RNF4

Summary

RNF4 (ring finger protein 4, HGNC:10067) is a protein-coding gene on chromosome 4p16.3, encoding E3 ubiquitin-protein ligase RNF4 (P78317). E3 ubiquitin-protein ligase which binds polysumoylated chains covalently attached to proteins and mediates ‘Lys-6’-, ‘Lys-11’-, ‘Lys-48’- and ‘Lys-63’-linked polyubiquitination of those substrates and their subsequent targeting to the proteasome for degradation. It is a selective cancer dependency (DepMap: 63.3% of cell lines).

The protein encoded by this gene contains a RING finger motif and acts as a transcription regulator. This protein has been shown to interact with, and inhibit the activity of, TRPS1, a transcription suppressor of GATA-mediated transcription. Transcription repressor ZNF278/PATZ is found to interact with this protein, and thus reduce the enhancement of androgen receptor-dependent transcription mediated by this protein. Studies of the mouse and rat counterparts suggested a role of this protein in spermatogenesis. A pseudogene of this gene is found on chromosome 1.

Source: NCBI Gene 6047 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 49 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 63.3% of screened cell lines
• MANE Select transcript: NM_002938

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10067
Approved symbol	RNF4
Name	ring finger protein 4
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	RES4-26, SNURF, SLX5
Ensembl gene	ENSG00000063978
Ensembl biotype	protein_coding
OMIM	602850
Entrez	6047

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 13 protein_coding, 7 protein_coding_CDS_not_defined, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000314289, ENST00000502316, ENST00000503123, ENST00000503659, ENST00000504224, ENST00000504782, ENST00000506706, ENST00000507247, ENST00000507784, ENST00000509206, ENST00000509258, ENST00000509388, ENST00000511600, ENST00000511843, ENST00000511859, ENST00000511892, ENST00000513284, ENST00000513450, ENST00000513578, ENST00000513643, ENST00000541204, ENST00000927016, ENST00000927017

RefSeq mRNA: 3 — MANE Select: NM_002938 NM_001185009, NM_001185010, NM_002938

CCDS: CCDS47001, CCDS54713

Canonical transcript exons

ENST00000314289 — 8 exons

Exon	Start	End
ENSE00002065436	2469106	2469258
ENSE00002083271	2513670	2515857
ENSE00003458595	2490337	2490502
ENSE00003478018	2513083	2513131
ENSE00003504207	2512438	2512597
ENSE00003517203	2497007	2497121
ENSE00003525962	2511956	2511965
ENSE00003786920	2500659	2500738

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 95.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.8340 / max 312.5287, expressed in 1826 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46615	60.5087	1826
46616	1.3253	745

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	95.93	gold quality
oocyte	CL:0000023	95.22	gold quality
middle temporal gyrus	UBERON:0002771	94.92	gold quality
colonic epithelium	UBERON:0000397	94.47	gold quality
tonsil	UBERON:0002372	94.28	gold quality
secondary oocyte	CL:0000655	94.27	gold quality
bone marrow cell	CL:0002092	94.13	gold quality
lymph node	UBERON:0000029	94.12	gold quality
type B pancreatic cell	CL:0000169	94.00	gold quality
stromal cell of endometrium	CL:0002255	93.97	gold quality
tibia	UBERON:0000979	93.91	gold quality
blood	UBERON:0000178	93.89	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.77	gold quality
mucosa of urinary bladder	UBERON:0001259	93.71	gold quality
epithelium of nasopharynx	UBERON:0001951	93.69	gold quality
granulocyte	CL:0000094	93.68	gold quality
nasopharynx	UBERON:0001728	93.67	gold quality
palpebral conjunctiva	UBERON:0001812	93.46	gold quality
superficial temporal artery	UBERON:0001614	93.43	gold quality
smooth muscle tissue	UBERON:0001135	93.33	gold quality
adult organism	UBERON:0007023	93.24	gold quality
vermiform appendix	UBERON:0001154	93.22	gold quality
parotid gland	UBERON:0001831	93.07	gold quality
adrenal tissue	UBERON:0018303	93.05	gold quality
caput epididymis	UBERON:0004358	93.02	gold quality
spleen	UBERON:0002106	92.97	gold quality
gingival epithelium	UBERON:0001949	92.96	gold quality
caecum	UBERON:0001153	92.94	gold quality
corpus epididymis	UBERON:0004359	92.94	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.82	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.65
E-ENAD-17	no	1627.53

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR5A1, PATZ1

miRNA regulators (miRDB)

101 targeting RNF4, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-5580-3P	99.70	69.41	2052

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 63.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Functional analysis of the rat homolog (PMID:12351196)
• Functional analysis of the mouse homolog (PMID:12874792)
• RNF4 is a negative regulator of TRPS1 activity (PMID:12885770)
• Data show that the RING-domain-containing ubiquitin E3 ligase, RNF4 (also known as SNURF), targets poly-SUMO-modified proteins for degradation mediated by ubiquitin. (PMID:18408734)
• sumoylation- and Sumo binding domain-dependent PML oligomerization within nuclear bodies is sufficient for RNF4-mediated PML degradation (PMID:19380586)
• The different subtypes of malignant ovarian germ cell tumours all express ERalpha, ERbeta, and SNURF. (PMID:19524139)
• Mechanistic studies show that RNF4 interacts with and requires the base excision repair enzymes TDG and APE1 for active demethylation. (PMID:20696907)
• RNF4 regulates the localization and function of the HTLV-1 oncoprotein Tax. (PMID:22106342)
• RNF4 operates as a DSB response factor at the crossroads between the SUMO and ubiquitin systems. (PMID:22661229)
• RNF4 is a novel DNA damage-responsive protein that plays a role in homologous recombination and integrates SUMO modification and ubiquitin signaling in the cellular response to genotoxic stress. (PMID:22661230)
• SUMO interacting motif is dispensable for PML SUMOylation and interaction with RNF4 but is required for efficient PML ubiquitination, recruitment of proteasome components within NBs and proteasome-dependent degradation of PML in response to AsO (PMID:23028697)
• connect ubiquitin- and SUMO-dependent DSB recognition, revealing that RNF4-synthesized hybrid SUMO-ubiquitin chains are recognized by RAP80 to promote BRCA1 recruitment and DNA repair. (PMID:23211528)
• RNF4 is a SUMO-targeted ubiquitin E3 ligase of Rta. (PMID:23504328)
• The sequence and spacing of the SIMs (SUMO-interaction motifs) in RNF4 regulate the avidity-driven recognition of substrate proteins carrying SUMO chains of variable length. (PMID:24151981)
• SUMO chain-induced dimerization activates RNF4. (PMID:24656128)
• the ARM dynamically regulates the SIM-dependent recruitment of targets to RNF4, which could be critical to dynamically fine-tune the abundance of Ser(P)-824-SUMO-KAP1 and, potentially, other SUMOylated proteins during DNA damage response. (PMID:24907272)
• NMR spectroscopy and biochemical characterization reveal how RNF4 manipulates the conformation of the SUMO chain, thereby facilitating optimal delivery of the distal SUMO domain for ubiquitin transfer. (PMID:24969970)
• RNF4 mediates ubiquitination and turnover of MeCP2 and thus derepresses transcription from DNA methylation. (PMID:25355316)
• RecQ-like helicase BLM subcellular localization is regulated by SUMO-targeted ubiquitin ligase RNF4 in response to DNA damage, presumably to prevent illegitimate recombination events. (PMID:25588990)
• Cells lacking RNF4 exhibited interstrand cross-linker hypersensitivity. The gene encoding RNF4 was epistatic with the other genes encoding members of the FA/BRCA pathway. (PMID:25751062)
• c-Myc is targeted to the proteasome for degradation in a SUMOylation-dependent manner, regulated by PIAS1, SENP7 and RNF4 (PMID:25895136)
• RNF4 enhances Ube2E1 self-ubiquitination. (PMID:25960396)
• novel insight into cross-talk between ubiquitin and SUMO and uncover USP11 and RNF4 as a balanced SUMO-targeted ubiquitin ligase/protease pair with a role in the DDR. (PMID:25969536)
• RNF4 negatively regulates NF-kappaB signaling by down-regulating TAB2 (PMID:26299341)
• Data show that RNF4 is a SUMO-targeted ubiquitin ligase that targets TRF2 for ubiquitination. (PMID:26450775)
• Combined effect of dynamic recruitment of RNF4 to KAP1 regulates the relative occupancy of 53BP1 and BRCA1 at double-strand break sites to direct DNA repair in a cell cycle-dependent manner. (PMID:26766492)
• These findings indicate that SUMOylation of NDRG2 is necessary for its tumor suppressor function in lung adenocarcinoma and that RNF4 increases the efficiency of this process. (PMID:27072586)
• Thus, although Rnf4 and Ube2w functionally interact in vitro, these genetic experiments indicate that in response to DNA damage Ube2w and Rnf4 function in distinct pathways. (PMID:27185577)
• post-translational modification of Nkx3.2 employing HDAC9-PIASy-RNF4 axis plays a crucial role in controlling chondrocyte viability and hypertrophic maturation during skeletal development in vertebrates. (PMID:27312341)
• RNF4-dependent ubiquitylation translates transient phosphorylation signal(s) into long-term protein stabilization, resulting in enhanced oncoprotein activation (PMID:27653698)
• These results point to an important role of the affinity between RNF4 and its cognate RAD6B or UBCH5B in governing the multiplicity of substrate ubiquitination. (PMID:27678051)
• The E3 ligase RNF4 is required to ubiquitinate FXR in response to SUMOylation. (PMID:28201649)
• the opposing activities of RNF4 and ataxin-3 consolidate robust MDC1-dependent signaling and repair ofDNA double-strand break. (PMID:28275011)
• These findings illustrate a novel strategy for viral interference with the SUMO pathway, and identify the EBV miR-BHRF1-1 and the cellular RNF4 as regulators of the productive virus cycle. (PMID:28414785)
• Taken together, these data demonstrate that the protein kinase activity and levels of PIM1 can be regulated by a covalent post-translational modification via RNF4. (PMID:28620180)
• Respiratory syncytial virus induces NRF2 degradation through a PML-RNF4 pathway. (PMID:29107745)
• Study provides an insight into the role of the RNF4 to balance the role of SUMO signaling by directly targeting Ubc9 and SUMO E3 ligases. (PMID:29180619)
• DNMT1 as a potential new small ubiquitin-related modifier-(SUMO)-targeted ubiquitin E3 ligase substrate of RNF4, with knockdown of dnmt1 largely restoring primitive and definitive granulopoiesis in rnf4-deficient zebrafish (PMID:29634367)
• High RNF4 expression is associated with adenovirus infections. (PMID:29695423)
• the SUMO pathway contributes to the clearance of aggregated ATXN7 and suggest that its deregulation might be associated with SCA7 disease progression. (PMID:30559154)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnf4	ENSDARG00000090993
mus_musculus	Rnf4	ENSMUSG00000029110
rattus_norvegicus	Rnf4	ENSRNOG00000013930

Protein

Protein identifiers

E3 ubiquitin-protein ligase RNF4 — P78317 (reviewed: P78317)

Alternative names: RING finger protein 4, Small nuclear ring finger protein

All UniProt accessions (7): P78317, D6R9E0, D6RA71, D6RAD8, D6RBQ7, D6RBZ1, D6RJF5

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which binds polysumoylated chains covalently attached to proteins and mediates ‘Lys-6’-, ‘Lys-11’-, ‘Lys-48’- and ‘Lys-63’-linked polyubiquitination of those substrates and their subsequent targeting to the proteasome for degradation. Regulates the degradation of several proteins including PML and the transcriptional activator PEA3. Involved in chromosome alignment and spindle assembly, it regulates the kinetochore CENPH-CENPI-CENPK complex by targeting polysumoylated CENPI to proteasomal degradation. Regulates the cellular responses to hypoxia and heat shock through degradation of respectively EPAS1 and PARP1. Alternatively, it may also bind DNA/nucleosomes and have a more direct role in the regulation of transcription for instance enhancing basal transcription and steroid receptor-mediated transcriptional activation. Catalyzes ubiquitination of sumoylated PARP1 in response to PARP1 trapping to chromatin, leading to PARP1 removal from chromatin by VCP/p97.

Subunit / interactions. Homodimer (via RING-type zinc finger domain). Interacts with GSC2. Interacts with AR/the androgen receptor and TBP. Interacts with TCF20. Interacts with PATZ1. Interacts with TRPS1; negatively regulates TRPS1 transcriptional repressor activity. Interacts with PML (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6). Interacts with PRDM1/Blimp-1.

Subcellular location. Cytoplasm. Nucleus. PML body.

Tissue specificity. Widely expressed at low levels in many tissues; highly expressed in testis.

Post-translational modifications. Sumoylated; conjugated by one or two SUMO1 moieties. Autoubiquitinated.

Domain organisation. The SUMO interaction motifs (SIMs) mediates the binding to polysumoylated substrate. The RING-type zinc finger domain is required for the ubiquitination of polysumoylated substrates.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
P78317-1	1	yes
P78317-2	2

RefSeq proteins (3): NP_001171938, NP_001171939, NP_002929* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR043295	RING-HC_RNF4	Domain
IPR047134	RNF4	Family

Pfam: PF13639

UniProt features (33 total): binding site 8, strand 4, short sequence motif 4, region of interest 3, mutagenesis site 3, turn 3, modified residue 2, splice variant 2, helix 2, chain 1, zinc finger region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2XEU	X-RAY DIFFRACTION	1.5
4PPE	X-RAY DIFFRACTION	2
2EA6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78317-F1	73.04	0.31

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 (8): 135; 154; 156; 159; 162; 173; 176; 132

Post-translational modifications (2): 94, 95

Mutagenesis-validated functional residues (3):

Position	Phenotype
136	dominant-negative e2-binding mutant, leads to increased trapping of parp1 to chromatin; when associated with a-177.
156	abolished e3 ubiquitin-protein ligase activity.
177	dominant-negative e2-binding mutant, leads to increased trapping of parp1 to chromatin; when associated with s-136.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-5693532	DNA Double-Strand Break Repair
R-HSA-5693538	Homology Directed Repair
R-HSA-5693567	HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)
R-HSA-73894	DNA Repair
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 303 (showing top): GCACCTT_MIR18A_MIR18B, GOBP_CHROMOSOME_ORGANIZATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, TGCGCANK_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GENTILE_RESPONSE_CLUSTER_D3, TGACCTY_ERR1_Q2, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, YY1_Q6, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, MODULE_503

GO Biological Process (14): proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), response to arsenic-containing substance (GO:0046685), protein autoubiquitination (GO:0051865), protein K63-linked ubiquitination (GO:0070534), protein K48-linked ubiquitination (GO:0070936), protein K11-linked ubiquitination (GO:0070979), protein K6-linked ubiquitination (GO:0085020), regulation of spindle assembly (GO:0090169), regulation of kinetochore assembly (GO:0090234), negative regulation of protein localization to chromatin (GO:0120186), DNA damage response (GO:0006974), protein ubiquitination (GO:0016567)

GO Molecular Function (10): DNA binding (GO:0003677), ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), nucleosome binding (GO:0031491), SUMO polymer binding (GO:0032184), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear body (GO:0016604), PML body (GO:0016605), microtubule end (GO:1990752)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
DNA Repair	1
DNA Double-Strand Break Repair	1
Homology Directed Repair	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein polyubiquitination	4
cellular anatomical structure	3
regulation of organelle assembly	2
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
response to chemical	1
protein ubiquitination	1
spindle assembly	1
regulation of spindle organization	1
regulation of chromosome organization	1
regulation of protein-containing complex assembly	1
kinetochore assembly	1
protein localization to chromatin	1
negative regulation of protein localization	1
regulation of protein localization to chromatin	1
cellular response to stress	1
protein modification by small protein conjugation	1
nucleic acid binding	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
chromatin binding	1
protein-containing complex binding	1
SUMO binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

3862 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNF4	UBE2D1	P51668	979
RNF4	SUMO2	P55855	928
RNF4	ZNRF4	Q8WWF5	852
RNF4	UBE2I	P50550	849
RNF4	MDC1	Q14676	843
RNF4	PATZ1	Q9HBE1	832
RNF4	PIAS1	O75925	789
RNF4	PIAS4	Q8N2W9	761
RNF4	SUMO1	P55856	753
RNF4	BIRC7	Q96CA5	749
RNF4	NUP107	P57740	730
RNF4	DCAF16	Q9NXF7	729
RNF4	SENP1	Q9P0U3	714
RNF4	NUP133	Q8WUM0	711
RNF4	UIMC1	Q96RL1	711

IntAct

328 interactions, top by confidence:

A	B	Type	Score
HNRNPC	RNF4	psi-mi:“MI:0915”(physical association)	0.560
ZBTB34	RNF4	psi-mi:“MI:0915”(physical association)	0.560
RNF4	FADD	psi-mi:“MI:0915”(physical association)	0.560
VENTX	RNF4	psi-mi:“MI:0915”(physical association)	0.560
LCE2B	RNF4	psi-mi:“MI:0915”(physical association)	0.560
RNF4	PHC1	psi-mi:“MI:0915”(physical association)	0.560
RNF4	LCE5A	psi-mi:“MI:0915”(physical association)	0.560
SOX5	RNF4	psi-mi:“MI:0915”(physical association)	0.560
RNF4	TRIP13	psi-mi:“MI:0915”(physical association)	0.560
TRAF5	RNF4	psi-mi:“MI:0915”(physical association)	0.560
RNF4	TRAF4	psi-mi:“MI:0915”(physical association)	0.560
RNF4	LCE2C	psi-mi:“MI:0915”(physical association)	0.560
SUMO1	RNF4	psi-mi:“MI:0915”(physical association)	0.560
RNF4	GMCL1	psi-mi:“MI:0915”(physical association)	0.560
RNF4	RUNX1T1	psi-mi:“MI:0915”(physical association)	0.560
RNF4	TFG	psi-mi:“MI:0915”(physical association)	0.560
HGS	RNF4	psi-mi:“MI:0915”(physical association)	0.560
RNF4	ZNF319	psi-mi:“MI:0915”(physical association)	0.560
RNF4	UBTD2	psi-mi:“MI:0915”(physical association)	0.560
UBE2I	RNF4	psi-mi:“MI:0915”(physical association)	0.550
UEVLD	RNF4	psi-mi:“MI:0915”(physical association)	0.370
RNF4	HIP2	psi-mi:“MI:0915”(physical association)	0.370
UBE2D1	RNF4	psi-mi:“MI:0915”(physical association)	0.370
RNF4	UBE2D2	psi-mi:“MI:0915”(physical association)	0.370
UBE2D3	RNF4	psi-mi:“MI:0915”(physical association)	0.370
RNF4	UBE2E1	psi-mi:“MI:0915”(physical association)	0.370
UBE2E2	RNF4	psi-mi:“MI:0915”(physical association)	0.370
RNF4	UBE2H	psi-mi:“MI:0915”(physical association)	0.370
RNF4	UBE2E3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (1614): MECP2 (Biochemical Activity), PML (Biochemical Activity), SUMO2 (Reconstituted Complex), SUMO2 (Reconstituted Complex), RNF4 (PCA), SUMO2 (Reconstituted Complex), UBE2D1 (Reconstituted Complex), NCOA1 (Phenotypic Enhancement), TBP (Phenotypic Enhancement), TERF2 (Affinity Capture-Western), RNF4 (Affinity Capture-Western), TERF2 (Reconstituted Complex), RNF4 (Affinity Capture-Western), FANCA (Affinity Capture-Western), RNF4 (Affinity Capture-Western)

ESM2 similar proteins: A0A0R4IWG9, B0BLU1, D2H0Y8, E1B7X3, F4JYG0, O13826, O42354, O88846, P40072, P59997, P78317, Q0WX00, Q1LVK9, Q24558, Q2PFU6, Q32PH1, Q3T139, Q58WW2, Q5FWP4, Q5R9B8, Q5REL3, Q5U263, Q5XIK5, Q66JE4, Q6ASW7, Q6INS5, Q6NYJ3, Q6P2L6, Q6PIJ6, Q6XV80, Q6ZPS6, Q71M44, Q7T308, Q7ZX20, Q7ZXG4, Q803A0, Q803U7, Q8BMI0, Q96JK2, Q9CZW6

Diamond homologs: A2XW69, A2ZAC2, O64425, O75150, O88846, P0CQ62, P0CQ63, P78317, Q09463, Q2U9B0, Q336R3, Q3U319, Q4P3X7, Q4R7K7, Q4WDD7, Q568Y3, Q5DTM8, Q5RAU7, Q5RFK9, Q5ZIR9, Q5ZLS3, Q6CHI1, Q6LFN2, Q6PC78, Q7S304, Q7XU27, Q8CJB9, Q8GUK7, Q8RXD6, Q91YT2, Q96GF1, Q99942, Q9C895, Q9QZS2, A1YER5, A1YFY1, A2T6X5, H2KYH3, O35730, Q06587

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
RNF4	“up-regulates activity”	NFYA	binding
RNF4	“up-regulates activity”	NFYB	binding
RNF4	“up-regulates activity”	NFYC	binding
Ub:E2	“up-regulates activity”	RNF4	ubiquitination
RNF4	“down-regulates quantity by destabilization”	KDM5B	sumoylation
RNF4	“up-regulates activity”	KDM5C	sumoylation
RNF4	“down-regulates quantity by destabilization”	SP1	polyubiquitination
RNF4	“down-regulates quantity by destabilization”	PML	polyubiquitination
CDK2	“up-regulates activity”	RNF4	phosphorylation
RNF4	“down-regulates quantity”	SP1	ubiquitination
PATZ1	down-regulates	RNF4	binding
RNF4	“down-regulates quantity by destabilization”	SUMO2	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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
Synthesis of active ubiquitin: roles of E1 and E2 enzymes	6	36.8×	5e-06
SUMOylation of RNA binding proteins	5	19.8×	5e-04
Regulation of TNFR1 signaling	5	18.7×	5e-04
Formation of the cornified envelope	9	13.2×	5e-06
Keratinization	9	8.4×	2e-04
Signaling by Interleukins	6	6.4×	9e-03
Antigen processing: Ubiquitination & Proteasome degradation	10	6.2×	5e-04
Cytokine Signaling in Immune system	9	6.1×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein K11-linked ubiquitination	6	24.8×	3e-05
keratinization	9	22.2×	2e-07
protein monoubiquitination	6	21.7×	6e-05
protein K48-linked ubiquitination	9	16.0×	2e-06
ubiquitin-dependent protein catabolic process	10	7.8×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	32
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
979467	GRCh37/hg19 4p16.3-16.2(chr4:68345-5046326)x1	Pathogenic

SpliceAI

3414 predictions. Top by Δscore:

Variant	Effect	Δscore
15:24962106:T:A	acceptor_gain	1.0000
15:24962106:T:TA	acceptor_gain	1.0000
15:24962110:TCA:T	acceptor_loss	1.0000
15:24962112:A:AG	acceptor_gain	1.0000
15:24962112:A:AT	acceptor_loss	1.0000
15:24962112:A:C	acceptor_loss	1.0000
15:24962112:AG:A	acceptor_gain	1.0000
15:24962112:AGG:A	acceptor_gain	1.0000
15:24962113:G:A	acceptor_gain	1.0000
15:24962113:G:C	acceptor_loss	1.0000
15:24962113:G:GA	acceptor_gain	1.0000
15:24962113:GGG:G	acceptor_gain	1.0000
15:24962113:GGGA:G	acceptor_gain	1.0000
15:24962113:GGGAT:G	acceptor_gain	1.0000
15:24962205:CAAGA:C	donor_gain	1.0000
15:24962206:AAGA:A	donor_gain	1.0000
15:24962206:AAGAG:A	donor_loss	1.0000
15:24962207:AGA:A	donor_gain	1.0000
15:24962207:AGAG:A	donor_loss	1.0000
15:24962207:AGAGT:A	donor_loss	1.0000
15:24962208:GA:G	donor_gain	1.0000
15:24962208:GAG:G	donor_gain	1.0000
15:24962208:GAGTG:G	donor_loss	1.0000
15:24962209:AG:A	donor_loss	1.0000
15:24962210:G:C	donor_loss	1.0000
15:24962210:G:GG	donor_gain	1.0000
15:24962210:G:T	donor_loss	1.0000
15:24962211:T:G	donor_loss	1.0000
15:24962211:TGA:T	donor_loss	1.0000
15:24962212:GAG:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000069242 (4:2510627 C>A,T), RS1000103975 (4:2496483 T>C), RS1000158727 (4:2502025 T>C), RS1000185629 (4:2495511 T>G), RS1000330839 (4:2500396 T>A), RS1000395310 (4:2506719 C>T), RS1000397143 (4:2476009 A>G), RS10004477 (4:2475554 G>A,C), RS1000456828 (4:2512787 C>G), RS1000476013 (4:2496722 G>A), RS1000505100 (4:2490891 A>G), RS1000537385 (4:2491103 T>G), RS1000565286 (4:2500364 C>T), RS1000663205 (4:2501486 T>C,G), RS1000750624 (4:2505583 C>T)

Disease associations

OMIM: gene MIM:602850 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005150_16	Colorectal cancer	2.000000e-07
GCST005151_6	Colorectal adenoma (advanced)	2.000000e-06
GCST005174_8	Coronary artery calcified atherosclerotic plaque score in type 2 diabetes	2.000000e-06
GCST005759_7	Dimensional psychopathology (Social)	4.000000e-07
GCST007277_6	Tourette syndrome	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0009100	social domain measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291604 (SINGLE PROTEIN)

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

ChEMBL bioactivities

7 potent at pChembl≥5 of 7 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.27	IC50	540	nM	CHEMBL5274757
5.75	IC50	1800	nM	CHEMBL5274740
5.00	IC50	1e+04	nM	CHEMBL2164311

PubChem BioAssay actives

7 with measured affinity, of 7 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
N-[4-[4-[4-[benzyl-(2-chloroacetyl)amino]phenoxy]phenoxy]butyl]-2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetamide	1921389: Binding affinity to RNF4 (unknown origin)	ic50	0.5400	uM
N-benzyl-2-chloro-N-[4-(4-methoxyphenoxy)phenyl]acetamide	1921389: Binding affinity to RNF4 (unknown origin)	ic50	1.8000	uM
2-chloro-N-(4-phenoxyphenyl)acetamide	1987099: Inhibition of human recombinant RNF4 incubated for 30 mins by SDS-PAGE based densitometry	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases ubiquitination, affects localization, affects binding, increases degradation, increases reaction (+3 more)	4
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Air Pollutants	increases expression, decreases expression, affects cotreatment, increases abundance	2
Arsenic	affects binding, affects reaction, decreases reaction, increases degradation, increases reaction	2
Cycloheximide	affects localization, decreases reaction, decreases expression	2
Ozone	affects cotreatment, increases expression, increases abundance	2
Tobacco Smoke Pollution	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
CB-5083	decreases reaction, increases degradation, increases reaction	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation, affects localization, decreases reaction	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
beta-methylcholine	affects expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
fenpyroximate	increases expression	1
abrine	decreases expression	1
mono(carboxy-isooctyl)phthalate	affects expression	1
Resveratrol	decreases expression	1
Atrazine	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Cadmium	increases expression	1
Caffeine	increases phosphorylation	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5224354	Binding	Binding affinity to RNF4 (unknown origin)	Homobivalent, Trivalent, and Covalent PROTACs: Emerging Strategies for Protein Degradation. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2DZ	Abcam HeLa RNF4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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