RBX1

Summary

RBX1 (ring-box 1, HGNC:9928) is a protein-coding gene on chromosome 22q13.2, encoding E3 ubiquitin-protein ligase RBX1 (P62877). E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase (CRLs) complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transc…. It is a common-essential gene (DepMap: required in 96.9% of cancer cell lines).

This locus encodes a RING finger-like domain-containing protein. The encoded protein interacts with cullin proteins and likely plays a role in ubiquitination processes necessary for cell cycle progression. This protein may also affect protein turnover. Related pseudogenes exist on chromosomes 2 and 5.

Source: NCBI Gene 9978 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 5 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 96.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_014248

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9928
Approved symbol	RBX1
Name	ring-box 1
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	ROC1, RNF75, BA554C12.1
Ensembl gene	ENSG00000100387
Ensembl biotype	protein_coding
OMIM	603814
Entrez	9978

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 retained_intron

ENST00000216225, ENST00000467617, ENST00000476110, ENST00000872142, ENST00000872143, ENST00000872144, ENST00000920024, ENST00000920025

RefSeq mRNA: 1 — MANE Select: NM_014248 NM_014248

CCDS: CCDS14009

Canonical transcript exons

ENST00000216225 — 5 exons

Exon	Start	End
ENSE00000880432	40951378	40951476
ENSE00001814441	40972476	40973309
ENSE00003500731	40967799	40967884
ENSE00003510377	40953555	40953633
ENSE00003579127	40964047	40964117

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 95.2132 / max 1001.9987, expressed in 1823 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192437	94.7595	1823
192438	0.2416	74
192436	0.2121	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
periodontal ligament	UBERON:0008266	98.61	gold quality
trabecular bone tissue	UBERON:0002483	98.10	gold quality
tongue squamous epithelium	UBERON:0006919	97.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.62	gold quality
heart right ventricle	UBERON:0002080	97.55	gold quality
monocyte	CL:0000576	97.54	gold quality
palpebral conjunctiva	UBERON:0001812	97.48	gold quality
mononuclear cell	CL:0000842	97.45	gold quality
type B pancreatic cell	CL:0000169	97.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.39	gold quality
olfactory bulb	UBERON:0002264	97.30	gold quality
leukocyte	CL:0000738	97.23	gold quality
oral cavity	UBERON:0000167	97.09	gold quality
eye	UBERON:0000970	97.08	gold quality
upper leg skin	UBERON:0004262	97.01	gold quality
spinal cord	UBERON:0002240	97.00	gold quality
biceps brachii	UBERON:0001507	96.98	gold quality
triceps brachii	UBERON:0001509	96.97	gold quality
vastus lateralis	UBERON:0001379	96.93	gold quality
diaphragm	UBERON:0001103	96.86	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.86	gold quality
quadriceps femoris	UBERON:0001377	96.79	gold quality
gingiva	UBERON:0001828	96.74	gold quality
adult organism	UBERON:0007023	96.63	gold quality
corpus epididymis	UBERON:0004359	96.57	gold quality
skin of hip	UBERON:0001554	96.55	gold quality
hair follicle	UBERON:0002073	96.48	gold quality
gingival epithelium	UBERON:0001949	96.46	gold quality
placenta	UBERON:0001987	96.46	gold quality
cingulate cortex	UBERON:0003027	96.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	141.92
E-CURD-88	yes	9.47
E-HCAD-9	yes	5.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFE2L2

miRNA regulators (miRDB)

33 targeting RBX1, 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-3646	100.00	73.56	5283
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-100-3P	99.20	67.33	672
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573
HSA-MIR-378C	98.43	66.10	548
HSA-MIR-378D	98.43	66.10	548
HSA-MIR-378E	98.43	65.99	551
HSA-MIR-378F	98.43	65.66	554
HSA-MIR-378H	98.43	66.16	545
HSA-MIR-378I	98.43	66.10	548
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-5000-5P	97.40	66.11	1055
HSA-MIR-6509-5P	97.39	68.27	969

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• crystal structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF complex (PMID:11961546)
• findings report that HIV-1 Vif interacts with cellular proteins Cul5, elongins B and C, and Rbx1 to form an Skp1-cullin-F-box (SCF)-like complex (PMID:14564014)
• DET1 promotes ubiquitination and degradation of c-Jun by assembling a multisubunit ubiquitin ligase containing DNA Damage Binding Protein-1 (DDB1), cullin 4A (CUL4A), Regulator of Cullins-1 (ROC1), and constitutively photomorphogenic-1 (PMID:14739464)
• Keap1 negatively regulates Nrf2 function in part by targeting Nrf2 for ubiquitination by the CUL3-ROC1 ligase and subsequent degradation by the proteasome (PMID:15601839)
• the SCF complex (Skp1/Cul1/F-box protein/Roc1) intervenes in the surveillance of Cdh1 cellular abundance in S-phase (PMID:16123585)
• This study uncovers CUL4-DDB-ROC1 as a histone ubiquitin ligase and demonstrate that histone H3 and H4 ubiquitylation participates in the cellular response to DNA damage. (PMID:16678110)
• ROC1 protein binds to the proinactive form of pro-caspase 3 and shortens the half life of the enzyme. (PMID:17217622)
• VprBP depletion abolished the in vivo interaction of Merlin and Roc1-Cullin4A-DDB1, which resulted in Merlin stabilization and inhibited ERK and Rac activation (PMID:18332868)
• Results indicate that FBW5-DDB1-CUL4-ROC1 is an E3 ubiquitin ligase regulating TSC2 protein stability and TSC complex turnover. (PMID:18381890)
• CUL1 ECTD (extreme C-terminal domain; spanning the C-terminal 50 amino acids), did not contribute to CUL1’s stable association with ROC1. (PMID:18723677)
• SCCRO recruits Ubc12 approximately NEDD8 to the CAND1-Cul1-ROC1 complex but that this is not sufficient to dissociate or overcome the inhibitory effects of CAND1 on cullin neddylation (PMID:18826954)
• ROC1 silencing triggers multiple death and growth arrest pathways to effectively suppress tumor cell growth, suggesting that ROC1 may serve as a potential anticancer target (PMID:19509229)
• Data show that REDD1 is subject to ubiquitin-mediated degradation mediated by the CUL4A-DDB1-ROC1-beta-TRCP E3 ligase complex and through the activity of glycogen synthase kinase 3beta. (PMID:19557001)
• The data suggest that RBX1 could potentially be developed into biomarkers of resistance to acyl sulfonamide-based cancer drugs. This will require clinical validation in a series of patients treated with R3200. (PMID:19723642)
• KLHL20-Cul3-ROC1 is an E3 ligase for DAPK ubiquitination (PMID:20389280)
• Nrf2 regulates Cul3-Rbx1 by controlling regulation of expression and induction of Cul3-Rbx1 (PMID:20452971)
• in human cancer cells, RBX1 silencing causes the accumulation of DNA replication licensing proteins CDT1 and ORC1, leading to DNA double-strand breaks, DDR, G(2) arrest, and, eventually, aneuploidy (PMID:21115485)
• Data show that CRN7 interacted with Cullin1 and Roc1 to form a novel SCF-like E3 complex. (PMID:21130766)
• ROC1 expression is negatively correlated with cyclin D1 expression, demonstrating its importance in the degradation of cyclin D1 in melanomas. (PMID:21300445)
• A new conformation of RBX1 involved in the e2-to-substrate ubiquitin-like protein transfer is discussed. (PMID:21765416)
• Glomulin binds Rbx1 and regulates cullin-1 RING ligase-mediated turnover of Fbw7. (PMID:22405651)
• Numb regulates glioma stem cell fate and growth by altering epidermal growth factor receptor and Skp1-Cullin-F-box ubiquitin ligase activity (PMID:22553175)
• Structural and biochemical analyses reveal that GLMN adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of RBX1, inhibiting CRL-mediated chain formation by the E2 CDC34. (PMID:22748924)
• a model by which N-terminal cleavage of RBX1 impairs its activity and promotes susceptibility to ER stress induction. (PMID:22822056)
• ROC1 knockdown significantly inhibited the growth of liver cancer cells by sequentially and independently inducing autophagy and p21-dependent cell senescence. (PMID:22935614)
• A genome-wide association study on a southern European population identified a new Crohn’s disease susceptibility locus at RBX1-EP300. (PMID:22936669)
• Overexpression of RBX1 protein contributes to tumor progression and poor prognosis of non-muscle-invasive bladder cancer (NMIBC). (PMID:23609182)
• RBX1 expression level was associated with the proliferation of gastric cancer. (PMID:24292229)
• RBX1 E3 ubiquitin protein expression responsible with multiple genetic mechanism in the development of head and neck cancer. (PMID:24596130)
• data suggest a new paradigm for Hsp90-modulated assembly of a Cul3/DBC2 E3 ubiquitin ligase complex that may extend to other E3 ligase complexes. (PMID:24608665)
• CUL4A-DDB1-Rbx1 E3 ligase controls the quality of the PTS2 receptor Pex7p. (PMID:24989250)
• Studied the DNA-level mechanisms affecting KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex as a regulator of NRF2 levels in ovarian cancer. (PMID:25114896)
• upregulation of miR-194 can inhibit proliferation, migration, and invasion of GC cells, possibly by targeting RBX1. Aberrant expression of miR-194 and RBX1 is correlated to GC patient survival time. (PMID:25412959)
• eEF1A1 may mediate SAMHD1 turnover by targeting it to the proteosome for degradation through association with Cullin4A and Rbx1. (PMID:25423367)
• These findings indicate that Rbx1 and Rbx2 can both activate Cul5-Vif E3 ligase in vitro, but they may undergo a more delicate selection mechanism in vivo. (PMID:25912140)
• This work sheds new light on the roles of NEDD8 lysines on neddylation cascades and provides a dominant negative mutant for the study of neddylation and its biological functions. (PMID:25918018)
• Data show that melanoma antigen, family C, 2 protein (MAGE-C2) binds with RING-box protein 1 (Rbx1) and Cullin 1, and regulates cyclin E stability in melanoma cells. (PMID:26540345)
• Nedd8(Q40E) cannot induce the same structural effect on Cul1-Rbx1 as wild-type Nedd8. (PMID:26632597)
• ROC1 has an important role in the malignant progression of bladder transitional cell carcinoma via the mTOR/DEPTOR pathway. (PMID:26742010)
• High RBX1 expression was related to poor tumor differentiation, advanced TNM stage, and lymph node metastasis in non-small cell lung cancer. (PMID:27566015)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rbx1	ENSDARG00000038030
mus_musculus	Rbx1	ENSMUSG00000022400
rattus_norvegicus	Rbx1	ENSRNOG00000058914
rattus_norvegicus		ENSRNOG00000066935
drosophila_melanogaster	Roc1a	FBGN0025638
caenorhabditis_elegans		WBGENE00004320

Paralogs (2): RNF7 (ENSG00000114125), ANAPC11 (ENSG00000141552)

Protein

Protein identifiers

E3 ubiquitin-protein ligase RBX1 — P62877 (reviewed: P62877)

Alternative names: E3 ubiquitin-protein transferase RBX1, Protein ZYP, RING finger protein 75, RING-box protein 1, Regulator of cullins 1

All UniProt accessions (1): P62877

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase (CRLs) complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transcription and transcription-coupled nucleotide excision repair. CRLs complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins, ARIH1 mediating addition of the first ubiquitin on CRLs targets. The functional specificity of the E3 ubiquitin-protein ligase complexes depends on the variable substrate recognition components. As a component of the CSA complex mediates ubiquitination of Pol II subunit POLR2A at ‘Lys-1268’, a critical TC-NER checkpoint. Core component of the Cul7-RING(FBXW8) ubiquitin ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Core component of a Cul9-RING ubiquitin ligase complex composed of CUL9 and RBX1, which mediates mono-ubiquitination of p53/TP53. Recruits the E2 ubiquitin-conjugating enzyme CDC34 to the complex and brings it into close proximity to the substrate. Probably also stimulates CDC34 autoubiquitination. May be required for histone H3 and histone H4 ubiquitination in response to ultraviolet and for subsequent DNA repair. Promotes the neddylation of CUL1, CUL2, CUL4 and CUL4 via its interaction with UBE2M. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and CUL3, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM. As part of a multisubunit complex composed of elongin BC complex (ELOB and ELOC), elongin A/ELOA, RBX1 and CUL5; polyubiquitinates monoubiquitinated POLR2A.

Subunit / interactions. Component of multiple Cul1-RING E3 ubiquitin-protein ligase complexes commonly known as SCF (SKP1-CUL1-F-box) complexes, consisting of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein. Part of a SCF(SKP2) complex consisting of CUL1, RBX1, SKP1 and SKP2. Part of a SCF(FBXO3) complex consisting of CUL1, FBXO3, RBX1 and SKP1; this complex interacts with PML via FBXO3. Component of the SCF(Cyclin F) complex consisting of CUL1, RBX1, SKP1 and CCNF. Identified in a SCF E3 ubiquitin ligase complex together with HINT1 and CDC34. Component of multiple Cul2-RING (CRL2) E3 ubiquitin-protein ligase complexes consisting of CUL2, Elongin BC (ELOB and ELOC), RBX1 and a variable substrate-specific adapter; this complex is also known as ECS (Elongin BC-CUL2/5-SOCS-box protein) complex and may consists of CUL2 or CUL5. Component of the CRL2(LRR1) complex with the substrate recognition component LRR1. Part of the ECS(VHL) or CBC(VHL) complex composed of CUL2 or CUL5, RBX1, ELOB, ELOC and VHL. Part of the CRL2 complex with elongin BC complex (ELOB and ELOC), CUL2 and MED8; and part of the CRL5 complex with elongin BC complex (ELOB and ELOC), CUL5 and MUF1. Component of multiple BCR (BTB-CUL3-RBX1) or Cul3-RING E3 ubiquitin-protein ligase complexes formed of CUL3, RBX1 and a variable BTB domain-containing protein. Part of the BCR(ENC1) complex containing ENC1. Part of the BCR(GAN) complex containing GAN. Part of the BCR(KLHL41) complex containing KLHL41. Part of the BCR(KEAP1) complex containing KEAP1. Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1. Component of the BCR(KBTBD4) E3 ubiquitin ligase complex, at least composed of CUL3, KBTBD4 and RBX1. Component of a BCR(KBTBD6/7) complex, composed of CUL3, RBX1, KBTBD6 and KBTBD7. Component of the BCR(ARMC5) E3 ubiquitin ligase complex, composed of CUL3, ARMC5 and RBX1. Component of Cul4-RING E3 ubiquitin-protein ligase complex, known as the CSA complex or DCX(ERCC8) complex, containing CUL4A, ERCC8, RBX1 and DDB1; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II. Component of the DCX DET1-COP1 ubiquitin ligase complex at least composed of CUL4A, RBX1, DET1, DDB1, and COP1. Part of an E3 ligase complex composed of CUL4A or CUL4B, RBX1, DDB1 and DDB2. Component of a Cul5-RING (CRL5) ubiquitin ligase complex consisting of CUL5, ELOB, ELOC, elongin A/ELOA, and RBX1. Part of CRL5 ubiquitin ligase complex with CUL5, ELOB, ELOC, SOCS1 or WSB1. Component of the Cul7-RING(FBXW8) complex consisting of CUL7, RBX1, SKP1 and FBXW8; within the complex interacts with CUL7. Component of the Cul9-RING complex consisting of CUL9 and RBX1; the CUL9-RBX1 complex is a heterododecamer composed of six CUL9 and six RBX1 protomers. Interacts directly with CUL1, CUL2, CUL7 and CUL9; probably also with CUL3, CUL4A, CUL4B and CUL5. Interacts with CDC34. Interacts with GLMN; GLMN competes for the binding site of the E2 ubiquitin-conjugating enzyme CDC34 and disrupts CDC34 binding. Interacts with COPS6. Interacts with UBE2M. Interacts with SESN1 and SESN2. Interacts with NOTCH2. Interacts with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5. Interacts with CAND1. (Microbial infection) Interacts with human adenovirus 5 protein E1A; this interaction inhibits RBX1-CUL1-dependent elongation reaction of ubiquitin chains by the SCF(FBW7) complex.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed.

Domain organisation. The RING-type zinc finger domain is essential for ubiquitin ligase activity. It coordinates an additional third zinc ion.

Pathway. Protein modification; protein ubiquitination. Protein modification; protein neddylation.

Similarity. Belongs to the RING-box family.

RefSeq proteins (1): NP_055063* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR024766	Znf_RING_H2	Domain
IPR051031	RING-box_E3_Ubiquitin_Ligase	Family

Pfam: PF12678

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)
• EC 2.3.2.32 — cullin-RING-type E3 NEDD8 transferase (BRENDA: 6 organisms, 26 substrates, 31 inhibitors, 0 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (39 total): binding site 12, strand 11, mutagenesis site 5, modified residue 3, helix 3, chain 2, initiator methionine 1, sequence conflict 1, zinc finger region 1

Structure

Experimental structures (PDB)

102 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3DPL	X-RAY DIFFRACTION	2.6
7Z8R	ELECTRON MICROSCOPY	2.7
7Z8V	ELECTRON MICROSCOPY	2.7
7PLO	ELECTRON MICROSCOPY	2.8
7Z8B	ELECTRON MICROSCOPY	2.8
8OR3	ELECTRON MICROSCOPY	2.9
9QO4	ELECTRON MICROSCOPY	2.95
9EFQ	ELECTRON MICROSCOPY	2.96
1LDJ	X-RAY DIFFRACTION	3
3DQV	X-RAY DIFFRACTION	3
4F52	X-RAY DIFFRACTION	3
7Z8T	ELECTRON MICROSCOPY	3
9EFV	ELECTRON MICROSCOPY	3.03
1LDK	X-RAY DIFFRACTION	3.1
1U6G	X-RAY DIFFRACTION	3.1
2HYE	X-RAY DIFFRACTION	3.1
7ZBZ	ELECTRON MICROSCOPY	3.1
8OR0	ELECTRON MICROSCOPY	3.1
4P5O	X-RAY DIFFRACTION	3.11
9LWI	ELECTRON MICROSCOPY	3.12
9XZJ	ELECTRON MICROSCOPY	3.13
9EFM	ELECTRON MICROSCOPY	3.16
8OR2	ELECTRON MICROSCOPY	3.2
3RTR	X-RAY DIFFRACTION	3.21
9QO1	ELECTRON MICROSCOPY	3.23
8JAQ	ELECTRON MICROSCOPY	3.26
9QO0	ELECTRON MICROSCOPY	3.26
8WQF	ELECTRON MICROSCOPY	3.27
8CDK	ELECTRON MICROSCOPY	3.32
8RHZ	ELECTRON MICROSCOPY	3.37

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62877-F1	80.55	0.26

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): 77; 80; 82; 83; 94; 97; 42; 45; 53; 56; 68; 75

Post-translational modifications (3): 1, 2, 9

Mutagenesis-validated functional residues (5):

Position	Phenotype
53	strong reduction in ligase activity; when associated with a-56.
56	strong reduction in ligase activity; when associated with a-53.
75	strong reduction in ligase activity; when associated with a-77.
77	strong reduction in ligase activity; when associated with a-75.
91	impairs ube2r2 activation by neddylated cul2-ring(fem1c) complex.

Function

Pathways and Gene Ontology

Reactome pathways

41 pathways

ID	Pathway
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-1170546	Prolactin receptor signaling
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-180585	Vif-mediated degradation of APOBEC3G
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-2122947	NOTCH1 Intracellular Domain Regulates Transcription
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2644607	Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-4641258	Degradation of DVL
R-HSA-5610780	Degradation of GLI1 by the proteasome
R-HSA-5610783	Degradation of GLI2 by the proteasome
R-HSA-5610785	GLI3 is processed to GLI3R by the proteasome
R-HSA-5632684	Hedgehog ‘on’ state
R-HSA-5658442	Regulation of RAS by GAPs
R-HSA-5696394	DNA Damage Recognition in GG-NER
R-HSA-5696395	Formation of Incision Complex in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-6781823	Formation of TC-NER Pre-Incision Complex
R-HSA-6781827	Transcription-Coupled Nucleotide Excision Repair (TC-NER)
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-68949	Orc1 removal from chromatin
R-HSA-69601	Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A
R-HSA-8854050	FBXL7 down-regulates AURKA during mitotic entry and in early mitosis
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-8951664	Neddylation
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9020702	Interleukin-1 signaling
R-HSA-9604323	Negative regulation of NOTCH4 signaling

MSigDB gene sets: 0 (showing top):

GO Biological Process (69): MAPK cascade (GO:0000165), protein polyubiquitination (GO:0000209), transcription-coupled nucleotide-excision repair (GO:0006283), ubiquitin-dependent protein catabolic process (GO:0006511), protein monoubiquitination (GO:0006513), DNA damage response (GO:0006974), spermatogenesis (GO:0007283), protein ubiquitination (GO:0016567), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), negative regulation of type I interferon production (GO:0032480), cellular response to oxidative stress (GO:0034599), cellular response to UV (GO:0034644), T cell activation (GO:0042110), signal transduction in response to DNA damage (GO:0042770), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), post-translational protein modification (GO:0043687), protein K27-linked ubiquitination (GO:0044314), protein neddylation (GO:0045116), positive regulation of protein catabolic process (GO:0045732), negative regulation of insulin receptor signaling pathway (GO:0046627), cellular response to chemical stress (GO:0062197), protein K48-linked ubiquitination (GO:0070936), cellular response to amino acid stimulus (GO:0071230), negative regulation of canonical Wnt signaling pathway (GO:0090090), ubiquitin-dependent protein catabolic process via the C-end degron rule pathway (GO:0140627), RNA polymerase II transcription initiation surveillance (GO:0160240), negative regulation of beige fat cell differentiation (GO:0160276), regulation of cellular response to insulin stimulus (GO:1900076), negative regulation of mitophagy (GO:1901525), positive regulation of protein autoubiquitination (GO:1902499), negative regulation of response to oxidative stress (GO:1902883), positive regulation of TORC1 signaling (GO:1904263), autophagosome assembly (GO:0000045), G1/S transition of mitotic cell cycle (GO:0000082), mitophagy (GO:0000423), epithelial to mesenchymal transition (GO:0001837), DNA repair (GO:0006281)

GO Molecular Function (14): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), NEDD8 transferase activity (GO:0019788), ubiquitin protein ligase binding (GO:0031625), ubiquitin-ubiquitin ligase activity (GO:0034450), protein-containing complex binding (GO:0044877), molecular adaptor activity (GO:0060090), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), ubiquitin protein ligase activity (GO:0061630), NEDD8 ligase activity (GO:0061663), cullin family protein binding (GO:0097602), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (16): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), SCF ubiquitin ligase complex (GO:0019005), VCB complex (GO:0030891), cullin-RING ubiquitin ligase complex (GO:0031461), Cul2-RING ubiquitin ligase complex (GO:0031462), Cul3-RING ubiquitin ligase complex (GO:0031463), Cul4A-RING E3 ubiquitin ligase complex (GO:0031464), Cul4B-RING E3 ubiquitin ligase complex (GO:0031465), Cul5-RING ubiquitin ligase complex (GO:0031466), Cul7-RING ubiquitin ligase complex (GO:0031467), Cul4-RING E3 ubiquitin ligase complex (GO:0080008), site of DNA damage (GO:0090734)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Hedgehog ‘off’ state	3
Global Genome Nucleotide Excision Repair (GG-NER)	3
DNA Damage Bypass	1
Cytokine Signaling in Immune system	1
Cellular response to hypoxia	1
Host Interactions of HIV factors	1
Signaling by WNT	1
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
FBXW7 Mutants and NOTCH1 in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
TCF dependent signaling in response to WNT	1
Signaling by Hedgehog	1
RAF/MAP kinase cascade	1
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cullin-RING ubiquitin ligase complex	6
cellular anatomical structure	4
protein ubiquitination	3
binding	3
proteasome-mediated ubiquitin-dependent protein catabolic process	2
canonical NF-kappaB signal transduction	2
regulation of canonical NF-kappaB signal transduction	2
ubiquitin-like protein transferase activity	2
ubiquitin-like protein ligase activity	2
Cul4-RING E3 ubiquitin ligase complex	2
intracellular signaling cassette	1
nucleotide-excision repair	1
modification-dependent protein catabolic process	1
cellular response to stress	1
developmental process involved in reproduction	1
male gamete generation	1
protein modification by small protein conjugation	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
response to oxidative stress	1
cellular response to chemical stress	1
response to UV	1
cellular response to light stimulus	1
lymphocyte activation	1
DNA damage response	1
intracellular signal transduction	1
positive regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein modification process	1
protein polyubiquitination	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
ubiquitin protein ligase activity	1
molecular_function	1

Protein interactions and networks

STRING

4264 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RBX1	SKP1	P34991	999
RBX1	CUL1	Q13616	999
RBX1	CUL2	Q13617	999
RBX1	CUL3	Q13618	999
RBX1	CUL4A	Q13619	999
RBX1	ELOB	Q15370	999
RBX1	DDB1	Q16531	999
RBX1	CUL5	Q93034	999
RBX1	SKP2	Q13309	998
RBX1	CUL7	Q14999	998
RBX1	ELOC	Q15369	998
RBX1	CRBN	Q96SW2	998
RBX1	CUL4B	Q13620	997
RBX1	BTRC	Q9Y297	997
RBX1	KEAP1	Q14145	996
RBX1	NEDD8	Q15843	996

IntAct

202 interactions, top by confidence:

A	B	Type	Score
CUL1	RBX1	psi-mi:“MI:0915”(physical association)	0.980
CUL1	RBX1	psi-mi:“MI:0407”(direct interaction)	0.980
RBX1	CUL1	psi-mi:“MI:0407”(direct interaction)	0.980
CUL1	RBX1	psi-mi:“MI:0194”(cleavage reaction)	0.980
RBX1	CUL1	psi-mi:“MI:0915”(physical association)	0.980
CUL1	RBX1	psi-mi:“MI:0914”(association)	0.980
CCNA2	CDK2	psi-mi:“MI:0914”(association)	0.980
CUL2	VHL	psi-mi:“MI:0914”(association)	0.940
GPS1	COPS2	psi-mi:“MI:0915”(physical association)	0.860
SKP2	CKS1B	psi-mi:“MI:0914”(association)	0.860
RBX1	CUL2	psi-mi:“MI:0915”(physical association)	0.850
KLHL22	GLUD1	psi-mi:“MI:0914”(association)	0.840
SKP1	CKS1B	psi-mi:“MI:0914”(association)	0.830
CUL4B	RBX1	psi-mi:“MI:0914”(association)	0.820
CUL3	RBX1	psi-mi:“MI:0914”(association)	0.820

BioGRID (1492): RBX1 (Co-fractionation), RBX1 (Reconstituted Complex), RBX1 (Reconstituted Complex), RBX1 (Two-hybrid), UBE2D3 (Reconstituted Complex), UBE2D2 (Reconstituted Complex), UBE2D2 (Reconstituted Complex), UBE2D1 (Reconstituted Complex), CDC34 (Reconstituted Complex), UBE2D1 (Reconstituted Complex), CDC34 (Reconstituted Complex), UBE2D1 (Reconstituted Complex), UBE2L6 (Reconstituted Complex), UBE2D1 (Reconstituted Complex), UBE2D3 (Reconstituted Complex)

ESM2 similar proteins: A0JN27, A6H769, C9WPN6, F1QGW6, O93377, O95164, P02362, P06730, P20461, P29338, P41091, P47814, P62081, P62082, P62877, P62878, P63073, P63074, P63220, P63221, P81795, Q13888, Q24572, Q2KHU8, Q2TA46, Q2TBV5, Q2VIR3, Q2YDH6, Q32PB8, Q54K33, Q5BJT2, Q5HZM6, Q5R797, Q5RIC0, Q5ZHS1, Q5ZMS3, Q6NVL5, Q6P1K8, Q6P315, Q7ZTY4

Diamond homologs: O13959, P62877, P62878, Q08273, Q20052, Q23457, Q3ZCF6, Q54K33, Q54L48, Q5R8A2, Q5UQ40, Q7X843, Q8BGI1, Q8QG64, Q940X7, Q9CPX9, Q9M2B0, Q9M9L0, Q9NHX0, Q9NYG5, Q9UBF6, Q9W5E1, Q9WTZ1, Q9Y225, O74757, P0C041, Q08CG8, Q12157, Q9LF64, O22755, Q8W571, Q9LZJ6, Q9LZV8, Q9SG96, Q9SRQ8, Q9UT86, Q9ZT49, Q6AXU4, Q5XF85, Q67YI6

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
RBX1	up-regulates	NFKB1	ubiquitination
RBX1	up-regulates	NFKB2	ubiquitination
RBX1	“form complex”	“DCX DET1-COP1”	binding
RBX1	“form complex”	Cullin4-RBX1-DDB1	binding
Ub:E2	“up-regulates activity”	RBX1	ubiquitination
RBX1	“down-regulates quantity by destabilization”	ESR1	ubiquitination
RBX1	“form complex”	“BAF250b E3 ligase”	binding
RBX1	“form complex”	VCB-Cul2	binding
RBX1	“form complex”	“Cullin 3-RBX1-Skp1”	binding
RBX1	“form complex”	“Cullin 7-RBX1-Skp1”	binding
RBX1	“form complex”	“Cullin 1-RBX1-Skp1”	binding
RBX1	“form complex”	CUL3-RBX1-KEAP1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 126 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
DNA Damage Recognition in GG-NER	9	30.6×	2e-09
Formation of TC-NER Pre-Incision Complex	8	20.1×	6e-07
Neddylation	34	19.2×	7e-33
Transcriptional Regulation by E2F6	5	17.4×	5e-04
SCF(Skp2)-mediated degradation of p27/p21	7	17.3×	1e-05
Cyclin E associated events during G1/S transition	5	17.0×	5e-04
Cyclin D associated events in G1	6	16.6×	1e-04
Cyclin A:Cdk2-associated events at S phase entry	5	15.8×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
regulation of protein neddylation	5	44.6×	7e-06
protein neddylation	6	40.1×	8e-07
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	9	32.1×	2e-09
G1/S transition of mitotic cell cycle	12	22.9×	5e-11
intrinsic apoptotic signaling pathway	6	20.5×	4e-05
protein monoubiquitination	5	16.4×	9e-04
protein K48-linked ubiquitination	10	16.1×	1e-07
cellular response to UV	5	14.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

963 predictions. Top by Δscore:

Variant	Effect	Δscore
22:40951465:G:GT	donor_gain	1.0000
22:40951478:T:G	donor_gain	1.0000
22:40951505:G:GT	donor_gain	1.0000
22:40951505:G:T	donor_gain	1.0000
22:40951579:G:GT	donor_gain	1.0000
22:40953553:A:AG	acceptor_gain	1.0000
22:40953554:G:GG	acceptor_gain	1.0000
22:40953634:G:GG	donor_gain	1.0000
22:40964113:GTAAC:G	donor_gain	1.0000
22:40964118:G:GG	donor_gain	1.0000
22:40964123:G:GT	donor_gain	1.0000
22:40967885:G:GG	donor_gain	1.0000
22:40951452:C:T	donor_gain	0.9900
22:40951455:G:GT	donor_gain	0.9900
22:40951468:G:GG	donor_gain	0.9900
22:40951472:AAAAG:A	donor_loss	0.9900
22:40951475:AGGT:A	donor_loss	0.9900
22:40951476:GGT:G	donor_gain	0.9900
22:40951477:GTTG:G	donor_loss	0.9900
22:40951543:G:GT	donor_gain	0.9900
22:40951557:G:GT	donor_gain	0.9900
22:40951608:G:GT	donor_gain	0.9900
22:40953553:AGT:A	acceptor_gain	0.9900
22:40953554:GT:G	acceptor_gain	0.9900
22:40953554:GTG:G	acceptor_gain	0.9900
22:40953554:GTGGA:G	acceptor_gain	0.9900
22:40953629:TCTTT:T	donor_gain	0.9900
22:40953630:CTTT:C	donor_gain	0.9900
22:40953631:TTT:T	donor_gain	0.9900
22:40953632:TT:T	donor_gain	0.9900

AlphaMissense

727 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:40953555:T:A	W27R	1.000
22:40953555:T:C	W27R	1.000
22:40953568:C:A	A31D	1.000
22:40953573:T:A	W33R	1.000
22:40953573:T:C	W33R	1.000
22:40953575:G:C	W33C	1.000
22:40953575:G:T	W33C	1.000
22:40953576:G:C	A34P	1.000
22:40953579:T:A	W35R	1.000
22:40953579:T:C	W35R	1.000
22:40953580:G:C	W35S	1.000
22:40953581:G:C	W35C	1.000
22:40953581:G:T	W35C	1.000
22:40953600:T:A	C42S	1.000
22:40953600:T:C	C42R	1.000
22:40953601:G:A	C42Y	1.000
22:40953601:G:C	C42S	1.000
22:40953601:G:T	C42F	1.000
22:40953602:T:G	C42W	1.000
22:40953604:C:A	A43D	1.000
22:40953606:A:T	I44F	1.000
22:40953607:T:A	I44N	1.000
22:40953607:T:C	I44T	1.000
22:40953607:T:G	I44S	1.000
22:40953609:T:A	C45S	1.000
22:40953609:T:C	C45R	1.000
22:40953610:G:A	C45Y	1.000
22:40953610:G:C	C45S	1.000
22:40953610:G:T	C45F	1.000
22:40953611:C:G	C45W	1.000

dbSNP variants (sampled 300 via entrez): RS1000069516 (22:40952988 T>A), RS1000098908 (22:40952676 A>G), RS1000126795 (22:40953756 C>T), RS1000151937 (22:40968392 G>A,C), RS1000233610 (22:40959278 G>A), RS1000322240 (22:40972180 C>G), RS1000346930 (22:40965160 G>A), RS1000627504 (22:40970350 CAAAAA>C,CA,CAA,CAAA,CAAAA,CAAAAAA,CAAAAAAA,CAAAAAAAA), RS1000660067 (22:40970748 C>A,T), RS1000753912 (22:40969946 A>G), RS1000821220 (22:40971770 T>C), RS1000961134 (22:40969548 G>A), RS1001258511 (22:40959805 C>G), RS1001280378 (22:40953085 G>T), RS1001567209 (22:40965624 A>G)

Disease associations

OMIM: gene MIM:603814 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001652_3	Crohn’s disease	3.000000e-08
GCST002550_26	Allergic rhinitis	4.000000e-07
GCST004521_42	Autism spectrum disorder or schizophrenia	1.000000e-08
GCST004521_55	Autism spectrum disorder or schizophrenia	9.000000e-09
GCST005232_52	Neuroticism	3.000000e-18
GCST008103_42	Bipolar disorder	2.000000e-07
GCST008115_35	Bipolar I disorder	3.000000e-07
GCST008258_7	Alcohol use disorder (consumption score)	1.000000e-08
GCST010002_83	Refractive error	2.000000e-27
GCST010245_45	LDL cholesterol levels	1.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0009963	bipolar I disorder
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0009458	alcohol use disorder measurement
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3833061 (PROTEIN COMPLEX), CHEMBL6067545 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs141084494	Toxicity	3	cyclophosphamide;epirubicin;fluorouracil	Breast Neoplasms;Neutropenia

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs141084494	RBX1	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil

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
5.53	Kd	2975	nM	CHEMBL3752910
5.53	ED50	2975	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149923: Binding affinity to human RBX1 incubated for 45 mins by Kinobead based pull down assay	kd	2.9752	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	4
bisphenol A	increases expression, affects expression, decreases expression	3
Valproic Acid	decreases expression	3
Air Pollutants	affects expression, increases abundance, decreases expression	2
dicrotophos	decreases expression	1
arsenite	affects binding, increases reaction	1
solanesol	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
pinosylvin	decreases expression	1
dinophysistoxin 1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CD 437	decreases expression	1
chloropicrin	increases expression	1
deguelin	decreases expression	1
7,3’-dihydroxy-4’-methoxyisoflavone	increases expression	1
CPG-oligonucleotide	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
pyrimidifen	decreases expression	1
thifluzamide	decreases expression	1
Zoledronic Acid	decreases expression	1
Antimycin A	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Chelating Agents	decreases expression, affects binding	1
Cisplatin	affects cotreatment, increases expression	1
Copper	affects binding, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652965	Binding	Binding affinity to human RBX1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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