is essential for both activities while the Lin28-interacting module (LIM) at the N-terminal part is indispensable for oligouridylation.

Similarity. Belongs to the DNA polymerase type-B-like family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5TAX3-1	1	yes
Q5TAX3-3	3

RefSeq proteins (2): NP_001009881, NP_056084 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001878	Znf_CCHC	Domain
IPR002058	PAP_assoc	Domain
IPR036875	Znf_CCHC_sf	Homologous_superfamily
IPR043519	NT_sf	Homologous_superfamily
IPR045100	TUT4/7_NTP_transf	Domain
IPR054708	MTPAP-like_central	Domain

Pfam: PF00098, PF03828, PF19088, PF22600

Enzyme classification (BRENDA):

• EC 2.7.7.52 — RNA uridylyltransferase (BRENDA: 12 organisms, 81 substrates, 9 inhibitors, 35 Km, 33 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
UTP	0.0004–0.3084	20
RNAN	0.0002–0.132	7
RNAN CONTAINING A TERMINAL U RESIDUE	0.0126–0.0208	2
ATP	0.0002	1
CTP	0.055	1
GTP	0.23	1
U6 SNRNAN	0.0001	1
RNA	—	0

Catalyzed reactions (Rhea), 1 shown:

• RNA(n) + UTP = RNA(n)-3’-uridine ribonucleotide + diphosphate (RHEA:14785)

UniProt features (96 total): strand 18, helix 16, binding site 12, mutagenesis site 11, compositionally biased region 10, region of interest 9, turn 8, modified residue 4, zinc finger region 3, domain 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6IW6	X-RAY DIFFRACTION	2.4
8OST	ELECTRON MICROSCOPY	3.69
9W4R	ELECTRON MICROSCOPY	3.78
9W4S	ELECTRON MICROSCOPY	3.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TAX3-F1	63.82	0.36

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 (12): 306; 309; 322; 328; 998–1001; 1008–1011; 1009; 1011; 1081; 1103; 1121–1125; 1237

Post-translational modifications (4): 104, 134, 156, 1624

Mutagenesis-validated functional residues (11):

Position	Phenotype
253–333	loss of interaction with lin28a and pre-let-7 rna.
306	loss of lin28a and pre-let-7 rna binding and loss of pre-let-7 rna uridylylation; when associated with a-309.
309	loss of lin28a and pre-let-7 rna binding and loss of pre-let-7 rna uridylylation; when associated with a-306.
321	strongly decreased lin28a and pre-let-7 rna binding and pre-let-7 rna uridylylation; when associated with a-324.
324	strongly decreased lin28a and pre-let-7 rna binding and pre-let-7 rna uridylylation; when associated with a-321.
326–327	strongly decreased lin28a and pre-let-7 rna binding and pre-let-7 rna uridylylation.
329–330	decreased lin28a and pre-let-7 rna binding and pre-let-7 rna uridylylation.
450	decreased lin28a and pre-let-7 rna binding and pre-let-7 rna uridylylation; when associated with a-452.
452	decreased lin28a and pre-let-7 rna binding and pre-let-7 rna uridylylation; when associated with a-450.
669–670	decreased lin28a and pre-let-7 rna binding and pre-let-7 rna uridylylation.
1011	loss of nucleotidyltransferase activity and stabilization of pre-let-7 mirnas. abolishes inhibition of lire1 retrotransp

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-429947	Deadenylation of mRNA
R-HSA-9819196	Zygotic genome activation (ZGA)
R-HSA-9820865	Z-decay: degradation of maternal mRNAs by zygotically expressed factors

MSigDB gene sets: 231 (showing top): GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_OOGENESIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_CELL_MATURATION, ATTACAT_MIR3803P, REACTOME_DEADENYLATION_OF_MRNA, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, ATTCTTT_MIR186, GOBP_MAINTENANCE_OF_CELL_NUMBER, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_OOCYTE_MATURATION

GO Biological Process (9): oocyte maturation (GO:0001556), miRNA metabolic process (GO:0010586), miRNA catabolic process (GO:0010587), stem cell population maintenance (GO:0019827), pre-miRNA processing (GO:0031054), RNA 3’-end processing (GO:0031123), transposable element silencing by mRNA destabilization (GO:0141008), polyuridylation-dependent mRNA catabolic process (GO:1990074), regulatory ncRNA-mediated gene silencing (GO:0031047)

GO Molecular Function (9): RNA binding (GO:0003723), zinc ion binding (GO:0008270), miRNA binding (GO:0035198), RNA uridylyltransferase activity (GO:0050265), nucleic acid binding (GO:0003676), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), metal ion binding (GO:0046872)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic ribonucleoprotein granule (GO:0036464), extracellular exosome (GO:0070062), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Maternal to zygotic transition (MZT)	2
Deadenylation-dependent mRNA decay	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mRNA destabilization	2
binding	2
cellular anatomical structure	2
cytoplasm	2
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
RNA metabolic process	1
RNA catabolic process	1
miRNA metabolic process	1
multicellular organismal process	1
maintenance of cell number	1
miRNA processing	1
RNA processing	1
transposable element silencing	1
mRNA catabolic process	1
modification-dependent macromolecule catabolic process	1
negative regulation of gene expression	1
nucleic acid binding	1
transition metal ion binding	1
regulatory RNA binding	1
uridylyltransferase activity	1
catalytic activity, acting on RNA	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
cation binding	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
ribonucleoprotein granule	1
extracellular vesicle	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

928 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TUT4	LIN28A	Q9H9Z2	995
TUT4	LIN28B	Q6ZN17	925
TUT4	PAPOLG	Q9BWT3	893
TUT4	DIS3L2	Q8IYB7	885
TUT4	PAPOLA	P51003	872
TUT4	PAPOLB	Q9NRJ5	864
TUT4	TENT4B	Q8NDF8	756
TUT4	DICER1	Q9UPY3	718
TUT4	DROSHA	Q9NRR4	655
TUT4	TUT1	Q9H6E5	623
TUT4	AFP	P02771	550
TUT4	IL6	P05231	549
TUT4	RNH1	P13489	541
TUT4	XRN1	Q8IZH2	532
TUT4	DIS3L	Q8TF46	531

IntAct

37 interactions, top by confidence:

A	B	Type	Score
LIN28B		psi-mi:“MI:0414”(enzymatic reaction)	0.540
CBX1	KPNA3	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
	TUT4	psi-mi:“MI:0914”(association)	0.520
TUT4		psi-mi:“MI:0414”(enzymatic reaction)	0.520
LIN28A		psi-mi:“MI:0414”(enzymatic reaction)	0.520
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
LIN28B		psi-mi:“MI:0414”(enzymatic reaction)	0.440
TUT4	FXR2	psi-mi:“MI:0915”(physical association)	0.370
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350
COPS5	FBLL1	psi-mi:“MI:0914”(association)	0.350
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
CUL4B	APBB1	psi-mi:“MI:0914”(association)	0.350
CUL5	DDX3X	psi-mi:“MI:0914”(association)	0.350
	DDX3Y	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
GABARAPL2		psi-mi:“MI:0914”(association)	0.350
MYC	PDZD2	psi-mi:“MI:0914”(association)	0.350
CSNK2A2	VWA8	psi-mi:“MI:0914”(association)	0.350
FKBP5	IFT56	psi-mi:“MI:0914”(association)	0.350
DUSP16	MEIOC	psi-mi:“MI:0914”(association)	0.350
HNRNPCL2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
CREB3L2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
KRR1	ZNF316	psi-mi:“MI:0914”(association)	0.350
CFTR	UBA6	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (101): ZCCHC11 (Affinity Capture-RNA), ZCCHC11 (Affinity Capture-RNA), ZCCHC11 (Affinity Capture-RNA), ZCCHC11 (Affinity Capture-MS), ZCCHC11 (Affinity Capture-MS), ZCCHC11 (Synthetic Lethality), ZCCHC11 (Affinity Capture-RNA), ZCCHC11 (Affinity Capture-MS), ZCCHC11 (Protein-RNA), ZCCHC11 (Protein-RNA), ZCCHC11 (Protein-RNA), ZCCHC11 (Protein-RNA), ZCCHC11 (Protein-RNA), ZCCHC11 (Protein-RNA), ZCCHC11 (Protein-RNA)

ESM2 similar proteins: A7MBJ2, B2GUN4, B2RX14, B8A5Y1, D2H3M0, D3ZF42, E1BZ85, E2QTD3, E2RK09, F1N5V1, G3V8T1, O15151, O35618, P38432, P46100, P56273, P62297, Q0VEE6, Q17RS7, Q3TYA6, Q5BLK4, Q5TAX3, Q5VCS6, Q5VYS8, Q5W0Q7, Q5XIN1, Q5ZI58, Q62187, Q63679, Q6P4F7, Q6P7W0, Q6PCM1, Q7YQM3, Q7YQM4, Q86T82, Q8BJ34, Q8BMI4, Q8BUH8, Q8C0R0, Q8IW19

Diamond homologs: B2RX14, D2HS90, O13833, O17087, O64642, Q0VFA3, Q1JPD6, Q2HJ44, Q3MHT4, Q503I9, Q5BLK4, Q5TAX3, Q5U315, Q5VYS8, Q641A1, Q6DFA8, Q6PIY7, Q8R3F9, Q91YI6, Q9H6E5, Q9UT49, Q9VD44, A9JTS5, O13798, Q4KMD7, Q9VYS4, O74326, Q5XET5, Q8WQX6, Q9UTN3, Q8WQX5, Q7KVS9, Q9D0D3, Q9NVV4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
TUT4	down-regulates	mRNA_polyadenylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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
Neddylation	7	9.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
G1/S transition of mitotic cell cycle	5	22.3×	5e-04
DNA damage response	8	9.5×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	185
Likely benign	8
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

6140 predictions. Top by Δscore:

Variant	Effect	Δscore
1:52408563:TCTCA:T	acceptor_loss	1.0000
1:52408564:CTCAG:C	acceptor_loss	1.0000
1:52408565:TCA:T	acceptor_loss	1.0000
1:52408566:CAG:C	acceptor_loss	1.0000
1:52408568:G:GT	acceptor_loss	1.0000
1:52408568:GGT:G	acceptor_gain	1.0000
1:52408568:GGTAT:G	acceptor_gain	1.0000
1:52408686:TGGGG:T	donor_gain	1.0000
1:52408687:GGGG:G	donor_gain	1.0000
1:52408687:GGGGG:G	donor_gain	1.0000
1:52408688:GGG:G	donor_gain	1.0000
1:52408688:GGGG:G	donor_gain	1.0000
1:52408689:GG:G	donor_gain	1.0000
1:52408689:GGG:G	donor_gain	1.0000
1:52408689:GGGTA:G	donor_loss	1.0000
1:52408690:GG:G	donor_gain	1.0000
1:52408690:GGTA:G	donor_loss	1.0000
1:52408691:G:GG	donor_gain	1.0000
1:52408692:T:G	donor_loss	1.0000
1:52411114:GA:G	acceptor_gain	1.0000
1:52411196:TACAG:T	donor_loss	1.0000
1:52411197:ACAG:A	donor_loss	1.0000
1:52411198:CAGG:C	donor_loss	1.0000
1:52411199:AGGTA:A	donor_loss	1.0000
1:52411200:GG:G	donor_loss	1.0000
1:52411202:T:A	donor_loss	1.0000
1:52412509:TGTA:T	acceptor_loss	1.0000
1:52412510:GTA:G	acceptor_loss	1.0000
1:52412512:A:AG	acceptor_gain	1.0000
1:52412512:AGA:A	acceptor_loss	1.0000

AlphaMissense

10879 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:52436798:G:C	C1372W	1.000
1:52436799:C:A	C1372F	1.000
1:52436799:C:G	C1372S	1.000
1:52436799:C:T	C1372Y	1.000
1:52436800:A:G	C1372R	1.000
1:52436800:A:T	C1372S	1.000
1:52436813:A:C	H1367Q	1.000
1:52436813:A:T	H1367Q	1.000
1:52436815:G:C	H1367D	1.000
1:52436828:A:C	C1362W	1.000
1:52436829:C:A	C1362F	1.000
1:52436829:C:G	C1362S	1.000
1:52436829:C:T	C1362Y	1.000
1:52436830:A:G	C1362R	1.000
1:52436830:A:T	C1362S	1.000
1:52436834:A:C	F1360L	1.000
1:52436834:A:T	F1360L	1.000
1:52436836:A:G	F1360L	1.000
1:52436837:A:C	C1359W	1.000
1:52436838:C:A	C1359F	1.000
1:52436838:C:G	C1359S	1.000
1:52436838:C:T	C1359Y	1.000
1:52436839:A:C	C1359G	1.000
1:52436839:A:G	C1359R	1.000
1:52436839:A:T	C1359S	1.000
1:52438234:G:C	C1308W	1.000
1:52438235:C:A	C1308F	1.000
1:52438235:C:G	C1308S	1.000
1:52438235:C:T	C1308Y	1.000
1:52438236:A:C	C1308G	1.000

dbSNP variants (sampled 300 via entrez): RS1000027586 (1:52517129 C>T), RS1000029564 (1:52553171 G>A), RS1000034878 (1:52510864 C>G), RS1000037070 (1:52426172 A>G), RS1000048446 (1:52425357 T>C), RS1000057276 (1:52456463 C>A), RS1000088509 (1:52510544 T>C), RS1000104174 (1:52551415 CTTTT>C), RS1000152859 (1:52425826 T>C), RS1000186647 (1:52546892 G>A), RS1000208489 (1:52462277 C>T), RS1000218100 (1:52485372 A>G), RS1000237882 (1:52462395 C>A,T), RS1000244817 (1:52505743 G>A,C), RS1000289269 (1:52519174 T>C)

Disease associations

OMIM: gene MIM:613692 | 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
GCST003998_18	Joint mobility (Beighton score)	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007905	joint hypermobility measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation, decreases expression, increases expression, affects cotreatment	4
Valproic Acid	affects cotreatment, decreases expression	4
trichostatin A	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases methylation	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	increases abundance, increases expression	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Nicotine	increases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1

Clinical trials (associated diseases)

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